Antiepileptic Drugs
Antiepileptic drugs control seizures through diverse mechanisms including sodium channel blockade, GABA enhancement, and calcium current modulation. Drug selection depends on seizure type, comorbidities, and reproductive considerations.
## Mechanisms of Action
Antiepileptic drugs (AEDs) suppress seizures through several overlapping mechanisms:
- **Sodium channel blockade** -- Prolonging the inactivated state of voltage-gated sodium channels reduces repetitive neuronal firing. Phenytoin, carbamazepine, lamotrigine, lacosamide.
- **GABA enhancement** -- Increasing inhibitory neurotransmission via GABA-A receptor potentiation (benzodiazepines, phenobarbital), GABA transaminase inhibition (vigabatrin), or GABA reuptake blockade (tiagabine).
- **Calcium current modulation** -- Blocking T-type calcium channels in thalamic neurons suppresses absence seizures (ethosuximide). Reducing P/Q-type calcium channel function (gabapentin, pregabalin -- actually bind alpha-2-delta subunit).
- **SV2A binding** -- Levetiracetam and brivaracetam bind synaptic vesicle protein 2A, modulating neurotransmitter release.
- **Multiple mechanisms** -- Valproate affects sodium channels, T-type calcium channels, GABA metabolism, and NMDA receptors.
## Drug Selection by Seizure Type
| Seizure Type | First-Line Options | Avoid |
|-------------|-------------------|-------|
| Focal (partial) | Lamotrigine, levetiracetam, carbamazepine | Ethosuximide |
| Generalized tonic-clonic | Valproate, lamotrigine, levetiracetam | Carbamazepine (may worsen) |
| Absence | Ethosuximide, valproate | Carbamazepine, phenytoin |
| Myoclonic | Valproate, levetiracetam | Carbamazepine, gabapentin |
## Commonly Used AEDs
**Levetiracetam** -- Broad-spectrum, minimal drug interactions, renally cleared. First-line for many centers. Main side effect is irritability and behavioral changes.
**Lamotrigine** -- Effective for focal and generalized seizures. Requires slow titration to avoid Stevens-Johnson syndrome (especially with concurrent valproate). Weight-neutral, mood-stabilizing properties.
**Valproate** -- Broadest spectrum AED. Effective for nearly all seizure types. Significant concerns: teratogenicity (neural tube defects, cognitive impairment in exposed children), hepatotoxicity, pancreatitis, weight gain, tremor, thrombocytopenia.
**Carbamazepine** -- Effective for focal seizures. Potent CYP3A4 inducer with numerous drug interactions. Risk of hyponatremia (SIADH). HLA-B*1502 testing recommended in patients of Southeast Asian descent (Stevens-Johnson syndrome risk).
## Drug Interactions
Enzyme-inducing AEDs (phenytoin, carbamazepine, phenobarbital) accelerate metabolism of oral contraceptives, warfarin, immunosuppressants, and other AEDs. This has major implications for women of childbearing age -- hormonal contraceptive failure risk is real.
Valproate inhibits glucuronidation and can double lamotrigine levels, requiring dose adjustment when used together.
## Teratogenicity and Pregnancy
Valproate has the highest teratogenic risk (NTD 1-2%, major malformations 6-11%). It should be avoided in women of childbearing potential unless no alternative exists. Lamotrigine and levetiracetam have the most favorable safety profiles in pregnancy. High-dose folic acid (5 mg daily) is recommended for all women on AEDs planning pregnancy.
## Key Takeaways
- Seizure type determines drug choice -- not all AEDs work for all seizures.
- Levetiracetam and lamotrigine are often first-line due to broad efficacy and tolerability.
- Avoid valproate in women of childbearing age whenever possible.
- Enzyme-inducing AEDs complicate polypharmacy -- always check interactions.