Neuropharmacology of

Antiepileptic Drugs
American Epilepsy Society

P-Slide 1
Definitions

 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

P-Slide 2
Antiepileptic 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

P-Slide 3
History of Antiepileptic
Drug Therapy in the U.S.
 1857 - Bromides

 1912 - Phenobarbital

 1937 - Phenytoin

 1954 - Primidone

 1960 - Ethosuximide

P-Slide 4
History of Antiepileptic
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
P-Slide 5
Antiepileptic Drug Therapy
Structures of Commonly Used AEDs

Chemical formulas of commonly used old and new

antiepileptic drugs
P-Slide 6
Adapted from Rogawski and Porter, 1993, and Engel, 1989
Antiepileptic Drug Therapy
Structures of Commonly Used AEDs

P-Slide 7
Antiepileptic Drug Therapy
Structures of Commonly Used AEDs

Levetiracetam

Oxcarbazepine

Zonisamide

P-Slide 8
Antiepileptic Drug Therapy
Structures of Commonly Used AEDs

■ Pregabalin

P-Slide 9
Cellular Mechanisms of
Seizure Generation

 Excitation (too much)

• Ionic-inward Na+, Ca++ currents
• Neurotransmitter: glutamate, aspartate

 Inhibition (too little)

• Ionic-inward CI-, outward K+ currents
• Neurotransmitter: GABA

P-Slide 10
AEDs: Molecular and
Cellular 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

P-Slide 11
AEDs: Molecular and
Cellular Mechanisms
 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

P-Slide 12
AEDs: Molecular and
Cellular Mechanisms

 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

P-Slide 13
AEDs: Molecular and
Cellular Mechanisms

 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

P-Slide 14
AEDs: Molecular and
Cellular Mechanisms

 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 P-Slide 15
AEDs: Molecular and
Cellular Mechanisms

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

P-Slide 16
 The GABA System

The GABA
system and its
associated
chloride channel

From Engel, 1989 P-Slide 17

Pharmacokinetic 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)

P-Slide 18
The Cytochrome P-450
Enzyme System
Inducers Inhibitors
phenobarbital erythromycin
primidone nifedipine/verapamil
phenytoin trimethoprim/sulfa
carbamazepine propoxyphene
tobacco/cigarettes cimetidine
valproate
P-Slide 19
The Cytochrome P-450
Enzyme System

 Substrates (metabolism enhanced by inducers):

steroid hormones
theophylline
tricyclic antidepressants
vitamins
warfarin
(many more)

P-Slide 20
The Cytochrome P-450
Isozyme 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

P-Slide 21
Drug Metabolizing Enzymes:
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)

P-Slide 22
Drug Metabolizing
Isozymes 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

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

P-Slide 23
Enzyme Inducers/Inhibitors:
General Considerations

 Inducers: Increase clearance and decrease

steady-state concentrations of other substrates

 Inhibitors: Decrease clearance and increase

steady-state concentrations of other substrates

P-Slide 24
Pharmacokinetic 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

P-Slide 25
AED Inducers: General
Considerations
 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

P-Slide 26
Inhibition

 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

P-Slide 27
AED 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

P-Slide 28
Hepatic Drug Metabolizing
Enzymes and Specific AED
Interactions

 Phenytoin CYP2C9 CYP2C19

− Inhibitors: valproate, ticlopidine, fluoxetine,
topiramate, fluconazole

 Carbamazepine CYP3A4 CYP2C8 CYP1A2

− Inhibitors: ketoconazole, fluconazole, erythromycin,
diltiazem

 Lamotrigine UGT 1A4

− Inhibitor: valproate

P-Slide 29
Isozyme Specific Drug
Interactions
Category CYP3A4 CYP2C9 CYP2C19 UGT

Inhibitor Erythromycin VPA Ticlopidine VPA

Clarithromycin Fluconazole Felbamate
Diltiazem metronidazole OXC/MHD
Fluconazole Sertraline Omeprazole
Itraconazole Paroxetine
Ketoconazole Trimethoprim/
Cimetidine sulfa
propoxyphene
Grapefruit
juice

Inducer CBZ CBZ CBZ CBZ

PHT PHT PHT PHT
PB PB PB PB
felbamate Rifampin rifampin OXC/MHD
Rifampin LTG (?)
TPM
OXC/MHD

P-Slide 30
Therapeutic Index

 T.I. = ED 5O% /TD 50%

 “Therapeutic range” of AED serum

concentrations

• Limited data

• Broad generalization

• Individual differences
P-Slide 31
Steady State and Half Life

From Engel, 1989

P-Slide 32
AED 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.

P-Slide 33
AED 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”.

P-Slide 34
Potential Target Range of AED
Serum Concentrations

AED Serum Concentration

(mg/l)
Carbamazepine 4-12
Ethosuximide 40-100
Phenobarbital 10-40
Phenytoin 10-20
Valproic acid 50-100

P-Slide 35
Potential Target Range of AED
Serum 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

P-Slide 36
AEDs 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:
Gabapentin
Lamotrigine
Pregabalin
Tiagabine
Levetiracetam
Zonisamide

P-Slide 37
Pharmacodynamic Interactions

 Wanted and unwanted effects on target organ

• Efficacy — seizure control

• Toxicity — adverse effects

(dizziness, ataxia, nausea, etc.)

P-Slide 38
Pharmacokinetic Interactions:
Possible 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

P-Slide 39
Pharmacokinetic Factors
in 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
P-Slide 40
Pharmacokinetic Factors
in Pediatrics

 Neonate—often lower per kg doses

• Low protein binding
• Low metabolic rate

 Children—higher, more frequent doses

• Faster metabolism

P-Slide 41
Pharmacokinetics 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

P-Slide 42
Adverse Effects

 Acute dose-related—reversible

 Idiosyncratic—
• uncommon rare
• potentially serious or life threatening

 Chronic—reversibility and seriousness vary

P-Slide 43
Acute, Dose-Related Adverse
Effects 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

P-Slide 44
Acute, Dose-Related Adverse
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

P-Slide 45
Idiosyncratic Adverse
Effects 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

P-Slide 46
Idiosyncratic Adverse
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

P-Slide 47
Long-Term Adverse
Effects 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
P-Slide 48
Pharmacology Resident
Case Studies

American Epilepsy Society

Medical Education Program

P-Slide 49
Pharmacology Resident
Case 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.

P-Slide 50
Case #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.

P-Slide 51
Case #1 – Pediatric Con’t

1. Briefly describe what characteristics are

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

P-Slide 52
Case #1 – Pediatric Con’t

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.)

P-Slide 53
Case #1 – Pediatric Con’t

4. Based on your recommendations above, what

patient education points would you want to
emphasize?

P-Slide 54