1

Pharmacokinetics of Psychotropic Drugs

Terence A Ketter MDStanford University School of Medicine

2

Teaching Pointsbull Key pharmacokinetic parameters include volume of

distribution half life and clearance

bull Most drugs undergo hepatic metabolism and are thus at risk for drug interactions related to hepatic metabolism but a few drugs (such as lithium) have renal excretion and are thus at risk for drug interactions related to renal excretion

bull Characterizing medications as substrates inducers and inhibitors of specific cytochrome p450 metabolic enzymes can help predict and prevent adverse events related to drug interactions

bull The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are CYP2D6 and CYP3A34

3

Pre Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

4

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

5

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

6

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

7

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

8

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

2

Teaching Pointsbull Key pharmacokinetic parameters include volume of

distribution half life and clearance

bull Most drugs undergo hepatic metabolism and are thus at risk for drug interactions related to hepatic metabolism but a few drugs (such as lithium) have renal excretion and are thus at risk for drug interactions related to renal excretion

bull Characterizing medications as substrates inducers and inhibitors of specific cytochrome p450 metabolic enzymes can help predict and prevent adverse events related to drug interactions

bull The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are CYP2D6 and CYP3A34

3

Pre Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

4

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

5

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

6

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

7

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

8

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

3

Pre Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

4

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

5

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

6

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

7

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

8

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

4

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

5

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

6

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

7

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

8

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

5

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

6

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

7

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

8

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

6

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

7

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

8

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

7

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

8

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

8

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

9

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

10

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

11

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

12

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

13

Outline

bull CONCEPTSPharmacokinetics Pharmacodynamics

bull CYTOCHROME P450 Isoforms Substrates Inhibitors Inducers

bull MOOD STABILIZERS Li CBZ VPA

bull ANTIDEPRESSANTSSSRIs SNRIs bupropion TCAs MAOIs

bull OTHER AGENTS Anxiolytics Antipsychotics Anticonvulsants Ca blockers

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

14

PHARMACOKINETICS

bullTime course of drug absorption distribution metabolism amp excretion

bullDrug transport to amp from receptors

bullWhat the body does to the drug

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

15

PHARMACODYNAMICS

bull Relationships between drug concentrations amp responses

bull Drug activity at receptors

bull What the drug does to the body

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

16

CONCEPT DEFINITION

V (vol of distrib) Volume needed to contain drug at concentration same as plasma

t12 Time for [drug] to darr 50(half life)

Cl Volume of blood cleared(clearance) of drug per unit time

PHARMACOKINETIC CONCEPTS

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

17

CONCEPT RELEVANCE

V (vol of distrib) Extracirculatory distribution(binding lipophilicity)

Loading dose(Load with V x[desired conc change])

t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)

Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)

PHARMACOKINETIC CONCEPTS

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

18

CONCEPT EXAMPLE

V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)

VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)

t12 fluoxetine - 5 wk MAOI wait(half life) venlafaxine - 2 wk MAOI wait

Cl uarr [Li] in renal failure(clearance) uarr [diazepam] in liver failure

PHARMACOKINETIC CONCEPTS

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

19

ABSORPTION

bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)

bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)

bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)

bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)

bull Speed affected by formulation(solution gt suspension gt capsule gt tab gt enteric coated tab)

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

20

DISTRIBUTION

bull Lipophilicity amp binding

bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral

bull Binding profiles ndash Alb VPA PHT diazepamndash Alb + α 1AG CBZ verapamilndash Alb + α 1AG + LP CPZ TCAs

bull darr binding in renal d amp hyperthyroidism

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

21

EXCRETION

Rate = filtration + secretion - reabsorption

bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease

bull Secretion (proximal tubule)ndash Drugs compete for active transport

bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

22

METABOLISM

PHASE I - Introduce functional groupsbull Oxidation

- Hydroxylation - alprazolam- Dealkylation - diazepam- Deamination - amphetamine- Sulfoxidation - chlorpromazine

bull Reduction - clonazepam bull Hydrolysis - acetylsalicylate

PHASE II - Form polar derivatives-CONJUGATIONbull Glucuronidation (UGTs)- oxazepambull Sulfation (SULTs) - acetaminophenbull Methylation - norepinephrinebull Acetylation (NATs) - clonazepam phenelzine

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

23

bull Longer t12

bull More water soluble

bull Generally less active but can be more active (hydroxylated demethylated)

bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf

trazodone anxiolytic)

METABOLITES COMPARED TOPARENT DRUGS

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

24

ACTIVE METABOLITES

Carbamazepine carbamazepine-1011-epoxideoxcarbazepinemonohydroxyderivitive (MHD)

valproate 2-ene-valproate 4-ene-valproate (toxic)

amitriptyline nortriptyline hydroxynortiptyline

IMIDMI imipramine desipramine hydroxy-IMI and DMI

amoxapine hydroxyamoxapinefluoxetine norfluoxetinesertraline N-desmethylsetraline (plusmn)

citalopramdidesmethylcitalopram

venlafaxine O-desmethylvenlafaxinebupropion hydroxybupropion

trazodone m-chlorophenylpiperazine (m-CPP)nefazodone m CPP hydroxynefazodone

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

25

ACTIVE METABOLITES

diazepam N-desmethyldiazepamclorazepate N-

desmethyldiazepam chlordiazepoxide N-desmethyldiazepam alprazolam apha-hydroxyalprazolam flurazepam

desalkylflurazepambuspironepyrimidinylpiperazine (1-PP)

chlorpromazine hydroxychlorpromazinethioridazine mesoridazine

haloperidol reduced haloperidolloxapine amoxapineclozapine desmethyclozapine (plusmn)

risperidone 9-hydroxyrisperidone aripiprazole dehydo-

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

26

CONCEPT DEFINITION RELEVANCE

Therapeutic index Efficacy relative to toxicity

Dose-response curve Linear sigmoidal curvilinear relationships

Tolerance darr therapeutic or adverse responses with time

Withdrawal Discontinuation effects

Response latency Delay to onset of effects

PHARMACODYNAMIC CONCEPTS

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

27

CONCEPT EXAMPLE

Therapeutic index High for SSRIs low for Li

Dose-response curve Curvilinear for nortriptyline(therapeutic window)

Tolerance BZ (sedation anticonvulsant) opiates (analgesia)

Withdrawal BZ (insomnia anxiety)

Response latency BZ - minutesLi CBZ VPA - days to wks

PHARMACODYNAMIC CONCEPTS

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

28

DRUG INTERACTIONS

PHARMACOKINETIC- Absorption- Distribution- Metabolism- Excretion

PHARMACODYNAMIC- Direct - at same receptor site

(AMI + CPZ anticholinergic toxicity)- Indirect - at different receptor sites

(MAOI + SSRI serotonin toxicity)

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

29

INTERACTION POTENTIAL

bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition

inductionbull Single metabolic route bull CYP2D6 CYP3A457

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

30

CYP2D6

P450 NOTATION

CYP - CYtochrome P (protein) 450 (wave length CO absorption)

2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

31

KEY ISOFORMS FOR DRUG METABOLISM

ISOFORM

CYP1A2

CYP2C910

CYP2C19

CYP2D6

CYP2E1

CYP3A457

SUBSTRATES

TCAsclozolanz

phenytoinTHCS-warfarin

BZsTCAs

TCAsparoxmirtaz venla plusmnfluox

Etoh

BZsCBZSertraline

NefazodoneTCAs mirtazCa blockers

Oral contraceptives

INHIBITORScipro

fluvoxamine

fluvoxamine

fluoxfluvox

paroxfluox plusmnfluvox

plusmnsertradisulfiram

fluoxetine fluvoxaminenefazodone

diltiazemverapamil

macrolides

INDUCERS

Cig smokeomep

rifambarb

rifampin

-

EtohINH

CBZphenytoin phenobarb

rifampin St Johnrsquos wort

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

32

CYP2D6SUBSTRATESatomoxetineduloxetine plusmn fluoxetineplusmn mirtazapine paroxetinevenlafaxine

2deg amp 3deg tricyclics(hydroxylation)

trazodone

plusmn clozapine haloperidol

fluphenazineperphenazine risperidonethioridazine

codeinemexiletine

IC antiarrhythmicsβ blockers

INHIBITORS

bupropionfluoxetine

plusmn fluvoxamine paroxetineplusmn sertraline

moclobemide

fluphenazine haloperidol

perphenazine thioridazine

amiodaronecimetidinemethadonequinidine

Ritonavir et al

INDUCERS

-

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

33

CYP3A457SUBSTRATES

plusmn citalopramplusmn mirtazapinenefazodonereboxetine sertraline

3deg tricyclics (demethylation)

alprazolam diazepam

midazolamtriazolam

buspironeCBZ

Ca blockersH1 blockers

local anestheticsmacrolides quinidinesteroids

INHIBITORS

fluvoxamine

nefazodone

diltiazemverapamil

cimetidineimidazolesmacrolidesnaringenin

INDUCERS

CBZphenobarbital

phenytoin

dexamethasonerifampin

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

34

INHIBITION PROFILES

POTENCY

highest

intermediate

lowest

CYP2D6

quinidine paroxetine fluoxetinebupropion

sertraline

fluvoxaminenefazodone venlafaxine

erythromycinketoconazole

CYP3A457

ketoconazoleclarithromycin

nefazodone

fluvoxamine

sertraline desmethylsertraline

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

35

INHIBITORS

barbituratescarbamazepine

phenytoinprimidone

cigarette smokechronic ethanol

isoniazidrifampin

glutethimideomeprazole

azole antifungalschloramphenicol

ciprofloxacincotrimoxazole

macrolidesmetronidazole

allopurinolcimetidine

omeprazolephenylbutazone

propranololpropoxyphene

quinidine

TCAs MAOIsbupropionfluoxetine

fluvoxamineparoxetineplusmn sertralinenefazodone

antipsychoticsacute ethanol

disulfirammethylphenidate

diltiazemverapamilvalproate

INDUCERS

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

36

GENETIC POLYMORPHISMS

CYP2D6 (Poor Metabolizers)Auto recessive 5-10 whites Asians 1Substrates 2deg amp 3deg TCAs duloxetine parox

venla plusmn fluox thioridazineIC antiarrhythmics β-blockers

CYP2C19 (Poor Metabolizers)Recessive 3-5 whites 15-20 AsiansSubstrates 3deg TCAs diazepam barbiturates

omeprazole S-mephenytoin

N-acetyltransferase (Slow Acetylators)Auto recessive 50 whites 10 AsiansSubstrates isoniazid clonazepam phenelzine

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

37

SPECIAL POPULATIONS

Group Protein Hepatic Renalbinding elimination elimination

Prebubes (=) (uarr) (uarr)

Elderly (=) (= darr) darr

Pregnant (=darr) (= darr uarr) uarr

Manic (=) (=) (uarr)

Renal d darr darr darr

Liver d (= darr) darr (= darr)

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

38

DRUG

lithiumcarbamazepine

valproate

phenytoinbarbiturateslamotriginegabapentin

SUBSTRATE OF

renal excretion3A4 3A5-7conjugation

β-hydroxylationP450 oxidation

2C910 plusmn 2C192C19

UGT1A4renal excretion

INDUCES INHIBITS

-induces 3A457 weak inhibitor

induces 3A457 induce 3A457

mildly self-

MOOD STABILIZER ANDANTICONVULSANT METABOLISM

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

39

LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

40

LITHIUM CLEARANCE

Decreased by

thiazides

NSAIDs

ACE inhibitors

dehydrationelderlyrenal disease

Increased by

acetazolamide mannitol

aminophyllinecaffeine theophylline

pregnancymania

Not changed by

amiloride furosemide

ASAsulindac

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

41

CARBAMAZEPINE

bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)

t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313

CARBAMAZEPINE METABOLISM

CYP3A34 EPOXIDEHYDROLASE

+

darr CBZ LEVELS WITHCARBAMAZEPINE (++)

FELBAMATE (+)PHENOBARBITAL (++)

PHENYTOIN (++)PRIMIDONE (++)

darr CBZ-E LEVELS WITHcarbamazepine (+)phenobarbital (+)

phenytoin (+)primidone (+)

uarrCBZ LEVELS WITHACETAZOLAMIDE

cimetidineCLARITHROMYCIN

DANAZOLDILTIAZEM

ERYTHROMYCINFLUOXETINE

FLUVOXAMINEgemfibrozilISONIAZID

NEFAZODONEnicotinamide

PROPOXYPHENEVERAPAMIL

uarr CBZ-E LEVELS WITHlamotrigine (-)

progabide (-)VALPROATE (-)

VALPROMIDE (--)

N

2NHO

CBZ

ACTIVEPARENT

DRUG

- -

+

molecular bichemical evidence supports CYP3A34

ACTIVEEPOXIDE

METABOLITE

CBZ-E

N

2NHO

O

INACTIVEDIOL

METABOLITE

CBZ-D

N

2NHO

OHHO

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

43

Antidepressants AnxiolyticsSedatives Anticonvulsants Antimicrobials SteroidsBupropion Alprazolam () Carbamazepine Caspofungin Hormonal contraceptivesCitalopram Buspirone Ethosuximide Doxycycline DexamethasoneMirtazapine () Clonazepam Felbamate MifepristoneTricyclics Midazolam Lamotrigine Antivirals Prednisolone

Zopiclone Oxcarbazepine DelavirdineAntipsychotics Phenytoin Protease inhibitors OthersAripiprazole Stimulants Primidone BepridilClozapine Methylphenidate Tiagabine Immunosuppressants Dihydropyridine CCBsFluphenazine () Modafinil Topiramate Cyclosporine () Oxiracetam ()Haloperidol Valproate Sirolimus PaclitaxelOlanzapine Analgesics Zonisamide Tacrolimus QuinidineQuetiapine () Alfentanil Remacemide ()Risperidone Buprenorphine Anticoagulants Muscle Relaxants RepaglinideThiothixene () Fentanyl () Dicumarol () Doxacurium Theophylline ()

Ziprasidone Levobupivacaine Phenprocoumon PancuroniumThoraloralyroidhormones

Methadone Warfarin RapacuroniumTramadol Rocuronium

Vecuronium

CarbamazepineDecreases Levels of Other Drugs

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

Antidepressants		AnxiolyticsSedatives		Anticonvulsants		Antimicrobials		Steroids
Bupropion		Alprazolam ()		Carbamazepine		Caspofungin		Hormonal contraceptives
Citalopram		Buspirone		Ethosuximide		Doxycycline		Dexamethasone
Mirtazapine ()		Clonazepam		Felbamate				Mifepristone
Tricyclics		Midazolam		Lamotrigine		Antivirals		Prednisolone
		Zopiclone		Oxcarbazepine		Delavirdine
Antipsychotics				Phenytoin		Protease inhibitors		Others
Aripiprazole		Stimulants		Primidone				Bepridil
Clozapine		Methylphenidate		Tiagabine		Immunosuppressants		Dihydropyridine CCBs
Fluphenazine ()		Modafinil		Topiramate		Cyclosporine ()		Oxiracetam ()
Haloperidol				Valproate		Sirolimus		Paclitaxel
Olanzapine		Analgesics		Zonisamide		Tacrolimus		Quinidine
Quetiapine ()		Alfentanil						Remacemide ()
Risperidone		Buprenorphine		Anticoagulants		Muscle Relaxants		Repaglinide
Thiothixene ()		Fentanyl ()		Dicumarol ()		Doxacurium		Theophylline ()
Ziprasidone		Levobupivacaine		Phenprocoumon		Pancuronium		Thoraloralyroid hormones
		Methadone		Warfarin		Rapacuronium
		Tramadol				Rocuronium
						Vecuronium

44

Antidepre ssants Calcium Channel Blockers Fluoxetine Diltiazem Fluvoxamine Verapamil Nefazodone Hypolipidemics Antimicrobials Gemfibrozil Isoniazid Nicotinamide Quinupristindalfopristin Others Macrolide Antibiotics Acetazolamide Clarithromycin Cimetidine Erythromycin Danazol Flurithromycin Omeprazole Josamycin d-Propoxyphene Ponsinomycin Ritonovir () Ticlopidine () VPA (increases CBZ-E)

Selected Drugs that Increase Levels ofCarbamazepine

(A Partial List)

Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

Antidepressants		Calcium Channel Blockers
Fluoxetine		Diltiazem
Fluvoxamine		Verapamil
Nefazodone
		Hypolipidemics
Antimicrobials		Gemfibrozil
Isoniazid		Nicotinamide
Quinupristindalfopristin
		Others
Macrolide Antibiotics		Acetazolamide
Clarithromycin		Cimetidine
Erythromycin		Danazol
Flurithromycin		Omeprazole
Josamycin		d-Propoxyphene
Ponsinomycin		Ritonovir ()
		Ticlopidine ()
		VPA (increases CBZ-E)

45

CYP3A4-MEDIATED CBZ DRUG INTERACTIONS

CBZ rarrdarr DRUG

3deg tricyclics (demethylation)

Ca blockers CBZ

benzodiazepines

dexamethasone oral contraceptives

prednisolone local anesthetics

ethosuximide

DRUG rarruarr CBZ

Fluoxetinefluvoxamine Nefazodone

Ca blockers

danazol

cimetidine

clarithromycin erythromycin

DRUG rarrdarr CBZ

CBZphenobarbitalphenytoin ()

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

46

VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites

50 conjugation glucuronides40 β oxidation 2-ene-valproate 10 P450 oxidation 4-ene-valproate hellip

bull Some metabolic interactionsbull Low-mod therapeutic index (gi neurotoxicity)

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56

VALPROATE METABOLISM

VPA glucuronide

Smooth Endoplasmic Reticulum Mitochondriaβ OXIDATION

3-oxo-VPA

2-ene-VPA

VPA

3-ene-VPA

23-diene-VPA

CO H2

[3-OH-VPA]

40VPACONJUGATION P450 OXIDATION

VPA

4-ene-VPA

O

OHOHHO

CO H2OO

CO H2

24-diene-VPA

3-OH-VPA 4-OH-VPA 5-OH-VPA

PGAPSA4-oxo-VPA

50 503 4woxidw-1 oxidddehyrdro

CO H2

O

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

48

VPAPLASMA PROTEIN BINDING INTERACTIONS

VPA rarruarr FREE DRUG

CBZdiazepamphenytointiagabine

tolbutamidewarfarin

DRUG rarruarr FREE VPA

ASANSAIDs

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

49

DVPX METABOLIC INTERACTIONS

VPA rarruarr DRUG

amitriptylineCBZ-E

diazepamethosuximidelamotriginelorazepam

nortriptylinephenobarbital

phenytoinzidovudine

DRUG rarruarr VPA

ASAcimetidinefluoxetinefelbamate

erythromycinphenothiazines

DRUG rarrdarr VPA

CBZplusmn lamotriginemefloquine

phenobarbitalphenytoinrifampin

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

50

KEY ISOFORMS FORANTIDEPRESSANT METABOLISM

ISOFORM

CYP1A2

CYP2C19

CYP2D6

CYP3A457

SUBSTRATES

TCAs plusmn mirtazdulox

plusmn citalopram TCAs

plusmn fluoxetineplusmn mirtazapine

paroxetine duloxvenlafaxineTCAs trazodone

plusmn citalopramplusmn mirtazapinenefazodonereboxetine

sertraline TCAs

INHIBITORS

fluvoxamine

fluox fluvox

bupropionfluoxetine

plusmn fluvoxamineparoxetineplusmn sertraline

fluvoxaminenefazodoneplusmn sertraline

INDUCERS

cigs omep

rifampin

-

CBZphenytoin

phenobarbrifampin

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

51

TRICYCLIC ANTIDEPRESSANTS

bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)

75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs

amitriptyline (NORT) imipramine (DMI)bull DMI (2-OH-DMI) NORT (10-OH-NORT) CMI

(desmethyl-CMI) DOX (desmethyl-DOX)bull 2deg 3deg amines - 2- 8- 10-hydroxylation [2D6]

(rate limiting)bull 3deg amines - N-demethylation [1A22C193A457]bull Low therapeutic index (anticholinergic)

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

52

TRICYCLIC INTERACTIONS

VIA 2D6

fluoxetineplusmn sertraline paroxetinehaloperidol

phenothiazinesmethadone

propafenonequinidine

DRUG rarruarr TCA

VIA

methylphenidate()disulfiram

acute ethanolvalproate ()

azole antifungals ()BCPs ()

cimetidinechloramphenicol

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

53

TRICYCLIC INTERACTIONS

DRUG rarrdarr TCA

carbamazepinechronic ethanolcigarette smokephenobarbital

phenytoinrifampin ()

TCA rarruarr DRUG

phenytoin ()warfarin ()

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

54

IMIPRAMINE METABOLISM

ACTIVE 2-HYDROXY METABOLITE

2-OH-IMI

IMI

ACTIVE PARENT

DRUG

N N

N N

OH

N N

DMI

ACTIVE N-DEMETHYL METABOLITE

2D6

-

2D6-

2-OH-DMIOH

N N

1A2 2C19 3A4- +

1A2 2C19 3A4

SSRIs HALOPERIDOL

PHENOTHIAZINES

SSRIs

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

RATE LIMITING REACTION GLUCURONIDES

ACTIVE N-DEMETHYL 2-HYDROXY METABOLITE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN CIGS

- +

SSRIs

SSRIs HALOPERIDOL

PHENOTHIAZINES

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

55

SSRIs amp SNRIs

DrugInhibits

SubstrateMetabolite

bullSSRIs - fluoxetine sertraline paroxetine fluvoxamine

bullSNRI - duloxetine venlafaxine

bulldarr side effects uarr therapeutic index cf TCAs

(es)Citalopramplusmn(1A22C192D6)

(3A42C19)plusmn

Paroxetine (2D6)(2D6)

-

Fluoxetine (2D63A4) (2D63A4)

+

Sertraline(plusmn2D6) (3A4)

plusmn

Fluvoxamine(1A22C93A4)

-

Venlafaxine-

(2D6) +

Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

56

FLUOXETINE

bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite

(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

57

FLUOXETINE INTERACTIONS

VIA 2D6AMI IMI

NORT DMIfluphenazinehaloperidolclozapine

dextromethorphanoxycodone

atomoxetineduloxetinevenlafaxine

VIA 2C19moclobemide

diazepamplusmn phenytoin

VIA valproate

VIA 3A4 3A5-7alprazolamdiazepam

+-carbamazepine

FLUOXETINE rarruarr DRUG

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

58

PAROXETINE

bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

59

PAROXETINE INTERACTIONS

PAROXETINE rarruarr DRUG

VIA 2D6AMI IMI

NORT DMIphenothiazinesIC antiarrhythmics

(propafenone flecainide encainide)beta blockersatomoxetine

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

60

FLUVOXAMINE

bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

61

FLUVOXAMINE INTERACTIONS

VIA 1A2

AMI IMI CMImaprotilineclozapine

olanzapinemethadone

caffeinephenacetinpropranololtheophylline

FLUVOXAMINE rarruarr DRUG

VIA 3A457

alprazolamdiazepam

carbamazepine

VIA 2C910

phenytoinwarfarin

VIA 2D6

haloperidol

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

62

SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite

(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA

levels than fluoxetine paroxetine but more significant at 200mgday

bull High therapeutic index

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

63

VENLAFAXINE

bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite

(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

64

DULOXETINE

bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6

ndash smoking reduces AUC by 13 ndash fluvoxamine (CYP1A2 inhibitor) increases AUC 6-fold

bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

65

CITALOPRAM-racemic mixtureescitalopram-enantiomer

bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite

(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite

(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

66

CITALOPRAM INTERACTIONS

VIA 2D6

DMI(citalopram given with IMI)

metoprolol

CITALOPRAM rarruarr DRUG DRUG rarruarr CITALOPRAM

VIA

cimetidineCMI

fluvoxamine

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

67

PHARMACOKINETICS OFSSRIs AND SNRIs

fluoxetine sertraline paroxetine fluvoxamine venlafaxine citalopram

drug t12 4 d 26 h 21 h 16 h 5 h 35 h

metab t12 7 d 3 d - - 11h -Binding 95 98 95 80 27 80

Nonlinear + +2D6 inhib ++ plusmn ++ plusmn plusmn- plusmn3A4 inhib + plusmn +1A2 inhib ++ plusmn2C9 inhib + plusmn +2C19 inhib + + + plusmn

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

68

BUPROPION

bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6

ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase

bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP

bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

69

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

70

DRUG rarruarr BUPVIA 2B6

orphenadrineifosfamide cimetidine

DRUG rarrdarr BUPVIA

carbamazepinephenobarbital

phenytoin

BUPROPION INTERACTIONS

BUP rarrdarr DRUGno evidence thus far

BUP rarruarr DRUGVIA 2D6

Desipraminevenlafaxine

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

71

MAO INHIBITORS

bull t12 brief amp not directly related to effects(irreversible MAO inhibition)

bull Dosendash Phenelzine - 45 - 90 mg ndash Tranylcypromine - 30 - 100 mg d

bull 85 MAO inhibition neededbull Therapeutic index

ndash Phenelzine - lowndash Tranylcypromine - low-mod

bull 2 week wait for SSRIs SNRIs bupropionbull Metabolism

ndash Not fully determinedndash ldquoSuiciderdquo inhibition componentndash CBZ inducible

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

72

MAO INHIBITORS

SERIOUS dietary restrictionshigh tyramine foods -cheese chianti fava hellip(give patients list)

SERIOUS drug interactionsSSRI CMI stimulants

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

73

MAO INHIBITOR INTERACTIONS

DRUGSdecongestants

opiatesSSRIs SNRIs CMI

stimulants

nefazodone bupropion

(Li VPA okay)(CBZ okay)

FOODShigh tyramine

cheesechianti

fava

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

74

TRAZODONE

bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

75

NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite

(anxiogenic 5HT-1 agonist t12 = 6 h) bull Active hydroxy-nefazodone metabolite

(blocks 5HT reuptake 5HT-2 t12 = 3 h) bull 3A4 inhibitoruarr triazolam alprazolam carbamazepine

bull 3A4 substrate nonlinear kineticsbull Moderate therapeutic index (sedation hepatotoxicity)

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

76

NEFAZODONE INTERACTIONS

NEFAZODONE rarruarr DRUG

VIA 3A34alprazolamtriazolam

carbamazepinecyclosporin

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

77

ANTIHISTAMINE INTERACTIONS

DRUG rarruarr ANTIHISTAMINE

VIA 3A34ketoconazoleitraconazolefluconazole

erythromycinclarithromycintroleandomycinnefazodone fluvoxamine

ANTIHISTAMINES

METABOLIZED VIA 3A34

loratadine (Claritin)cetirizine (Zyrtec)

fexofenadine (Allegra)

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

78

MIRTAZAPINE

bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT

3A rarr N-desmethyl-MIRT N-oxide-MIRTbull N-desmethyl-MIRT metabolite

110 activity 13 plasma level of MIRTbull No clinically significant enzyme inhibitionbull Sedation dizziness uarr weight uarr cholesterolbull 01 agranulocytosis 2 LFTs gt 3 x ULN

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

79

CLASS DRUG

2-KETOclorazepatediazepam

flurazepam

TRIAZOLOalprazolamtriazolam

7-NITRO clonazepam nitrazepam

3-HYDROXYlorazepamoxazepam

temazepam

SUBSTRATE OF

2C19 3A4

3A4

N-reduction(3A4)

ConjugationUGTs

INHIBITED BY

fluoxetinefluvoxamine

fluoxetinefluvoxaminenefazodone

-

-

ANXIOLYTIC METABOLISM

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

80

BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz

intermed (6-20 h) alpraz loraz oxaz temaz long (gt 20 h) diazepam clonazepam

bull Metabolites active (2-keto triazolo) inactive (3-hydroxy 7-nitro)

bull t12 short (lt 6 h) alpha-hydroxyalprazolam intermed (6-20 h) desmethylchlordiazepoxide long (gt 20 h) desmethyldiazepam

desalkyflurazepambull Kinetic interactions 2-keto (+) triazolo (+)

7-nitro (plusmn) 3-hydroxy (-)bull High therapeutic indices

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

81

BENZODIAZEPINES

TRIAZOLO

alprazolamtriazolam

4-hydrox [3A4]α-hydrox [3A4]

activeshort t12metab (alpraz)

+ kinetic ints

2-KETO

clorazepatediazepam

flurazepam

N-dealk [2C19] -3-hydrox [3A4]

activelong t12metabs

+ kinetic ints

3-HYDROX

lorazepamoxazepam

temazepam

directconjugation

inactivemetabs

plusmn kinetic ints

7-NITRO

clonazepamnitrazepam

N-reduction

inactivemetabs

plusmn kinetic ints

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

82

DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam

VIA 2C19 3A34fluoxetine

fluvoxaminedisulfiram

BCPsketoconazole

cimetidineisoniazid

omeprazolepropranolol

DRUG rarruarr TRIAZOLO BZalprazolam triazolam

VIA 3A34 fluoxetine

fluvoxaminenefazodone

diltiazemBCPs

ketoconazolecimetidine

erythromycinpropoxyphene

BENZODIAZEPINE INTERACTIONS

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

83

TRIAZOLOalprazolamtriazolam

4-hydroxylation [3A4]-hydroxylation [3A4]

uarr metabolism withCBZ

darr metabolism with fluoxetine fluvoxamine

nefazodone BCPs erythromycinketoconazole cimetidine propoxyphene

2-KETOclorazepate diazepam

flurazepam

N-dealkylation [2C19] rarr3-hydroxylation [3A4]

uarr metabolism withcigs barbiturate

rifampin

darr metabolism withfluoxetine fluvoxamine

disulfiram isoniazidBCPs cimetidine

ketoconazoleomeprazolepropranolol

BZ INTERACTIONS

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

84

DIAZEPAM METABOLISM

OXAZEPAM

2C19 (3A4)

ACTIVE 3-HYDROXY-BZ

(DIRECTLY CONJUGATED)

+ - + -

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

ACTIVE 2-KETO-BZ

N

N

O

ClN

HN

O

Cl

ACTIVE METABOLITE

N

O

Cl

HN

N-DEALKYLATION 3-HYDROXYLATION

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

DIAZEPAM N-DESMETHYL-DIAZEPAM

3A4 (2C19)

BCPs CIMETIDINE FLUOXETINE

FLUVOXAMINE OMEPRAZOLE

OH

CH3

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

85

ALPRAZOLAM METABOLISM

ALPRAZOLAM

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

+ -3A4

α-HYDROXYLATION

α-HYDROXY-ALPRAZOLAM

N

N

Cl

N

N

N

N

Cl

N

N

N

N

Cl

H3C

N

N

4-HYDROXY-ALPRAZOLAM+ -

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

CARBAMAZEPINE PHENOBARBITAL

PHENYTOIN RIFAMPIN

3A4

4-HYDROXYLA

TION

CIMETIDINE FLUOXETINE

FLUVOXAMINE KETOCONAZOLE

NEFAZODONE

OH

H3C

HO

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

86

DRUG

haloperidolfluphenazineperphenazinethioridazine

clozapinerisperidoneolanzapineziprasidoneAripirazolequetiapine

SUBSTRATE OF

2D62D6+-1A2

2D62D6

1A2 plusmn 2D62D6 3A4UGTs1A2

Aldehyde ox3A4 plusmn 1A22D6 3A4

3A4

INHIBITS

2D62D62D62D6

----

ANTIPSYCHOTIC METABOLISM

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

87

TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d

High potency 5 - 20 mg d

bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine

bull Low therapeutic index (neurotoxicity)

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

88

TYPICAL ANTIPSYCHOTIC INTERACTIONS

DRUGrarrdarrAPcarbamazepinephenobarbital

phenytoincigarettesrifampin

AP rarruarr DRUGtricyclics

DRUGrarruarrAPtricyclicsfluoxetine β blockerscimetidine

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

89

CLOZAPINE

bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite

(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

90

DRUG rarruarr CLOZfluoxetine

fluvoxaminecimetidinerisperidoneplusmn valproate

CLOZAPINE INTERACTIONS

DRUG rarrdarr CLOZCigarette smokecarbamazepine

phenytoin

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

91

RISPERIDONE

bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)

is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

92

OLANZAPINE

bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites

ndash N-glucuronidendash N-desmethyl-olanzapine (via CYP1A2)

bull CBZ smoking rarrdarr olanzapine bull Fluvoxamine rarruarr olanzapine

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

93

QUETIAPINE

bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

94

bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im

(in 2 divided doses)bull Metabolism

ndash 23 aldehyde oxidase reductionndash 13 P450 oxidation (CYP3A4)

bull carbamazepine rarr darr ziprasidonebull ketoconazole rarr uarr ziprasidone bull No effect on lithium or BCP levels

ZIPRASIDONE

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

95

bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite

(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA

ARIPIPRAZOLE

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

96

DRUG

carbamazepinevalproatefelbamategabapentinlamotriginetopiramate

tiagabineoxcarbazepinevigabatrinzonisamide

SUBSTRATE OF

3A4conjgt-oxidgtP450oxid

renalgtconjoxid renal excretion

conjugationrenalgthydroxhydrolconj

3A4 conjugationreduction

renal excretion3A4 (reduction)

INDUCES INHIBITS

induces 3A4 UGTsweak inhibitorinduces 3A4

-Weak inducer UGTs

plusmn inhibits 2C19 induces 3A4

-induces 3A4

--

ANTICONVULSANT ELIMINATION

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

97

GABAPENTIN

bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)

bull Does not alter Li kinetics (Frye 98)

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

98

LAMOTRIGINE

bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)

monoRx 28 40 150 [25 - 250]with CBZ 14 80 175 [25 - 350]with VPA 56 20 75 [25 - 200]

bull Inactive glucuronide metabolitesbull LTG rarruarrCBZ neurotoxicity

(dynamic vs uarr CBZ-E)bull LTG rarr plusmn darr VPA bull VPA plusmn sertaline rarr uarr LTGbull CBZ PHT PB PRIM BCPsrarr darr LTG

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

99

Lamotrigine Titration Influenced by Valproate and Carbamazepine

1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006

bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults12

Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg

Week 5 Add 50-100 mgwkonward as clinically indicated

Maintenance 100-400 mg

100

bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted

unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation

metabolitesbull 25 mgd rarruarr 25 mgd q wk rarr 200 - 400 mgdbull CBZ PHT rarr darr TPMbull TPM rarr plusmn uarr PHT (inhibits CYP2C19 in vitro)bull TPM rarr plusmn darr hormonal contraceptives

TOPIRAMATE

101

TIAGABINE

bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)

102

OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ

ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest

induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)

103

ZONISAMIDE

bull 15 bound

bull t12 = 60 h with monoRx

t12 = 30 h with inducers

bull Cl = 20 mL min

bull Reduced to 2-sulfamoylacetylphenol (SMAP)

bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd

bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS

104

LEVETIRACETAM

bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels

105

Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d

ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d

bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)

ndash 3A4 inhibitors (darr cyclosporin CBZ metab)

bull Varying therapeutic indices (cardiovascular)

106

CONCLUSIONS

bull Combination Rx often needed

bull Extensive observational clinical data

bull Evolving characterization of substrates inhibitors amp inducers

bull Understanding of drug metabolism

bull Prediction of drug interactions

107

REFERENCES

bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995

bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990

bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992

bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

101

TIAGABINE

bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)

102

OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ

ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest

induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)

103

ZONISAMIDE

bull 15 bound

bull t12 = 60 h with monoRx

t12 = 30 h with inducers

bull Cl = 20 mL min

bull Reduced to 2-sulfamoylacetylphenol (SMAP)

bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd

bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS

104

LEVETIRACETAM

bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels

105

Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d

ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d

bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)

ndash 3A4 inhibitors (darr cyclosporin CBZ metab)

bull Varying therapeutic indices (cardiovascular)

106

CONCLUSIONS

bull Combination Rx often needed

bull Extensive observational clinical data

bull Evolving characterization of substrates inhibitors amp inducers

bull Understanding of drug metabolism

bull Prediction of drug interactions

107

REFERENCES

bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995

bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990

bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992

bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

102

OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ

ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest

induction) bull OXC rarr uarr PHT (CYP2C19 inhibition)bull Low therapeutic index (neurotoxicity)

103

ZONISAMIDE

bull 15 bound

bull t12 = 60 h with monoRx

t12 = 30 h with inducers

bull Cl = 20 mL min

bull Reduced to 2-sulfamoylacetylphenol (SMAP)

bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd

bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS

104

LEVETIRACETAM

bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels

105

Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d

ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d

bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)

ndash 3A4 inhibitors (darr cyclosporin CBZ metab)

bull Varying therapeutic indices (cardiovascular)

106

CONCLUSIONS

bull Combination Rx often needed

bull Extensive observational clinical data

bull Evolving characterization of substrates inhibitors amp inducers

bull Understanding of drug metabolism

bull Prediction of drug interactions

107

REFERENCES

bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995

bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990

bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992

bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

103

ZONISAMIDE

bull 15 bound

bull t12 = 60 h with monoRx

t12 = 30 h with inducers

bull Cl = 20 mL min

bull Reduced to 2-sulfamoylacetylphenol (SMAP)

bull 100 mgd rarr uarr 100 mgd q 2wks -up to 300-600 mgd

bull CBZ PHT PB rarr darr ZNS LTG rarr uarr ZNS

104

LEVETIRACETAM

bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels

105

Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d

ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d

bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)

ndash 3A4 inhibitors (darr cyclosporin CBZ metab)

bull Varying therapeutic indices (cardiovascular)

106

CONCLUSIONS

bull Combination Rx often needed

bull Extensive observational clinical data

bull Evolving characterization of substrates inhibitors amp inducers

bull Understanding of drug metabolism

bull Prediction of drug interactions

107

REFERENCES

bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995

bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990

bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992

bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

104

LEVETIRACETAM

bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels

105

Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d

ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d

bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)

ndash 3A4 inhibitors (darr cyclosporin CBZ metab)

bull Varying therapeutic indices (cardiovascular)

106

CONCLUSIONS

bull Combination Rx often needed

bull Extensive observational clinical data

bull Evolving characterization of substrates inhibitors amp inducers

bull Understanding of drug metabolism

bull Prediction of drug interactions

107

REFERENCES

bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995

bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990

bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992

bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

105

Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d

ndash diltiazem (benzothiazepine) 120 - 480 mg dndash nimodipine (dihydropyridine) 60 - 360 mg dndash isradipine (dihydropyridine) 5 - 20 mg d

bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)

ndash 3A4 inhibitors (darr cyclosporin CBZ metab)

bull Varying therapeutic indices (cardiovascular)

106

CONCLUSIONS

bull Combination Rx often needed

bull Extensive observational clinical data

bull Evolving characterization of substrates inhibitors amp inducers

bull Understanding of drug metabolism

bull Prediction of drug interactions

107

REFERENCES

bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995

bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990

bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992

bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

106

CONCLUSIONS

bull Combination Rx often needed

bull Extensive observational clinical data

bull Evolving characterization of substrates inhibitors amp inducers

bull Understanding of drug metabolism

bull Prediction of drug interactions

107

REFERENCES

bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995

bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990

bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992

bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

107

REFERENCES

bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995

bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990

bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992

bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

108

Post Lecture ExamQuestion 1

1 Key pharmacokinetic parameters include (choose one)

A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

109

Question 2

2 After discontinuation how long does it take to completely clear a drug (choose one)

A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

110

Question 3

3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)

A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

111

Question 4

4 Which of the following drugs is NOT an enzyme inducer (choose one)

A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

112

Question 5

5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)

A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

113

Question 6

6 Which of the following drugs is NOT an enzyme inhibitor (choose one)

A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

114

Question 7

7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)

A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

115

Question 8

8 Which of the following drugs have exclusively renal excretion (choose one)

A GabapentinB ValproateC LithiumD CarbamazepineE A and C

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

116

Question 9

9 Monoamine oxidase inhibitor combination therapy is limited by

A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

117

Question 10

10Which of the following benzodiazepines has least potential for drug interactions

A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams

118

Answers to Pre amp PostCompetency Exams

1 F2 C3 D amp F4 B5 F

6 A7 B8 E9 E10D

• Nuacutemero de diapositiva 1
• Teaching Points
• Pre Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Outline
• Nuacutemero de diapositiva 14
• Nuacutemero de diapositiva 15
• Nuacutemero de diapositiva 16
• Nuacutemero de diapositiva 17
• Nuacutemero de diapositiva 18
• Nuacutemero de diapositiva 19
• Nuacutemero de diapositiva 20
• Nuacutemero de diapositiva 21
• Nuacutemero de diapositiva 22
• Nuacutemero de diapositiva 23
• Nuacutemero de diapositiva 24
• Nuacutemero de diapositiva 25
• Nuacutemero de diapositiva 26
• Nuacutemero de diapositiva 27
• Nuacutemero de diapositiva 28
• Nuacutemero de diapositiva 29
• Nuacutemero de diapositiva 30
• Nuacutemero de diapositiva 31
• Nuacutemero de diapositiva 32
• Nuacutemero de diapositiva 33
• Nuacutemero de diapositiva 34
• Nuacutemero de diapositiva 35
• Nuacutemero de diapositiva 36
• Nuacutemero de diapositiva 37
• Nuacutemero de diapositiva 38
• LITHIUM
• Nuacutemero de diapositiva 40
• CARBAMAZEPINE
• Nuacutemero de diapositiva 42
• Nuacutemero de diapositiva 43
• Nuacutemero de diapositiva 44
• Nuacutemero de diapositiva 45
• VALPROATE
• Nuacutemero de diapositiva 47
• Nuacutemero de diapositiva 48
• Nuacutemero de diapositiva 49
• Nuacutemero de diapositiva 50
• Nuacutemero de diapositiva 51
• Nuacutemero de diapositiva 52
• Nuacutemero de diapositiva 53
• Nuacutemero de diapositiva 54
• SSRIs amp SNRIs
• FLUOXETINE
• Nuacutemero de diapositiva 57
• PAROXETINE
• Nuacutemero de diapositiva 59
• Nuacutemero de diapositiva 60
• Nuacutemero de diapositiva 61
• SERTRALINE
• VENLAFAXINE
• DULOXETINE
• CITALOPRAM-racemic mixtureescitalopram-enantiomer
• Nuacutemero de diapositiva 66
• PHARMACOKINETICS OFSSRIs AND SNRIs
• BUPROPION
• Nuacutemero de diapositiva 69
• Nuacutemero de diapositiva 70
• Nuacutemero de diapositiva 71
• MAO INHIBITORS
• MAO INHIBITOR INTERACTIONS
• Nuacutemero de diapositiva 74
• Nuacutemero de diapositiva 75
• Nuacutemero de diapositiva 76
• Nuacutemero de diapositiva 77
• Nuacutemero de diapositiva 78
• Nuacutemero de diapositiva 79
• BENZODIAZEPINES
• Nuacutemero de diapositiva 81
• Nuacutemero de diapositiva 82
• Nuacutemero de diapositiva 83
• Nuacutemero de diapositiva 84
• Nuacutemero de diapositiva 85
• Nuacutemero de diapositiva 86
• TYPCIAL ANTIPSYCHOTICS
• Nuacutemero de diapositiva 88
• Nuacutemero de diapositiva 89
• Nuacutemero de diapositiva 90
• Nuacutemero de diapositiva 91
• Nuacutemero de diapositiva 92
• Nuacutemero de diapositiva 93
• Nuacutemero de diapositiva 94
• Nuacutemero de diapositiva 95
• Nuacutemero de diapositiva 96
• Nuacutemero de diapositiva 97
• Nuacutemero de diapositiva 98
• Lamotrigine Titration Influenced by Valproate and Carbamazepine
• Nuacutemero de diapositiva 100
• Nuacutemero de diapositiva 101
• OXCARBAZEPINE
• Nuacutemero de diapositiva 103
• Nuacutemero de diapositiva 104
• Nuacutemero de diapositiva 105
• CONCLUSIONS
• Nuacutemero de diapositiva 107
• Post Lecture ExamQuestion 1
• Question 2
• Question 3
• Question 4
• Question 5
• Question 6
• Question 7
• Question 8
• Question 9
• Question 10
• Answers to Pre amp PostCompetency Exams