Thomas M Penders MDThomas M Penders MDAssociate ProfessorAssociate Professor

Brody School of MedicineBrody School of Medicine

September, 1999 Institute of Medicine issued report on preventable medical errors.

Estimated that 50 – 100,000 patients die in hospitals as a result of errors made by medical care providers.

Economic loss of $17 to 29 billion in costs of care and lost productivity

To Err is Human

Errors in administration of drugs are a significant portion of this problem.

Excessive dosages

Failure to monitor results of drug administration

Drug-drug interactions – 5% of hospitalizations per year.

Drug-Drug Interactions

Multiple Drug Overdose

Clinically significant interaction takes place when the therapeutic or toxic effects of a medication are altered by co-administration of another drug.

Increasing pharmacopeia and lengthening life span make co-administration of drugs commonplace

Particularly notable when drugs have a narrow therapeutic index e.g. Lithium, Digoxin, tricyclics

Definition

CNS depression – additive with multiple sedating agents – antidepressants and antipsychotics

Interference with or potentiation of drug metabolism

Fluoxetine – AntipsychoticsTobacco tars & several antipsychoticsCiprofloxin & clozaril through P450

Common Examples

Pharmacokinetics – What the body does to the drug –Absorption, bioavailability, metabolism, excretion

Pharmacodynamics – What drug does to the body.Drugs effect on end organ or receptor site

Drug metabolism -

Interactions due to one drugs effect on movement through the body.

Absorption – Gut – pH, food administration

Distribution – Protein binding – free drug is activee.g. Warfarin

Metabolic – result in change in drug concentrationExcretion – Change in ability to eliminate – e.g. diuretics and lithium

Pharmacokinetic Interactions

Steady state

Drugs influence on another drugs effects

Occurs at end organ or receptor siteMost commonly additive effects

e.g. SSRIs and MAOIs

Pharmacodynamic Interactions

Over course of history plants that developed toxins survived.

Animal developed enzyme systems to detoxify plant and other toxins

Metabolic enzymes are oxidative – render toxins less active and prepare for further degradation and elimination

Purpose of Metabolism

Red Queen

Primary purpose is to metabolize endogenous compound such as steroids and neuropeptides

Secondary role for enzymes in GI tract and liver is to detoxify ingested chemicals

Including foods, medicines, smokes or other environmental exposures

P450 system

40 enzymes identified in humans

Capable of metabolism of multiple substances

Six enzymes responsible for 90% of drug oxidation

1A2, 3A4, 2C9, 2C19, 2D6 and 2E1.

Characteristics of P450

Most drugs are lipophilic

Lipophilic compounds are difficult to eliminate

Biotransformation to more polar and water soluble compounds facilitates elimination

Metabolites exit via urine, bile or stool

Metabolism

Most drug metabolism occurs in liver and gut wall.

First-pass effect – Enzymes in endoplasmic reticulum of gut and liver cells alter most drugs and toxins upon absorption into hepatic circulation

CYP 3A4 accounts for 70% of intestinal activity

Metabolism proceeds in two phases; phase I oxidationPhase II - glucuronidation

Sites of Drug Metabolism

Addition of small polar groups through oxidative mechanisms; N-dealkylination, O-dealkylination, hydroxylation, N-oxidation, s-oxidation and deamination

P450 enzymes contain red-pigmented heme, absorb at wavelength 450 nm.

Each enzyme is encoded by one gene

Other enzyme systems: Alcohol dehydrogenase, esterase, amidase and flavin monoxygenase

Phase I metabolism

Inhibition

Induction

Genetic polymorphisms

Variability of drug response

Enzyme Variability

Drugs metabolized by a common enzyme type will be competing for sites in the liver endoplasmic reticulum

A drug’s affinity for an enzyme is “inhibitory potential”

Values (Ki) are published from in vitro studies

Drugs with little affinity have high Ki and do not bindDrugs with low Ki bind and compete for enzyme

Inhibition

Drugs with Ki <2 μM are potent inhibitors

When two drugs are co-administered, the one with greater affinity (lower Ki) will competetively inhibit

Some drugs inhibit without utilizing the enzyme

Drugs that inhibit lead to elevated serum levels of the other drug.

Inhibition

Inhibition

Leads to more potent and prolonged pharmacological effect that might result in drug toxicity.

Inhibition is rapid in onset and in offset upon discontinuation of blocking agent

Effects of inhibition are rapid in developing and disappear quickly.

Inhibition

P450 greatly affected by competetive inhibition

Ketoconazole has low Ki for 3A4 - PROBES

When co-administered with terfenadine (metabolic product fexofenadine), leads to elevated levels of terfenidine

Toxic cardiac arrhythmias resultTerfenidine removed from the market after several deaths

Inhibition

Some xenobiotics stimulate synthesis of P450 enzymes.With more sites available metabolic activity increases

This may lead to decreases in amount of parent drug and increased amounts of metabolic product

Co-administration of a potent inducer may result in decline in serum levels below that required for therapeutic effect. Carbamazepine induces metabolism of many antidepressants

Induction

Induction

Drugs utilizing P450 may have increased side effects or become toxic if active metabolic product increases

Hepatotoxicity of Valproic Acid likely due to such a mechanism

3A4, 2D6, 1A2, 2C9 2C19 and 2E1 may all be induced

Induction

Drug metabolism varies between groups and individuals

Each individual has two copies of each allele

Most common sequence is “wild type”

Genetic alterations result in minor changes an sequence affecting enzymatic activity

Genetic Polymorphisms

Poor metabolizers – slower biotransformation

Extensive metabolizers – homozygous wild type transform substrate at rate expected for population

Ultra-extensive metabolizers – transform at a higher rate than population resulting in reduced levels of drug at site of action

Metabolizer types

Population variation in enzyme activity

Conjugation reactions provide water soluble products easily excreted

In most cases more than one enzyme is involved in metabolism of a particular drug

Less likely involved in clinically significant DDI

Result in glucuronidation, sulfation, methylation

Phase II metabolism

Most abundant phase II enzymes inlcude uridine 5’-diphosphate glucuronyltransferases (UGTs).

Major detoxification system. Most activity in liver

Most drugs go through phase I

Some are directly glucuronidated; lorazepam, oxazapam and temazepam

Glucuronidation

These benzodiazepines are favored with liver disease

Lamotrigine, valporate, NSAIDs, zidovudine, most opiates

UGTs

S-adenosylmethionine – SAMeUsed as treatment for depression

Catecol O-Methyltransferase (COMT)One of two ways that catecholamines are metabolized(other is monoamine oxidases)

Some CNS drugs are inhibitors of COMT

Methylation

Located in intestines and liver as well as blood-brain barrier

SLC transporters – importing transporters

ABC - effluxing transporters

Phase III - transporters

N-demethylates fluoxetine to norfluoxetine (half life of up to 16 days with long term use).

For many psychotropics 2D6 is considered a low capacity, high affinity enzyme

Clears drugs at lower concentrations. When inhibited processing with flow to 3A4 and 1A2, high capacity, low affinity enzymes

Drug clearance will be slower and blood levels higher

2D6

Present in brain, bone marrow, gut and liver

Only 2% of all enzyme by concentration

Most action in liver. Plays a major role in degradation of fluoxatine, tricyclics, most antipsychotics, methadone, codeine, benztropine, amphetamines, donepazil

25% of all psychotropics

2D6

Strong Inhibitors: Fluoxetine, Paroxetine, Quinidine

Moderate Inhibitors: Duloxetine, Fluphenazine, Risperidone, Buproprion

Weak Inhibitors: Venlafaxine, Sertaline, Citalopram

Substrates: Most antidepressants, Most Antipsychotics, Benztropine, Diphenhydramine, Metprolol

2D6

Analgesic effect depends on conversion to morphine.Depends on 2D6. Inhibition can result in poorer pain control.

Fluoxetine and Paroxetine are strong inhibitors

Fluoxetine is oxidized to norfluoxetine

Fluoxetine (Ki .22) and norfluoxetine (Ki 1.48) – may require a 4-8 week washout period before introduction of other 2D6Metabolized agents

Pro drugs - Codeine

Potent 2D6 inhibitor (Ki 2.0)

Half life 21 hours, no active metabolites

Fluoxetine and Paroxetine are relative contraindicated together with drugs that increase QT interval

i.e. tricyclics, phenothiazines, some second generation antipsychotics

Paroxetine

Ritanovir – potent 2D6 inhibitor (Ki .16)

Also inhibits most other enzymes

2D6 is induced in pregnancy

Not a lot of evidence of drug induction of 2D6

Other Drugs

Used to treat estrogen receptor positive beast cancer.

Active metabolite, endoxefen, has 10 to 100X the affinity to estrogen receptor.

Breast cancer survivors suffer depression and hot flashes frequently treated with SSRIs

Woman on Tamoxifen plus fluoxetine, paroxetine and sertriline have relapse rate of 16% compared to usual rate of 7.5%.

Tamoxifen

Tamoxifen

Wild type exists in 90%, PMs in about 8% of caucasiansAsians have 1% PMs. Northern African populations have high prevalence of UEMs (29% Ethiopians)

Over 100 SNPs for 2D6 gene identified.

Those with greater potency as enzymes has side effectsTo codeine (nausea), Tamoxifen (hot flashes) and other agents.

Star D suggested ultra rapid metabolizers may fail to respond to some SSRIs.

2D6 genetics

Accounts for 30% of P450 activity in liver and 70% in gut

Performs the bulk of oxidative metabolism of drugs

Phase I metabolism of endogenous and exogenous compounds including hydroxylation, demethylation and dealkylation

Metabolism of endogenous steroids, cholesterol and lipidsIncluding oral contraceptives

3A4

50 variations identified

High activity variants seen require increased doses of drugs metabolized by 3A4

Poor metabolism alleles are likely incompatible with life

Genetic variability

Strong inhibitors increase plasma levels of substrate 3 to 5 times.Nefazodone, ketoconazole, grapefruit juice

Some drugs affected by 3A4 inhibition; fentanyl, quinidine, pimozide

Deaths prompted contraindication of pimozide with any azole antifungals, macrolide antibiotic or protease inhibitor

Inhibitors

Alprazolam, midazolam, triazolam depend on 3A4

50% dose reduction recommended for alprazolam75% reduction of triazolam when administered with nefazodone.

Buspirone levels enhanced with 3A4 blockers i.e.Erythromycin, efaverenze

Benzodiazepines

Furanocoumarins inhibit 3A4 6-8 ounces of Grapefruit juice taken with a 3A4 substrate will significantly increase blood levels

Drug sparing and augmentation – cimetidine and Clozaril

Grapefruit juice

Carbamazepine – induces its own metabolism

Also Topiramate, Methylprednisone, modafanil, prednisone and St. John’s Wort

May lead to lower levels of oral contraceptives

Inducers

A main metabolic pathway for oral hypoglycemics and NSAIDS. Substrates include Phentoin, Warfarin, modafanil

10 % of caucasians are 2C9 poor metabolizers (these polymorphs rare in African Americans or Asians

Valproate is an inhibitor of 2C9 and may lead to increased levels of substrates

2C9

Polymorphs common; Asians have high prevalence of poor metabolizers

Most proton pump inhibitors metabolized by this pathway

Citalopram, Escitaloprem, Sertaline, diazepam levels are increased in populations who have poor metabolism

Fluoxetine is a potent inhibitor

2C19

Overall 14% of population are PMs

Clopidogrel (Plavix) is a pro-drug metabolized by 2C19

Inhibitors (proton pump inhibitors, antidepressants)Reduce effectiveness i.e. reinfarction rate with concomiant use

2C19

Several services now available to provide a profile of P450 activity

Roche’s Amplichip Gene Test approved by FDA to confirm genotypes for 2D6 and 2C19. Cost $600.00

This test only provides genotyping, an approximation of the phenotype

Ampli-Chip

Enzyme important in the metabolism of many xenobiotics including polycyclic hydrocarbons found in cigarette smoke

Linked to carcinogenesis

Major enzyme in oxidation of melatonin and methylxanthines: caffeine and theophylline

Expressed in liver, codon on chromosome 15

1A2

About 20 variations known, mostly rare.

SNPs involved with inducibility of enzyme

One SNP associated with susceptibility to Tardive Dyskinesia. Same SNIP (1a2*F) associated with increased QT with antipsychotics

Relationship between caffeine metabolism and plasma concentrations of olanzapine and clozapine

1A2

Fluvoxamine is a potent inhibitor and may increase clozapine levels tenfold

Ciprofloxin increases clozapine levels threefold

Estrogen containing oral contraceptives or replacement hormones moderately inhibit 1A2 leading to toxicities with use of caffeine, clozapine and haldol.

1A2

1A2 induced by hydrocarbons in cigarette smoke.

1A2 induction increases clearance of many antipsychotic drugs: clozapine and olanzapine

Smoking cessation in schizophrenic patients leads to elevated blood levels of substrate

Alternately stabilization of schizophrenic symptoms on a smoke free inpatient unit leads to increased clearance,declining blood levels and relapse upon resumption ofsmoking

1A2

Other inducers of 1A2 include brussel sprouts, broccoli and cabbage, charcoal grilling

Heavy exercise will induce as potently as heavy cigarette smoking.

1A2

Unique enzyme with limited but important substrates.

Inactivation of industrial solvents, acetaminophen hepatotoxicity, activator of chemical carcinogenesis and producer of free radicals causing cytotoxicity and tissue damage

Role in metabolism of alcohol

Anesthetics

2E1

Inhibitors include acute alcohol, isoniazid, disulfram, watercress

Chronic alcohol use increases enzyme activity 10 fold

Uncontrolled diabetes, obesity, smoking (including marijuana) may result in induction

Organic compounds are metabolized to compounds which are carcinogenic. Increase 2E1 associated with increased cancer risk

2E1

Acetaminophen is metabolized by glucuronadation.

When glucuronide is overwhelmed (i.e. overdose) it is metabolized by 2E1.

The metabolic product of this interaction (NAPQI) is hepatotoxic.

Situations where glutathione levels are reduced or 2E1 (smoking, opiate consumption, HIV, Hepatitis C) carryHigher risk for acetaminophen hapatotoxicity

2E1

Drugs or active metabolites cleared primarily by renal excretion:

Lithium Carbonate – thiazides increase levelsExcretion enhanced by xanthines (Caffeine, theobromine)

Gabapentin – Excreted unchanged in urine with no known interactions involving elimination

Renal Clearance

Which of the following statements is true in regard to venlafaxine?

A.It is highly protein boundB.It is unlikely to inhibit cytochrome P450 enzymesC.It has a flat dose-response curveD.It is not FDA approved for generalized anxiety disorder (GAD)E.It has a high risk of inducing hypertension at low dosesB.

Board Questions 1

A 68 year old man with bipolar I disorder has done well on lithium. His most recent blood level was 0.8 mEq/L. He has a variety of medical problems. He now presents with pressured speech, racing thoughts and insomnia. Serum lithium level is now 0.3 mEq/L. Wife noted changes about two weeks after addition of a new medication. You are confident of adherence to lithium regimen.What class of drug was added to his regimen?

Board Questions 2

A. ACE inhibitorB. Beta blockerC. NSAIDD. Thiazide diureticE.Xanthine bronchodilator

E

Board Questions 2

A 27 year old patient announces she is pregnant despite having taken an oral contraceptive for 4 years. Which of the following four medications might account for failure of oral contraceptives?A. LithiumB. DivalproexC. CarbamazepineD. LamotrigineE.GabapentinC

Board Question 3

Which of the following will double blood levels of lamotrigine?

A. CarbamazepineB.DivalproexC.PhentoinD.Phenobarbital

B

Board Question 4

A 38 year-old woman with a history of estrogen receptor positive breast cancer is currently taking tamoxifen. She has recently become tearful, withdrawn and anergic. She notes difficulty with sleep and hot flashes since initiation of tamoxifen. Which of the following is the most appropriate agent to use to treat her depressive symptoms?

Board Question 5

A. VenlafaxineB. ParoxetineC. GabapentinD. FluoxetineE. Duloxetine

B

Board Question 5