Neurology / CNS · Medicine Class

Antiepileptic Drugs (AEDs / Anticonvulsants)

Sodium channel blockade, GABA enhancement, glutamate antagonism, calcium channel modulation, or synaptic vesicle protein binding

Mechanism of Action

Antiepileptic drugs reduce neuronal excitability through multiple mechanisms. Sodium channel blockers (phenytoin, carbamazepine, lamotrigine, oxcarbazepine) stabilize the inactive state of voltage-gated sodium channels, reducing the frequency of action potential firing — most effective for focal seizures. GABA enhancers (benzodiazepines, barbiturates, vigabatrin, tiagabine) increase inhibitory GABA neurotransmission. Calcium channel modulators (ethosuximide, gabapentin, pregabalin) reduce T-type or alpha-2-delta calcium currents involved in thalamic oscillations (absence seizures) or pain signaling. Valproate has multiple mechanisms. Levetiracetam binds SV2A synaptic vesicle protein, uniquely modulating neurotransmitter release. Newer agents (perampanel, cenobamate) introduce AMPA receptor antagonism and sodium channel enhancement.

Therapeutic Indications

Epilepsy — focal (partial) onset seizures, generalized onset seizures, absence seizures
Neuropathic pain — gabapentin, pregabalin for diabetic neuropathy, postherpetic neuralgia
Bipolar disorder — valproate, lamotrigine as mood stabilizers
Migraine prevention — valproate, topiramate, zonisamide
Status epilepticus — IV benzodiazepines, phenytoin/fosphenytoin, levetiracetam
Alcohol withdrawal seizure prophylaxis — benzodiazepines
Fibromyalgia — pregabalin
Trigeminal neuralgia — carbamazepine (first-line by guideline)

Medicines in This Class

Levetiracetam (Keppra)

Broadest use AED. SV2A mechanism. Minimal drug interactions. Available IV. Behavioral side effects (irritability, aggression — 'Keppra rage') in some. Safe in pregnancy relative to older AEDs.

Lamotrigine (Lamictal)

Sodium channel blocker. Broad spectrum — focal and generalized seizures. Preferred for bipolar depression maintenance. Slow titration required to reduce serious skin reaction (SJS) risk. Lower teratogenic risk.

Valproate / Valproic Acid (Depakote)

Most effective broad-spectrum AED for generalized epilepsy. Multiple mechanisms. Highly teratogenic — contraindicated in pregnancy (neural tube defects 1-2%, fetal valproate syndrome). Weight gain, polycystic ovary syndrome, hepatotoxicity.

Carbamazepine (Tegretol)

Gold standard for focal seizures and trigeminal neuralgia. CYP3A4 autoinducer — interactions. HLA-B*1502 testing required before use in Asian patients (SJS risk). Black box: aplastic anemia, SIADH.

Phenytoin (Dilantin)

Classic AED with narrow therapeutic index (10-20 mcg/mL). Zero-order kinetics at therapeutic levels — small dose changes cause large plasma level changes. IV fosphenytoin preferred. Long-term: gingival hyperplasia, peripheral neuropathy, osteoporosis.

Gabapentin (Neurontin)

Alpha-2-delta calcium channel ligand. Anticonvulsant and neuropathic pain. Very widely used off-label. Not metabolized by CYP enzymes. Dizziness, sedation. Misuse/abuse potential recognized.

Pregabalin (Lyrica)

Similar mechanism to gabapentin but more potent and predictable pharmacokinetics. FDA-approved for neuropathic pain, fibromyalgia, focal seizures. Schedule V controlled substance.

Topiramate (Topamax)

Multiple mechanisms. Used in epilepsy and migraine prevention. Cognitive side effects ('dopamax'), kidney stones, weight loss, oligohidrosis. Highly teratogenic (cleft lip/palate).

Class-Wide Side Effects

Common Side Effects

Sedation and cognitive impairment — older AEDs (phenobarbital, phenytoin, carbamazepine) >> newer AEDs
Dizziness and ataxia — dose-related; common with carbamazepine, phenytoin, lamotrigine
Weight gain — valproate, pregabalin, gabapentin; weight loss — topiramate, zonisamide
Gastrointestinal effects — nausea, vomiting especially with valproate (enteric-coated formulations reduce this)
Behavioral effects — levetiracetam: irritability, depression; topiramate: cognitive slowing

Serious Side Effects

Stevens-Johnson syndrome / toxic epidermal necrolysis — carbamazepine (especially HLA-B*1502 carriers), lamotrigine (with rapid titration or valproate co-administration), phenytoin, oxcarbazepine
Suicidal ideation — FDA black box warning across all AEDs (1.8× increased risk vs placebo in trials)
Teratogenicity — valproate (highest risk: ~11% major malformations), phenytoin, carbamazepine, topiramate all carry significant risks
Hepatotoxicity — valproate-induced fatal hepatotoxicity (rare, most at risk: children under 2, polytherapy, mitochondrial disease)
Aplastic anemia / agranulocytosis — carbamazepine, felbamate
Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) — carbamazepine, phenytoin, lamotrigine

Class Medicine Interactions

Oral contraceptives — enzyme-inducing AEDs (carbamazepine, phenytoin, oxcarbazepine, topiramate) reduce OCP effectiveness; contraceptive failure possible; use alternative/backup contraception

Warfarin — enzyme-inducing AEDs reduce warfarin levels; INR monitoring critical

Other CNS depressants — additive sedation with opioids, benzodiazepines, alcohol

Valproate + lamotrigine — valproate inhibits lamotrigine glucuronidation, doubling lamotrigine levels; reduce lamotrigine dose when adding valproate

CYP3A4 interactions — carbamazepine induces CYP3A4/2C9/2C19 affecting many drugs including immunosuppressants, statins, antiretrovirals

Contraindications

!Valproate in pregnancy (especially first trimester) or women of childbearing potential unless no alternatives
!Carbamazepine in known HLA-B*1502 carriers (without prior tolerance) — SJS risk
!Phenytoin in patients with sinus bradycardia or heart block
!Ethosuximide for non-absence seizure types (may worsen)

Monitoring Parameters

Serum drug levels — phenytoin (10-20 mcg/mL), valproate (50-100 mcg/mL), carbamazepine (4-12 mcg/mL); levetiracetam/lamotrigine levels less routinely monitored
LFTs and CBC — valproate and carbamazepine at baseline and periodically
Bone density — long-term AED use (enzyme inducers accelerate vitamin D metabolism); supplement vitamin D
Teratogenicity monitoring — women of childbearing potential: discuss contraception; folate supplementation (4 mg/day for valproate users)
Seizure frequency diary — assess treatment response

Frequently Asked Questions

Can AEDs cause birth defects?

Yes, antiepileptic drugs are among the most important drug classes for teratogenicity counseling. Valproate carries the highest risk (11% major malformations including neural tube defects, fetal valproate syndrome with cognitive impairment). Phenytoin, carbamazepine, and topiramate also carry significant teratogenic risks. Lamotrigine and levetiracetam have lower teratogenic profiles and are preferred for women of childbearing potential when possible. All women with epilepsy should discuss pregnancy planning with their neurologist, use appropriate contraception, and take high-dose folic acid. The risk of uncontrolled seizures during pregnancy must be weighed against medication risks.

Why do AEDs have narrow therapeutic windows?

Many older AEDs have narrow therapeutic windows because the doses needed for seizure control are close to those causing toxicity. Phenytoin is the classic example: it has zero-order (saturable) kinetics at therapeutic levels, meaning small dose increases cause disproportionately large plasma level increases. The difference between a subtherapeutic level (breakthrough seizures) and a toxic level (ataxia, nystagmus, confusion) may be just 2-3 mg/day. Plasma level monitoring helps guide dosing and is particularly important for phenytoin, carbamazepine, and valproate.