Sodium Channel Blocking Antiseizure Medicines

Sodium channel blocking antiseizure medicines slow recovery of voltage-gated sodium channels from inactivation, limiting high-frequency neuronal firing. They are the main drugs for focal seizures and generalised tonic-clonic seizures.

Pharmacokinetics. Carbamazepine induces its own metabolism over 2 to 4 weeks. Phenytoin has saturable kinetics, so small dose increases can produce large rises in level. Lamotrigine is cleared by glucuronidation.

• Carbamazepine 100 to 200 mg twice daily, increased every 1 to 2 weeks to 400 to 1,200 mg daily in two divided doses; level 4 to 12 mg/L.
• Oxcarbazepine 300 mg twice daily, increased to 600 to 1,200 mg twice daily; maximum 2,400 mg daily.
• Phenytoin 3 to 5 mg/kg daily (usually 300 mg) in one or two doses; total level 10 to 20 mg/L.
• Lamotrigine: 25 mg daily for 2 weeks, 50 mg daily for 2 weeks, then 100 to 200 mg daily, up to 400 mg daily. With valproate, halve the dose and slow the titration. With enzyme inducers, about double the dose.
• Lacosamide 50 mg twice daily, increased to 100 to 200 mg twice daily; maximum 400 mg daily.
• Eslicarbazepine 400 mg once daily, increased to 800 to 1,200 mg once daily.

Differences. Oxcarbazepine induces enzymes less than carbamazepine but causes more hyponatraemia. Lamotrigine has the best cognitive and teratogenic profile. Lacosamide prolongs the PR interval.

• Focal seizures: lamotrigine, carbamazepine, oxcarbazepine, lacosamide; phenytoin where others are unavailable.
• Generalised tonic-clonic seizures: lamotrigine; carbamazepine only when the epilepsy is not generalised with myoclonus or absences.
• Trigeminal neuralgia: carbamazepine 100 mg twice daily, increased to 200 mg three to four times daily.
• Phenytoin level interpretation: correct for low albumin; free level 1 to 2 mg/L is the target.

Selection. Do not use carbamazepine, oxcarbazepine or phenytoin in absence or myoclonic epilepsy.

Contraindications. Carbamazepine: atrioventricular block, bone marrow depression, acute intermittent porphyria. Lacosamide: second or third degree atrioventricular block. Phenytoin: sinus bradycardia, heart block (intravenous).

Adverse effects. Diplopia, ataxia, nystagmus, hyponatraemia and leucopenia (carbamazepine). Gum hyperplasia, hirsutism, coarse facies, neuropathy and cerebellar atrophy (phenytoin). Rash including Stevens-Johnson syndrome, hypersensitivity syndrome and haemophagocytic lymphohistiocytosis (lamotrigine). Arrhythmia in structural heart disease (lamotrigine, lacosamide). In people of Han Chinese, Thai and some South Asian ancestry, test for HLA-B*15:02 before carbamazepine.

Interactions. Carbamazepine, phenytoin and oxcarbazepine induce enzymes. Erythromycin, clarithromycin, isoniazid and fluconazole raise carbamazepine or phenytoin levels. Oestrogen-containing contraceptives halve lamotrigine levels, and valproate doubles them.

Special groups.

• Pregnancy: carbamazepine carries a neural tube defect risk of about 1 percent; phenytoin causes foetal hydantoin syndrome; lamotrigine has the lowest risk, but levels fall and the dose may need to rise.
• Breastfeeding: carbamazepine and phenytoin are acceptable; lamotrigine reaches notable infant levels, so watch for rash and sedation.
• Children: carbamazepine 10 to 20 mg/kg daily in two doses; lamotrigine by age and co-medication from the product table.
• Older adults: avoid phenytoin and carbamazepine where possible.
• Kidney impairment: halve the starting dose of oxcarbazepine when creatinine clearance is under 30 mL/min; lacosamide maximum 250 mg daily in severe impairment.
• Liver impairment: lacosamide maximum 300 mg daily in moderate impairment; reduce carbamazepine and lamotrigine.

Monitoring. Sodium, full blood count and liver enzymes at baseline and periodically for carbamazepine and oxcarbazepine; phenytoin levels; ECG for lacosamide with cardiac disease; skin for rash in the first 8 weeks of lamotrigine.

Referral and escalation. Stop lamotrigine, carbamazepine and phenytoin at the first sign of rash with fever, mucosal involvement or blistering, and refer urgently. Unexplained rise in levels or toxicity needs a review of interacting drugs.