P-Slide 1 Neuropharmacology of Antiepileptic Drugs American Epilepsy Society

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Neuropharmacology of Neuropharmacology 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 cortical neurons

Epilepsy: a tendency toward recurrent seizures unprovoked by acute systemic or 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

Goal—maximize quality of life by minimizing seizures and adverse drug effects

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History of Antiepileptic History of Antiepileptic Drug 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 Antiepileptic History of Antiepileptic Drug 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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Pregabalin

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Cellular Mechanisms of Cellular Mechanisms of Seizure GenerationSeizure Generation

Excitation (too much)

• Ionic-inward Na+, Ca++ currents

• Neurotransmitter: glutamate, aspartate

Inhibition (too little)

• Ionic-inward CI-, outward K+ currents

• Neurotransmitter: GABA


AEDs: Molecular and AEDs: 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



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



Ethosuximide• Blocks low threshold, “transient” (T-type) calcium channels

in thalamic neurons

Valproate• May enhance GABA transmission in specific circuits

• Blocks voltage-dependent sodium channels

Vigabatrin• Irreversibly inhibits GABA-transaminase



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



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



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


The GABA SystemThe GABA System

The GABA system and its associated chloride channel

From Engel, 1989


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)


The Cytochrome P-450 The Cytochrome P-450 Enzyme SystemEnzyme System

Inducers Inhibitors

phenobarbital erythromycin

primidone nifedipine/verapamil

phenytoin trimethoprim/sulfa

carbamazepine propoxyphene

tobacco/cigarettes cimetidine

valproate


The Cytochrome P-450 The Cytochrome P-450 Enzyme SystemEnzyme System

Substrates (metabolism enhanced by inducers):

steroid hormones

theophylline

tricyclic antidepressants

vitamins

warfarin

(many more)


The Cytochrome P-450 The Cytochrome P-450 Isozyme SystemIsozyme System

The enzymes most involved with drug metabolism

Nomenclature based upon homology of amino acid sequences

Enzymes have broad substrate specificity, and individual drugs may be substrates for several enzymes

The principle enzymes involved with AED metabolism include CYP2C9, CYP2C19, CYP3A4


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)


Drug Metabolizing Drug 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 CYP AEDs 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.


Enzyme Inducers/Inhibitors: Enzyme Inducers/Inhibitors: General ConsiderationsGeneral Considerations

Inducers: Increase clearance and decrease steady-state concentrations of other substrates

Inhibitors: Decrease clearance and increase steady-state concentrations of other substrates


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


AED Inducers: General AED 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


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 and major pathways of AED metabolism


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


Hepatic Drug Metabolizing Hepatic Drug Metabolizing Enzymes and Specific AED Enzymes 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


Isozyme Specific Drug Isozyme Specific Drug InteractionsInteractionsCategory CYP3A4 CYP2C9 CYP2C19 UGT

Inhibitor ErythromycinClarithromycinDiltiazemFluconazoleItraconazoleKetoconazoleCimetidinepropoxypheneGrapefruitjuice

VPAFluconazolemetronidazoleSertralineParoxetineTrimethoprim/sulfa

TiclopidineFelbamateOXC/MHDOmeprazole

VPA

Inducer CBZPHTPBfelbamateRifampinTPMOXC/MHD

CBZPHTPBRifampin

CBZPHTPBrifampin

CBZPHTPBOXC/MHDLTG (?)


Therapeutic IndexTherapeutic Index

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

“Therapeutic range” of AED serum concentrations

• Limited data

• Broad generalization

• Individual differences


Steady State and Half LifeSteady State and Half Life

From Engel, 1989


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 when optimizing AED therapy, assessing compliance, or teasing out drug-drug interactions.

They should be used to monitor pharmacodynamic and pharmacokinetic interactions.


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”.


Potential Target Range of AED Potential 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


Potential Target Range of AED Potential Target Range of AED Serum ConcentrationsSerum Concentrations

AED Serum Concentration

(mg/l)

Gabapentin 6-21

Lamotrigine 5-18

Levetiracetam 10-40

Oxcarbazepine 12-24 (MHD)

Pregabalin ??

Tiagabine ?

Topiramate 4.0-25

Zonisamide 7-40


AEDs and Drug InteractionsAEDs and Drug Interactions

Although many AEDs can cause pharmacokinetic interactions, several agents appear to be less problematic.

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

GabapentinLamotriginePregabalinTiagabineLevetiracetamZonisamide


Pharmacodynamic InteractionsPharmacodynamic Interactions

Wanted and unwanted effects on target organ

• Efficacy — seizure control

• Toxicity — adverse effects (dizziness, ataxia, nausea, etc.)


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


Pharmacokinetic Factors Pharmacokinetic Factors in the Elderlyin the Elderly

Absorption — little change

Distribution

• decrease in lean body mass important for highly lipid-soluble drugs

• fall in albumin leading to higher free fraction

Metabolism — decreased hepatic enzyme content and blood flow

Excretion — decreased renal clearance


Pharmacokinetic Factors Pharmacokinetic Factors in Pediatricsin Pediatrics

Neonate—often lower per kg doses

• Low protein binding

• Low metabolic rate

Children—higher, more frequent doses

• Faster metabolism


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


Adverse EffectsAdverse Effects

Acute dose-related—reversible

Idiosyncratic—• uncommon rare

• potentially serious or life threatening

Chronic—reversibility and seriousness vary


Acute, Dose-Related Adverse Acute, 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


Acute, Dose-Related Adverse Acute, 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


Idiosyncratic Adverse Idiosyncratic Adverse Effects of AEDsEffects of AEDs

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


Idiosyncratic Adverse Idiosyncratic Adverse Effects of AEDs Effects of AEDs

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


Long-Term Adverse Long-Term Adverse Effects of AEDsEffects of AEDs

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


Pharmacology ResidentPharmacology ResidentCase StudiesCase Studies

American Epilepsy Society

Medical Education Program


Pharmacology ResidentPharmacology ResidentCase 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 anticonvulsant regimens (i.e., carbamazepine, valproic acid, ethosuximide, phenytoin, and phenobarbital) without significant benefit.


Case #1 – Pediatric Con’tCase #1 – Pediatric Con’t

Tommy’s 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.



1. Briefly describe what characteristics are associated with Lennox-Gastaut Syndrome.

2. What anticonvulsants are currently FDA approved for Lennox-Gastaut Syndrome?



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 Tommy’s current regimen and asks you for your recommendations. (Hint: Evaluate current anticonvulsants based on positive clinical benefit in combination therapy and adverse effect profile.)



4. Based on your recommendations above, what patient education points would you want to emphasize?

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P-Slide 1 Neuropharmacology of Antiepileptic Drugs American Epilepsy Society