AEDs: Pharmacology and

Interactions

RITE Exam Review 2007

Tiffini Voss, M.D.

AED Treatment Options:Narrow Spectrum

Partial Seizures (SPS, CPS, 2ndary GTC)

phenytoin
carbemazepine
phenobarbital
leviteracetam
oxcarbazepine
gabapentin

Absence Seizures

ethosuximide

Infantile Spasms
ACTH
vigabatrin
topiramate

AED Treatment Options: Broad Spectrum

Can be used for prior seizure types, and primary
therapies for the following seizure types: tonic, tonicclonic, atonic, myoclonic

valproate
lamotrigine
topiramate
zonisamide
benzodiazepines

Also effective but limited use due to side effects

felbamate

Phenobarbital (Luminal)
Pharmacology

Binds GABA R and prolongs Cl channel open duration

Protein binding: 50-60%
Metabolism: 75% hepatic, enzyme inducer

Adverse Effects

Idiosyncratic

Skin rash, hepatitis, bone marrow depression

SLE-like reaction
Dose-related
Sedation, slowing in intellectual processes, fatigue
Paradoxical hyperactive behavior in children
Depression
Fetal depletion of vitamin K
Osteopenia
Megaloblastic anemia from folate depletion

Primidone (Mysoline)
Pharmacology

Protein binding: 19% (primidone and PEMA)

Metabolism: hepatic to PEMA and phenobarbital
Drug interactions: same as PB

Adverse Effects

Similar to PB
Idiosyncratic

Rash, hepatitis
Acute initial toxicity
Drowsiness, dizziness, ataxia, nausea, vomiting
Dose-related
sedation, nystagmus, ataxia, vertigo
impotence, decreased libido
crystalluria

Tiagabine (Gabitril)
Pharmacology
Inhibits GABA reuptake
Protein binding: 95%
Metabolism: hepatic, nearly 100%, no induction

Adverse Effects
Neuropsychiatric: dizziness, fatigue, somnolence, nervousness,

tremor, headache, abnormal thinking (trouble concentrating, mental

lethargy, or slowing of thought)
Weight gain
Depression
Diarrhea, abdominal pain
Can induce spike-wake stupor/absence status in partial epilepsies

Vigabatrin
Pharmacology

irreversible inhibitor of GABA transaminase

Renal excretion

Adverse Effects

visual field defects: circumferential constriction with nasal sparing

(as a result unavailable in US); thought to be due to selective

vulnerability of cells of the inner retina that use GABA as a
neurotransmitter

Notes

Useful in infantile spasms (esp. in Tuberous sclerosis)

Phenytoin (Dilantin)
Pharmacology

Inhibits voltage-gated Na+ channels (binds to inactive form)

Protein binding: 90%
Metabolism: hepatic, P450 (>95%) to inactive metabolites
Zero-order pharmacokinetics
Drug interactions: many; potent enzyme inducer
Adverse Effects
Idiosyncratic
Rash (8-10%), Stevens-Johnson syndrome or TEN
Allergic hepatitis
Dose-related
nystagmus (20); ataxia, dysarthria, diplopia, nausea,
incoordination (30); extra-pyramidal, autonomic dysfunction
(30-40); lethargy, increased seizures (40); stupor, coma (>40)
Nausea, vomiting, constipation
Movement disorders
Cerebellar atrophy (rare)

Phenytoin (Dilantin)
Adverse Effects (cont)
Peripheral neuropathy
Gingival hyperplasia (20% adults, higher children)
Hirsutism, coarsening of facial features (5-10%)
Immunosuppression (5-10%): reduced IgA
Metabolic bone disease: osteomalacia, osteoporosis
Megaloblastic anemia (0.15-0.75%): folate deficiency
Aplastic anemia, leukopenia, thrombocytopenia, erythroid
hyperplasia, pancytopenia
Cardiac arrhythmias (rare)
Lupus-like syndrome (rare)

Carbamazepine (Tegretol)
Pharmacology

Inhibits voltage-gated Na+ channels (binds to inactive form)

Protein binding: 75%
Metabolism: 98% hepatic, P450 enzymes (CYP 3A4)
Major active metabolite: CBZ-10,11-epoxide
Drug interactions: many, strong enzyme inducer

Adverse Effects

Idiosyncratic
Skin rashes (10-15%), Stevens-Johnson
Aplastic anemia (1/200,000) or agranulocytosis
Granulomatous hepatitis, cholangitis
Dose-related
CNS: dysequilibrium, drowsiness, nystagmus, dizziness, headache,
irritability, hyperactivity, impaired attention, memory
Anorexia, nausea, vomiting, Gl discomfort
Leukopenia, thrombocytopenia
Hyponatremia
Osteomalacia

Notes

Worsens atonic, absence seizures

Oxcarbazepine (Trileptal)
Pharmacology
Inhibits voltage-gated Na+ channels (binds to inactive form)

Protein binding: 38% of active metabolite

Metabolism: hepatic; less pronounced induction of P450
Drug interactions much less problematic than with CBZ

Adverse Effects
Idiosyncratic

Allergic skin rashes less frequent than CBZ (10%)

Crossover rash from CBZ in 27%; first 4 wks
Dose-related
fatigue, headache, dizziness, ataxia: less frequent and
severe than with CBZ
Hyponatremia

Valproate (Depakote/Depakene)
Pharmacology

Acts on both Na+ and Ca+ channels

Protein binding: 90%
Metabolism: >95% hepatic
Marked fluctuations in plasma levels (10-fold)
Drug interactions: many, P450 inhibitor

Adverse Effects

Idiosyncratic

Hepatotoxicity: overall fatal 1:10,000

Under age 2, polytherapy, neurological abnl (1/500)
Under age 2, monoRx, nl (1/7000)
May be able to prevent with carnitine
Rash: uncommon, less than 1%
Thrombocytopenia
Acute hemorrhagic pancreatitis

Valproate (Depakote/Depakene)
Adverse Effects (cont)
Dose-related
Mental dulling, sedation: polytherapy, levels 100mcg/ml
Anorexia, nausea, vomiting, Gl distress, rare diarrhea
Weight gain
Hair loss
Tremor
Hyperammonemia / encephalopathy
Hepatic dysfunction
Thrombocytopenia, platelet defects, fibrinogen depletion, and
coagulopathy
Polycystic ovarian disease, menstrual irregularities
Teratogenicity

Notes
Drug of choice for childhood absence, JME
Useful in Lennox-Gastaut
Useful in bipolar disorder

Lamotrigine (Lamictal)
Pharmacology

Inhibits voltage-gated Na+ channels (binds to inactive form)

Protein binding: 55%
Metabolism: 90% hepatic; little induction
Drug interactions: moderate

Adverse Effects
Rash in 10-12%

Increased with rapid titration, high initial dose, VPA

SJ/TEN: 1:1000 adults, 1:50-100 children
Dose-related
Blurred vision, ataxia, diplopia, dizziness, somnolence
Headache, nausea, vomiting

Notes
Useful in Lennox-Gastaut, absence

Zonisamide (Zonegran)
Pharmacology

Inhibits voltage-gated Na+ channels, Ca+ channels

Little protein binding
Metabolism: 65% hepatic, acetylation and reduction
Few drug interactions: EI-AEDs decrease serum level of zonisamide

Adverse Effects

Idiosyncratic

Hypersensitivity to sulfa drugs

Rare hematologic effects
Renal stones (1.2%)
Impairment of renal function
Dose-related
Somnolence
Dizziness
Anorexia, nausea
Headache
Agitation, irritability
Impaired concentration, memory

Ethosuximide (Zarontin)
Pharmacology
Inhibits T-type Ca+ channels, modulating thalamic circuits
Protein binding: none
Metabolism: 80% hepatic, P450

Adverse Effects
Idiosyncratic

Skin rash (erythema multiforme, Stevens-Johnson

syndrome)
Rare blood dyscrasias
Hepatic failure
Dose-related
Drowsiness, dizziness, fatigue, headache
Irritability, hyperactivity, depression, sleep disturbance,
psychosis, hallucinations, cognitive impairment
Gl: abdominal discomfort, nausea, vomiting, anorexia,
weight loss, diarrhea

Gabapentin (Neurontin)
Pharmacology

GABA analogue but acts on Ca+ channels, indirect GABA+

Protein binding: none
Metabolism: none; does not induce hepatic enzymes
Renal excretion, in proportion to creatinine clearance
Drug interactions: none

Adverse Effects

Headache, nausea, ataxia, somnolence, dizziness

Aggression, hyperactivity, tantrums in MR
3% incontinence in spastic patients
Increase myoclonic and absence seizures
Movement disorders
Weight gain (10%)
Ankle edema

Levetiracetam (Keppra)
Pharmacology
Mechanism unknown (K channel inhibition, synaptic vesicles)
Protein binding: <10%
Metabolism: ~25% by enzymatic hydrolysis of acetamide group,

not P450-dependent
minimal drug interactions

Adverse Effects
Somnolence and fatigue: not dose-related
Coordination difficulties: dizziness, ataxia, abnormal gait,
Behavioral abnormalities: agitation, hostility, anxiety, apathy,

emotional lability, depersonalization, depression

psychosis

Topiramate (Topamax)
Pharmacology

Multiple mechanisms (Na, Ca, GABA, kainate)

Metabolism: 70% unchanged in urine
Drug interactions: few

Adverse Effects

Dose-related

Notes

Psychomotor slowing, somnolence, nystagmus, tremor,

nervousness, headache, diplopia,
Children: similar, behavioral adverse effects
Renal stones: 1.5% (do not use with KTG, Diamox)
Anorexia, weight loss
Paresthesias
Metabolic acidosis
Hypohidrosis, which can lead to hyperthermia

Effective in JME, Lennox-Gastaut

Felbamate (Felbatol)
Pharmacology

Multiple mechanisms (Na, Ca, GABA, NMDA)

Protein binding: 25%
Metabolism: hepatic (~50%) P450 system

Adverse Effects

Notes

FATAL APLASTIC ANEMIA 1:2000-5000

FATAL ALLERGIC HEPATOTOXICITY 1:5000-10,000
Rash, hypersensitivity reactions in 3-4%
Dose-related
Insomnia, headache, dizziness, blurred vision
Gl: weight loss, anorexia, nausea, vomiting,
Stimulant-like effects at clinical doses
Anxiety, dysphoria
Tremor, involuntary movements

Used in Lennox-Gastaut

AEDs and Women

General points

All older AEDs have been associated with neural tube defects;

therefore recommend at least 1mg folate supplementation in all

women of childbearing age; t/c 2-4mg if considering pregnancy

Enzyme-inducing AEDs (dilantin, CBZ, OXC, topiramate) are

associated with fetal Vitamin K deficiency; supplement with Vitamin

K in third trimester and infants should receive Vitamin K at birth

Enzyme-inducing AEDs asociated with bone marrow suppression,

with strongest evidence for dilantin and weakest for OXC

Enzyme-inducing AEDs metabolize OCPs; Depo, Norplant, and

mini-pill preparations are rendered LESS effective: need estrogencontaining OCP or alternative method

VPA, CBZ, and epilepsy associated with PCOS

Interactions
Inducers: CBZ, dilantin, PB, primidone

Decrease effectiveness of OCPs

Decrease levels of: VPA, OXC, LTM, tiagabine, topiramate, ZNG
Decrease levels of: each other

Inhibitors: VPA, felbamate

Increase levels of: dilantin, LTM, PB

VPA displaces dilantin from protein binding leading to acute rise in

free dilantin levels, can precipitate acute dilantin toxicity

Topiramate: decreases effectiveness of OCPs

CBZ

levels can be increased by: INH, erythromycin, cimetidine, Ca

channel blockers
VPA inhibits metabolism of toxic epoxide metabolite, increasing
toxicity

Dilantin: levels increased by topiramate, CBZ

LTM: levels decreased by OCPs, pregnancy