neuropharm-epilepsy introduce-from ncbi

8/14/2019 NeuroPharm-epilepsy introduce-from NCBI

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Neuropharmacology ofNeuropharmacology of

Antiepileptic DrugsAntiepileptic Drugs

American Epilepsy Society


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DefinitionsDefinitions

Seizure: the clinical manifestation of an

abnormal synchronization and excessive

excitation of a population of corticalneurons

Epilepsy: a tendency toward recurrent

seizures unprovoked by acute systemicor neurologic insults


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Antiepileptic DrugAntiepileptic Drug

A drug which decreases the frequency and/or

severity of seizures in people with epilepsy

Treats the symptom of seizures, not the

underlying epileptic condition

Goalmaximize quality of life by minimizing

seizures and adverse drug effects


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History of AntiepilepticHistory of AntiepilepticDrug Therapy in the U.S.Drug Therapy in the U.S.

1857 - Bromides

1912 - Phenobarbital

1937 - Phenytoin

1954 - Primidone

1960 - Ethosuximide


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History of AntiepilepticHistory of AntiepilepticDrug Therapy in the U.S.Drug Therapy in the U.S.

1974 - Carbamazepine

1975 - Clonazepam

1978 - Valproate

1993 - Felbamate, Gabapentin

1995 - Lamotrigine

1997 - Topiramate, Tiagabine

1999 - Levetiracetam

2000 - Oxcarbazepine, Zonisamide


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Antiepileptic Drug TherapyAntiepileptic Drug TherapyStructures of Commonly Used AEDsStructures of Commonly Used AEDs

Chemical formulas of commonly used old and new

antiepileptic drugs

Adapted from Rogawski and Porter, 1993, and Engel, 1989


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LevetiracetamLevetiracetam

OxcarbazepineOxcarbazepine

ZonisamideZonisamide


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Cellular Mechanisms ofCellular Mechanisms ofSeizure GenerationSeizure Generation

Excitation (too much)

Ionic-inward Na+, Ca++ currents

Neurotransmitter: glutamate, aspartate

Inhibition (too little)

Ionic-inward CI-

, outward K+

currents Neurotransmitter: GABA


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AEDs: Molecular andAEDs: Molecular and

Cellular MechanismsCellular Mechanisms

Phenytoin, Carbamazepine

Block voltage-dependent sodium channels at high firing

frequencies

Barbiturates

Prolong GABA-mediated chloride channel openings

Some blockade of voltage-dependent sodium channels

Benzodiazepines

Increase frequency of GABA-mediated chloride channel

openings


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Felbamate May block voltage-dependent sodium channels at high

firing frequencies

May modulate NMDA receptor via strychnine-insensitive

glycine receptor Gabapentin

Increases neuronal GABA concentration

Enhances GABA mediated inhibition

Lamotrigine Blocks voltage-dependent sodium channels at high firing

frequencies

May interfere with pathologic glutamate release


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Topiramate

Blocks voltage-dependent sodium channels at high firing

frequencies

Increases frequency at which GABA opens Cl- channels(different site than benzodiazepines)

Antagonizes glutamate action at AMPA/kainate receptor

subtype

Inhibition of carbonic anydrase

Tiagabine

Interferes with GABA re-uptake


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Levetiracetam

Binding of reversible saturable specific binding site

Reduces high-voltsge- activated Ca2+ currents

Reverses inhibition of GABA and glycine gated currents

induced by negative allosteric modulators

Oxcarbazepine

Blocks voltage-dependent sodium channels at high firing

frequencies Exerts effect on K+ channels

Zonisamide

Blocks voltage-dependent sodium channels and

T-type calcium channels


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Pregabalin

Increases neuronal GABA

Increase in glutamic acid decarboxylase

Decrease in neuronal calcium currents by binding of alpha 2

delta subunit of the voltage gated calcium channel


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The GABA SystemThe GABA System

The GABA

system and its

associated

chloride channel

From Engel, 1989


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Pharmacokinetic PrinciplesPharmacokinetic Principles

Absorption: entry of drug into the blood

Essentially complete for all AEDs (except gabapentin)

Timing varies widely by drug, formulation,

patient characteristics Generally slowed by food in stomach (CBZ may be

exception)

Usually takes several hours (importance for interpreting

blood levels)


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The Cytochrome P-450The Cytochrome P-450

Enzyme SystemEnzyme System

Inducers Inhibitors

phenobarbital erythromycin

primidone nifedipine/verapamil

phenytoin trimethoprim/sulfa

carbamazepine propoxyphene

tobacco/cigarettes cimetidine

valproate


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Enzyme SystemEnzyme System

Substrates (metabolism enhanced by inducers):

steroid hormones

theophylline

tricyclic antidepressants

vitamins

warfarin(many more)


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Isozyme SystemIsozyme System

The enzymes most involved with drugmetabolism

Nomenclature based upon homology of amino

acid sequences Enzymes have broad substrate specificity, and

individual drugs may be substrates for severalenzymes

The principle enzymes involved with AEDmetabolism include CYP2C9, CYP2C19,CYP3A4


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Drug Metabolizing Enzymes:Drug Metabolizing Enzymes:

UDP- Glucuronyltransferase (UGT)UDP- Glucuronyltransferase (UGT)

Important pathway for drug

metabolism/inactivation

Currently less well described than CYP Several isozymes that are involved in AED

metabolism include: UGT1A9 (VPA), UGT2B7

(VPA, lorazepam), UGT1A4 (LTG)


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Drug MetabolizingDrug Metabolizing

Isozymes and AEDsIsozymes and AEDs

AED CYP3A4 CYP2C9 CYP2C19 UGT

CBZ +

PHT + +

VPA + +

PB +

ZNS +

TGB +

AEDs that do not appear to be either inducers or inhibitors of the CYPAEDs that do not appear to be either inducers or inhibitors of the CYP

system include: gabapentin, lamotrigine, tiagabine, levetiracetam,system include: gabapentin, lamotrigine, tiagabine, levetiracetam,

zonisamide.zonisamide.


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Enzyme Inducers/Inhibitors:Enzyme Inducers/Inhibitors:

General ConsiderationsGeneral Considerations

Inducers: Increase clearance and decreasesteady-state concentrations of other substrates

Inhibitors: Decrease clearance and increasesteady-state concentrations of other substrates


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Pharmacokinetic PrinciplesPharmacokinetic Principles

Elimination: removal of active drug from the

blood by metabolism and excretion

Metabolism/biotransformation generally hepatic; usually

rate-limiting step

Excretion mostly renal

Active and inactive metabolites

Changes in metabolism over time (auto-induction with

carbamazepine) or with polytherapy (enzyme induction or

inhibition)

Differences in metabolism by age, systemic disease


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AED Inducers: GeneralAED Inducers: General

ConsiderationsConsiderations

Results from synthesis of new enzyme

Tends to be slower in onset/offset than inhibition

interactions

Broad Spectrum Inducers: Carbamazepine

Phenytoin

Phenobarbital/primidone

Selective CYP3A Inducers:

Felbamate, Topiramate, Oxcarbazepine


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InhibitionInhibition

Competition at specific hepatic enzyme site

Onset typically rapid and concentration

(inhibitor) dependent

Possible to predict potential interactions by

knowledge of specific hepatic enzymes andmajor pathways of AED metabolism


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AED InhibitorsAED Inhibitors

Valproate

UDP glucuronosyltransferase (UGT)

plasma concentrations of Lamotrigine, Lorazepam

CYP2C19

plasma concentrations of Phenytoin, Phenobarbital

Topiramate & Oxcarbazepine

CYP2C19

plasma concentrations of Phenytoin

Felbamate CYP2C19

plasma concentrations of Phenytoin, Phenobarbital


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Enzymes and Specific AEDEnzymes and Specific AED

InteractionsInteractions

Phenytoin CYP2C9 CYP2C19

Inhibitors: valproate, ticlopidine, fluoxetine,topiramate, fluconazole

Carbamazepine CYP3A4 CYP2C8 CYP1A2

Inhibitors: ketoconazole, fluconazole, erythromycin,diltiazem

Lamotrigine UGT 1A4

Inhibitor: valproate


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Isozyme Specific DrugIsozyme Specific Drug

InteractionsInteractions

Category CYP3A4 CYP2C9 CYP2C19 UGT

Inhibitor ErythromycinClarithromycin

Diltiazem

Fluconazole

Itraconazole

Ketoconazole

Cimetidinepropoxyphene

Grapefruit

juice

VPA

Fluconazole

metronidazole

Sertraline

Paroxetine

Trimethoprim/

sulfa

Ticlopidine

Felbamate

OXC/MHD

Omeprazole

VPA

Inducer CBZPHT

PB

felbamate

RifampinTPM

OXC/MHD

CBZ

PHT

PB

Rifampin

CBZ

PHT

PB

rifampin

CBZ

PHT

PB

OXC/MHD

LTG (?)


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Therapeutic IndexTherapeutic Index

T.I. = ED 5O% /TD 50%

Therapeutic range of AED serum

concentrations

Limited data

Broad generalization

Individual differences


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Steady State and Half LifeSteady State and Half Life

From Engel, 1989


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AED Serum ConcentrationsAED Serum Concentrations

In general, AED serum concentrations can be

used as a guide for evaluating the efficacy of

medication therapy for epilepsy.

Serum concentrations are useful whenoptimizing AED therapy, assessing compliance,

or teasing out drug-drug interactions.

They should be used to monitor

pharmacodynamic and pharmacokineticinteractions.


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AED Serum ConcentrationsAED Serum Concentrations

Serum concentrations are also useful when

documenting positive or negative outcomes

associated with AED therapy.

Most often individual patients define their own therapeutic range for AEDs.

For the new AEDs there is no clearly defined

therapeutic range.


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Potential Target Range of AEDPotential Target Range of AED

Serum ConcentrationsSerum Concentrations

AED Serum Concentration

(mg/l)

Carbamazepine 4-12

Ethosuximide 40-100

Phenobarbital 10-40

Phenytoin 10-20

Valproic acid 50-100


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Potential Target Range of AEDPotential Target Range of AED

Serum ConcentrationsSerum Concentrations

AED Serum Concentration

(mg/l)

Gabapentin 6-21

Lamotrigine 5-18Levetiracetam 10-40

Oxcarbazepine 12-24 (MHD)

Pregabalin ??

Tiagabine ?Topiramate 4.0-25

Zonisamide 7-40


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AEDs and Drug InteractionsAEDs and Drug Interactions

Although many AEDs can cause pharmacokineticinteractions, several agents appear to be lessproblematic.

AEDs that do not appear to be either inducers orinhibitors of the CYP system include:

Gabapentin

Lamotrigine

Pregabalin

Tiagabine

Levetiracetam

Zonisamide


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Pharmacodynamic InteractionsPharmacodynamic Interactions

Wanted and unwanted effects on target organ

Efficacy seizure control

Toxicity adverse effects

(dizziness, ataxia, nausea, etc.)

Ph ki i I iPh ki i I i


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Pharmacokinetic Interactions:Pharmacokinetic Interactions:

Possible Clinical ScenariosPossible Clinical Scenarios

Be aware that drug interactions may

occur when:

Addition of a new medication when inducer/inhibitor is

present

Addition of inducer/inhibitor to existing medication regimen

Removal of an inducer/inhibitor from chronic medication

regimen

Ph ki i FPh ki i F


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Pharmacokinetic FactorsPharmacokinetic Factors

in the Elderlyin the Elderly

Absorption little change

Distribution

decrease in lean body mass important forhighly lipid-soluble drugs

fall in albumin leading to higher free fraction

Metabolism decreased hepatic enzyme

content and blood flow

Excretion decreased renal clearance

Ph ki i FPh ki ti F t


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Pharmacokinetic FactorsPharmacokinetic Factors

in Pediatricsin Pediatrics

Neonateoften lower per kg doses

Low protein binding Low metabolic rate

Childrenhigher, more frequent doses

Faster metabolism


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Pharmacokinetics in PregnancyPharmacokinetics in Pregnancy

Increased volume of distribution

Lower serum albumin

Faster metabolism

Higher dose, but probably less than predicted

by total level (measure free level)

Consider more frequent dosing


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Adverse EffectsAdverse Effects

Acute dose-relatedreversible

Idiosyncratic

uncommon rare

potentially serious or life threatening

Chronicreversibility and seriousness vary

A t D R l t d AdA t D R l t d Ad


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Acute, Dose-Related AdverseAcute, Dose-Related Adverse

Effects of AEDsEffects of AEDs

Neurologic/Psychiatric most common

Sedation, fatigue

Unsteadiness, uncoordination, dizziness

Tremor

Paresthesia

Diplopia, blurred vision

Mental/motor slowing or impairment

Mood or behavioral changes

Changes in libido or sexual function

A t D R l t d AdA t D R l t d Ad


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Acute, Dose-Related AdverseAcute, Dose-Related Adverse

Effects of AEDs (cont.)Effects of AEDs (cont.)

Gastrointestinal (nausea, heartburn)

Mild to moderate laboratory changes

Hyponatremia (may be asymptomatic)

Increases in ALT or AST

Leukopenia

Thrombocytopenia

Weight gain/appetite changes

Idi ti AdIdi ti Ad


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Idiosyncratic AdverseIdiosyncratic Adverse


Rash, Exfoliation

Signs of potential Stevens-Johnson syndrome

Hepatic Damage Early symptoms: abdominal pain, vomiting, jaundice

Laboratory monitoring probably not helpful in early

detection

Patient education

Fever and mucus membrane involvement

Idi ti AdIdi ti Ad


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Idiosyncratic AdverseIdiosyncratic Adverse


Hematologic Damage

(marrow aplasia, agranulocytosis)

Early symptoms: abnormal bleeding, acute onset of fever,symptoms of anemia

Laboratory monitoring probably not helpful in early

detection

Patient education

L T AdLong Term Adverse


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Long-Term AdverseLong-Term Adverse


Neurologic:

Neuropathy

Cerebellar syndrome

Endocrine/Metabolic Effects Vitamin D Osteomalacia, osteoporosis

Folate Anemia, teratogenesis

Altered connective tissue metabolism or growth

Facial coarsening

Hirsutism

Gingival hyperplasia

h l idPh l R id


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Pharmacology ResidentPharmacology Resident

Case StudiesCase Studies

American Epilepsy Society

Medical Education Program

Ph l R idPh l R id


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Pharmacology ResidentPharmacology Resident

Case StudiesCase Studies

Tommy is a 4 year old child with a history of

intractable seizures and developmental delay

since birth.

He has been tried on several anticonvulsantregimens (i.e., carbamazepine, valproic acid,

ethosuximide, phenytoin, and phenobarbital)

without significant benefit.


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Case #1 Pediatric ContCase #1 Pediatric Cont

Tommys seizures are characterized as tonic

seizures and atypical absence seizures and

has been diagnosed with a type of childhood

epilepsy known as Lennox-Gastaut Syndrome.


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1. Briefly describe what characteristics are

associated with Lennox-Gastaut Syndrome.

2. What anticonvulsants are currently FDA

approved for Lennox-Gastaut Syndrome?


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3. Tommy is currently being treated with

ethosuximide 250 mg BID and valproic acid

250 mg BID. The neurologist wants to add

another anticonvulsant onto Tommys currentregimen and asks you for your

recommendations. (Hint: Evaluate current

anticonvulsants based on positive clinical

benefit in combination therapy and adverseeffect profile.)


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4. Based on your recommendations above, what

patient education points would you want to

emphasize?

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