Antiseizure Medicines

Antiseizure medicines suppress seizures without altering the underlying cause of epilepsy. They are started after a second unprovoked seizure, or after a first seizure with a high recurrence risk (abnormal examination, focal imaging or EEG abnormality, nocturnal seizure), and aim at seizure freedom on one well-tolerated drug.

Mechanisms. Voltage-gated sodium channel blockade (carbamazepine, phenytoin, lamotrigine, lacosamide); enhanced GABA inhibition (benzodiazepines, phenobarbital, valproate, vigabatrin); synaptic vesicle protein SV2A binding (levetiracetam, brivaracetam); calcium channel modulation (ethosuximide, gabapentin, pregabalin); AMPA receptor blockade (perampanel); carbonic anhydrase inhibition (acetazolamide, topiramate, zonisamide).

Pharmacokinetics. Carbamazepine, phenytoin, phenobarbital and primidone induce liver enzymes; valproate inhibits them. Levetiracetam, gabapentin and pregabalin are cleared by the kidney without hepatic metabolism.

• Broad spectrum: valproate, lamotrigine, levetiracetam, topiramate, zonisamide, clobazam, perampanel.
• Focal onset: carbamazepine, oxcarbazepine, phenytoin, lacosamide, gabapentin, pregabalin.
• Absence: ethosuximide, valproate, lamotrigine.

Differences. Carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin and vigabatrin can worsen absence and myoclonic seizures. Enzyme inducers reduce the effect of hormonal contraception, warfarin, direct oral anticoagulants and many antiretrovirals.

• Focal seizures: lamotrigine or levetiracetam first; carbamazepine or oxcarbazepine as alternatives.
• Generalised tonic-clonic seizures: valproate in men, lamotrigine or levetiracetam in women of childbearing potential.
• Absence seizures: ethosuximide or valproate; lamotrigine is a second choice.
• Myoclonic seizures and juvenile myoclonic epilepsy: valproate in men; levetiracetam in women.
• Principles: one drug at a time, start low and increase slowly, titrate to effect, and switch rather than add if the first drug fails from poor tolerance. After 2 appropriate drugs fail, the epilepsy is drug-resistant.
• Withdrawal: consider after 2 years seizure free, over at least 3 months, one drug at a time.
• Regional: phenobarbital, phenytoin and carbamazepine are the most available and cheapest; where they are used, check interactions with antituberculosis and antiretroviral drugs.

Selection. Seizures from eclampsia, hypoglycaemia, alcohol withdrawal and other acute causes are treated by the cause, not by long-term antiseizure medicines.

Contraindications. Class-specific; for example valproate in pregnancy and in women of childbearing potential without a pregnancy prevention programme, carbamazepine in atrioventricular block, and phenytoin in sinus bradycardia.

Adverse effects. Drowsiness, dizziness, ataxia, diplopia, cognitive slowing, and rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis (carbamazepine, lamotrigine, phenytoin, phenobarbital). Hyponatraemia with carbamazepine and oxcarbazepine. Osteomalacia and bone loss with enzyme inducers. All carry a small increase in suicidal ideation.

Interactions. Enzyme inducers lower levels of hormonal contraceptives, warfarin, direct oral anticoagulants, dolutegravir and praziquantel. Isoniazid raises phenytoin and carbamazepine levels; rifampicin lowers them. With carbamazepine, give dolutegravir 50 mg twice daily; avoid phenytoin and phenobarbital with dolutegravir.

Special groups.

• Pregnancy: avoid valproate, topiramate and phenobarbital where possible; lamotrigine and levetiracetam carry the lowest malformation risk. Give folic acid 5 mg daily before conception and through the first trimester. Lamotrigine and levetiracetam levels fall in pregnancy.
• Contraception: medroxyprogesterone injection and levonorgestrel or copper intrauterine devices are unaffected by enzyme inducers.
• Breastfeeding: most are acceptable; watch for sedation with phenobarbital and benzodiazepines.
• Older adults: prefer lamotrigine, levetiracetam or lacosamide; avoid enzyme inducers.
• Kidney and liver impairment: adjust levetiracetam, gabapentin, pregabalin, lacosamide and topiramate for kidney function; valproate and carbamazepine need care in liver disease.

Monitoring. Seizure diary, adherence, mood, weight, bone health, sodium, liver enzymes and full blood count for relevant drugs. Drug levels only for phenytoin, and selectively for carbamazepine, phenobarbital, valproate and lamotrigine.

Referral and escalation. Refer for failure of 2 appropriate drugs, pregnancy planning, status epilepticus, suspected non-epileptic events, and any epilepsy in childhood.