Antiepileptic Drugs (AEDs)

Goals of Treatment

Mechanisms of Action

• Adams and Victor's Principles of Neurology, 12th Ed., Fig. 15-4; Bradley and Daroff's Neurology

Classification by Generation

First-Generation (Traditional) AEDs

Second-Generation AEDs

Third-Generation (Newer) AEDs

Pharmacology of Key Individual Drugs

1. Phenytoin (Dilantin)

• Mechanism: Voltage-gated Na+ channel blocker; inhibits abnormal repetitive neuronal firing
• Dose (adult): 300-400 mg/day | Serum level: 10-20 µg/mL | Half-life: 12-36 h
• Use: Focal seizures, generalized tonic-clonic (GTC) seizures; IV form for status epilepticus
• Key side effects: Nystagmus, ataxia, diplopia at toxic levels; gingival hyperplasia, hirsutism, coarsening of facial features (long-term); peripheral neuropathy; non-linear (zero-order) kinetics - small dose increases cause disproportionate level rises above 10 µg/mL
• Serious: Blood dyscrasias, hepatotoxicity, Stevens-Johnson syndrome (rare), teratogenicity (fetal hydantoin syndrome)
• Interactions: Warfarin (unpredictable INR changes), oral contraceptives (failure), CYP enzyme inducer

2. Carbamazepine (Tegretol)

• Mechanism: Na+ channel blocker (similar to phenytoin)
• Dose (adult): 600-1,200 mg/day | Serum level: 4-12 µg/mL | Half-life: 14-25 h
• Use: Focal seizures, GTC; also trigeminal neuralgia, bipolar disorder (mood stabilizer)
• Key side effects: Leukopenia (mild, common), diplopia, dizziness, ataxia; hyponatremia (SIADH); hepatotoxicity; pancytopenia (rare)
• Serious: Stevens-Johnson syndrome - HLA-B*1502 screening required in Asian patients; toxic epidermal necrolysis
• Important: Autoinduction - induces its own metabolism, so doses adequate initially become inadequate after weeks; induces CYP3A4 (reduces OCP, warfarin levels)

3. Valproate / Valproic Acid (Depakote)

• Mechanism: GABAergic (enhances GABA synthesis via glutamic acid decarboxylase), Na+ channel blockade, T-type Ca2+ channel blockade
• Dose (adult): 1,000-3,000 mg/day | Serum level: 50-100 µg/mL | Half-life: 6-15 h (shorter - split dosing)
• Use: Broad spectrum - GTC, absence, myoclonic, focal seizures; drug of choice for juvenile myoclonic epilepsy; mood stabilizer (bipolar); migraine prophylaxis
• Key side effects: Weight gain, tremor, hair loss (reversible), nausea/GI upset, hepatotoxicity (potentially fatal in children < 2 years), pancreatitis
• Serious - Teratogenicity: Major risk of neural tube defects (spina bifida, ~1-2%); cognitive impairment in offspring; contraindicated in pregnancy if alternatives exist; menstrual irregularities, polycystic ovarian syndrome
• Inhibits CYP enzymes - elevates levels of phenytoin, lamotrigine, phenobarbital; avoid in women of childbearing age when possible

4. Phenobarbital (Luminal)

• Mechanism: Enhances GABA-A receptor activity (prolongs Cl- channel opening); also inhibits Na+ currents
• Dose (adult): 90-200 mg/day | Serum level: 15-40 µg/mL | Half-life: 40-120 h (longest - once daily dosing)
• Use: GTC, focal, neonatal seizures; status epilepticus (IV)
• Key side effects: Sedation and cognitive dulling (major limiting factor); nystagmus; behavioral problems in children; Dupuytren contractures, frozen shoulder (chronic use); osteoporosis
• Strong CYP inducer - interacts extensively with warfarin, OCP, other AEDs; teratogenic (~5.5% major malformation rate)

5. Lamotrigine (Lamictal)

• Mechanism: Blocks slow voltage-gated Na+ channels - reduces release of excitatory transmitters (glutamate, aspartate)
• Dose (adult): 300-500 mg/day | Serum level: 2-7 µg/mL | Half-life: 15-60 h
• Use: Broad spectrum - focal, GTC, absence; preferred in women (no weight gain, no ovarian/hormonal issues, better teratogenic profile); mood stabilizer in bipolar
• Key side effects: Rash in ~12% (potentially severe); titrate slowly to minimize; Stevens-Johnson syndrome in ~1%
• Interaction: Valproate doubles lamotrigine levels (requires dose halving); enzyme-inducers reduce lamotrigine levels
• Psychiatric: Antidepressant and mood-stabilizing properties; rarely anxiogenic

6. Levetiracetam (Keppra)

• Mechanism: Binds synaptic vesicle protein SV2A - modulates vesicle release; precise anticonvulsant mechanism still under investigation
• Dose (adult): 500-3,000 mg/day | Half-life: 6-8 h | Renally excreted - dose reduce in renal failure
• Use: Focal and generalized seizures; widely used as first-line due to minimal drug interactions; safe in patients on chemotherapy, anticoagulants, complex polypharmacy
• Key side effects: Somnolence, dizziness; irritability, depression, behavioral changes, suicidality - significant psychiatric concern
• Major advantage: No significant hepatic metabolism, no CYP interactions; favorable in liver disease and complex polypharmacy

7. Ethosuximide (Zarontin)

• Mechanism: Blocks T-type Ca2+ channels in thalamic neurons
• Use: Drug of choice for childhood absence epilepsy (petit mal); NOT effective for other seizure types
• Half-life: Long (~40-60 h) - once daily dosing
• Side effects: GI upset, behavioral disturbance, depression, rarely psychosis

8. Gabapentin (Neurontin) & Pregabalin (Lyrica)

• Mechanism: Bind alpha-2-delta subunit of voltage-gated Ca2+ channels - reduce calcium-mediated neurotransmitter release; structurally GABA analogs but do NOT act on GABA receptors
• Use: Adjunctive therapy for focal seizures; also neuropathic pain, fibromyalgia, anxiety (pregabalin)
• Advantages: Not metabolized hepatically; few drug interactions; renally excreted (adjust in renal failure)
• Side effects: Sedation, weight gain, peripheral edema, dizziness; withdrawal anxiety/depression on cessation

9. Topiramate (Topamax)

• Mechanism: Multiple - Na+ channel blockade, GABA-A enhancement, AMPA/kainate receptor blockade, carbonic anhydrase inhibition
• Use: Focal and generalized seizures; migraine prophylaxis; weight loss (Qsymia)
• Side effects: Cognitive slowing ("dopamax"), word-finding difficulties, kidney stones (carbonic anhydrase inhibition), weight loss, metabolic acidosis
• Psychiatric: Anxiety, depression, psychosis (rare)

10. Oxcarbazepine (Trileptal)

• Mechanism: Na+ channel blockade (carbamazepine analogue - acts via active metabolite monohydroxy derivative, MHD)
• Use: Focal seizures; better tolerated than carbamazepine
• Advantages over carbamazepine: Less marrow toxicity, no autoinduction, fewer drug interactions
• Side effects: Hyponatremia (more common than carbamazepine, ~3%); rash; dizziness

Drug of Choice by Seizure Type

• Goldman-Cecil Medicine; Adams and Victor's Neurology

Pharmacokinetics Summary

• Adams and Victor's Principles of Neurology, Table 15-6

Drug Interactions (Key Points)

• Phenytoin, carbamazepine, phenobarbital, primidone, rufinamide

• Valproate - inhibits CYP2C9, displaces protein-bound drugs; raises phenytoin, lamotrigine, phenobarbital levels

• Levetiracetam, gabapentin, pregabalin - dose reduce in renal failure

• Valproate + lamotrigine: doubles lamotrigine levels → rash risk; halve lamotrigine dose
• Valproate + carbamazepine: carbamazepine epoxide builds up via epoxide hydrolase inhibition → toxicity
• Phenytoin/carbamazepine + oral contraceptives: OCP failure - adjust estradiol dose
• Fluoxetine/fluvoxamine + phenytoin or carbamazepine: raises AED levels (CYP inhibition)
• Adams and Victor's, p. 361; Maudsley Prescribing Guidelines, 15th Ed.

Special Populations

Pregnancy

• All AEDs are potentially teratogenic - folic acid supplementation and vitamin K before delivery are essential
• Valproate carries the highest teratogenic risk (neural tube defects, reduced IQ in offspring) - avoid if possible; switch to levetiracetam for juvenile myoclonic epilepsy before conception
• Lamotrigine has a more favorable teratogenic profile than most others
• Enzyme-inducing AEDs accelerate vitamin K metabolism - give to mother and newborn to prevent neonatal hemorrhage

Women of Childbearing Age

• Avoid valproate when alternatives exist
• Enzyme inducers reduce OCP efficacy
• Lamotrigine or levetiracetam are preferred first-line choices

Elderly

• Prefer drugs with fewer interactions: gabapentin, levetiracetam, brivaracetam, lacosamide
• Avoid enzyme inducers (carbamazepine, phenytoin, phenobarbital) due to complex polypharmacy

Renal Failure

• Reduce dose of renally excreted AEDs: levetiracetam, gabapentin, pregabalin

Liver Failure

• Monitor levels more closely; prefer renally excreted drugs

Psychiatric Side Effects

• Maudsley Prescribing Guidelines, 15th Ed., Table 10.4

Skin Reactions (Rashes)

• Aromatic AEDs (phenytoin, carbamazepine, phenobarbital, primidone, lamotrigine) have the highest rash risk with significant cross-reactivity
• Typical rash: maculopapular, trunk-predominant, within the first month
• Severe reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis - most common with lamotrigine (especially if escalated too fast) and carbamazepine
• HLA-B*1502: Screen Asian patients before starting carbamazepine (risk of SJS/TEN)
• HLA-A*3101: Associated with skin eruptions in Caucasians on carbamazepine
• If replacing an aromatic drug: use valproate, gabapentin, topiramate, or levetiracetam as substitutes

Discontinuation of AEDs

• Consider after 2 years of seizure freedom; taper slowly
• ~40% relapse risk at 2.5 years, ~50% at 5 years after stopping (vs ~20% on continued therapy)
• Obtain EEG before withdrawal - paroxysmal activity favors continuing treatment
• Juvenile myoclonic epilepsy: Lifelong therapy usually recommended
• Relapse risk is higher in focal seizures vs. absence/generalized-onset

Bone Health

• Adams and Victor's Principles of Neurology, 12th Ed., Ch. 15 (Antiepileptic Drugs - General Principles, Specific Drugs, Tables 15-5 & 15-6)
• Goldman-Cecil Medicine International Edition, Ch. 372 (Table 372-7)
• Maudsley Prescribing Guidelines in Psychiatry, 15th Ed., Table 10.4
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry