Antiepileptic Medications Overview
Antiepileptic drugs (ASDs) comprise over 20 distinct medications that fall into several major categories based on mechanism of action and clinical use, with the most frequently prescribed agents being carbamazepine, valproate, lamotrigine, lacosamide, and levetiracetam. 1
First-Generation (Older) Antiepileptics
These medications remain effective but have significant pharmacokinetic disadvantages including variable metabolism, narrow therapeutic indices, and substantial drug interaction potential 2, 3:
Carbamazepine: A potent CYP3A4 inducer used primarily for focal seizures, administered as 8 mg/kg oral loading dose, with common side effects of drowsiness, nausea, and dizziness 4, 5. This agent doubles the clearance of many concomitant medications through enzyme induction 5.
Phenytoin: Standard antiepileptic given as 20 mg/kg divided doses orally or 18 mg/kg IV at maximum 50 mg/min, with risks including hypotension (12% of patients), cardiac dysrhythmias, and purple glove syndrome with IV administration 6, 7, 4.
Valproic acid/Valproate: Highly effective across multiple seizure types including absence seizures, dosed at 30 mg/kg IV at 6 mg/kg per hour, achieving 88% seizure cessation within 20 minutes 6, 7. Must be avoided in women of childbearing potential due to teratogenicity 4, 8, 9. Side effects include thrombocytopenia, liver toxicity, and transient injection site irritation 4, 8.
Phenobarbital: Recommended in resource-limited settings due to lower cost, dosed at 10-20 mg/kg, but carries risks of respiratory depression and hypotension 4.
Second-Generation (Newer) Antiepileptics
These agents offer improved tolerability profiles and more predictable pharmacokinetics while maintaining equivalent efficacy 2, 3, 10:
Broad-Spectrum Agents (Focal and Generalized Seizures)
Lamotrigine: First-line therapy for focal epilepsy with demonstrated efficacy equal to older agents but superior tolerability 2, 10, 11. Effective against partial seizures and various generalized seizure types 3.
Topiramate: Protects against partial seizures and generalized seizure types, suitable for first-line management in certain patient subgroups 3, 10.
Zonisamide: Effective for focal seizures as first-line monotherapy with favorable tolerability compared to older agents 9, 10, 11.
Primarily Focal Seizure Agents
Levetiracetam: Demonstrates 67-73% efficacy in status epilepticus, dosed at 20-30 mg/kg IV or 1,500 mg oral load 6, 7. Particularly useful in elderly patients (78% seizure cessation) and has minimal hepatic metabolism, making it ideal for patients with liver disease 4. Should be avoided if psychiatric history exists 2. Has minimal drug interaction potential 3.
Oxcarbazepine: First-line therapy for focal epilepsy and primarily generalized tonic-clonic seizures 2, 3, 10.
Lacosamide: Available in oral and IV formulations for focal seizures, with side effects including dizziness, headache, and injection site pain 4, 10, 11.
Gabapentin: Adjunctive therapy for partial seizures, dosed at 900 mg/day oral for 3 days, with side effects of somnolence, dizziness, and ataxia 4. Requires significant dose reduction in renal impairment as it is primarily eliminated unchanged in urine 4.
Pregabalin: Less effective than lamotrigine in comparative trials, suitable for adjunctive therapy 10, 11.
Tiagabine: Use restricted to partial epilepsy 3.
Eslicarbazepine: Has undergone successful conversion to monotherapy trials 10, 11.
Brivaracetam: Newer agent approved for adjunctive therapy 11.
Specialized Agents
Vigabatrin: Effective for partial seizures and infantile spasms, but should only be prescribed in refractory patients due to serious toxicity risks including potential retinal toxicity 3, 9. First-line use may be justified specifically in infants with spasms 3.
Felbamate: Reserved only for refractory patients due to serious toxicity risks 3, 9.
Rufinamide: Toxicity profile precludes first-line use 9.
Cannabidiol: Recently approved agent 11.
Ganaxolone: Most recently FDA-approved antiseizure medication 10.
Critical Drug Interactions and Considerations
Enzyme-inducing antiepileptics (carbamazepine, phenytoin, phenobarbital) can double valproate clearance and significantly reduce levels of concomitant medications 5, 8. These agents worsen coronary and cerebrovascular disease through hyperlipidemia and accelerate osteoporosis development 2.
Carbapenem antibiotics (ertapenem, imipenem, meropenem) cause clinically significant reductions in valproic acid concentrations, potentially resulting in loss of seizure control 8. Alternative antibiotics should be strongly considered 8.
Common Pitfalls to Avoid
Never use polytherapy when monotherapy can achieve seizure control 4. Rational combinations should avoid agents with unfavorable pharmacokinetic or pharmacodynamic interactions 10, 11.
Do not discontinue treatment before 2 seizure-free years 4.
Avoid prescribing antiepileptics after a single unprovoked seizure 4.
For women with epilepsy, avoid valproic acid if possible and ensure folic acid supplementation when on any antiepileptic 4.
In patients with intellectual disability, avoid phenytoin or phenobarbital due to higher risk of behavioral adverse effects; prefer valproic acid or carbamazepine 4.
Initial administration of carbamazepine, valproate, lamotrigine, lacosamide, and levetiracetam may affect driving performance, warranting special attention, though this diminishes with continued use 1.