GABA Enhancing Antiseizure Medicines

GABA enhancing antiseizure medicines increase inhibitory neurotransmission through the GABA-A receptor, by blocking GABA breakdown or by other multiple actions. The group includes benzodiazepines, barbiturates, vigabatrin and valproate.

Mechanism. Benzodiazepines increase the frequency of GABA-A chloride channel opening; barbiturates prolong it. Vigabatrin irreversibly inhibits GABA transaminase. Valproate raises brain GABA and also blocks sodium and T-type calcium channels.

• Valproate 500 mg daily in divided doses, increased by 200 to 500 mg weekly to 1,000 to 2,000 mg daily (20 to 30 mg/kg); maximum 2,500 mg daily; trough level 50 to 100 mg/L. Intravenous in status epilepticus 40 mg/kg (maximum 3,000 mg).
• Phenobarbital 60 to 180 mg once daily at night (1 to 3 mg/kg daily); level 15 to 40 mg/L; intravenous load 15 to 20 mg/kg at up to 100 mg/min.
• Primidone 125 mg at night, increased to 750 to 1,500 mg daily.
• Clobazam 10 mg daily at night, up to 30 mg daily.
• Clonazepam 0.25 to 0.5 mg at night, increased to 1 to 4 mg daily.
• Vigabatrin 1 g daily, increased to 2 to 3 g daily; infantile spasms 50 mg/kg daily, up to 150 mg/kg daily.

Differences. Valproate is the most effective drug for generalised epilepsies but is the most teratogenic. Benzodiazepines lose effect through tolerance. Phenobarbital is cheap and widely available but sedating.

• Generalised epilepsies: valproate for men and for women unable to become pregnant.
• Infantile spasms: vigabatrin (especially in tuberous sclerosis) or corticosteroids.
• Adjunct: clobazam for focal and generalised seizures, intermittent use for clusters.
• Phenobarbital: first-line where resources are limited; avoid in women of childbearing potential.

Selection. In women and girls of childbearing potential, do not start valproate unless other drugs fail and a pregnancy prevention programme is in place.

Contraindications. Valproate: pregnancy without exceptions, liver disease, mitochondrial disorders (POLG mutations), urea cycle disorders, porphyria. Phenobarbital: acute porphyria, severe respiratory depression. Benzodiazepines: severe respiratory insufficiency, sleep apnoea, myasthenia gravis.

Adverse effects. Valproate: weight gain, tremor, hair loss, thrombocytopenia, hepatotoxicity, pancreatitis, hyperammonaemic encephalopathy, polycystic ovary syndrome. Major malformations occur in about 10 percent of exposed pregnancies, and neurodevelopmental disorders in up to 30 to 40 percent. Phenobarbital: sedation, cognitive and behavioural effects, osteomalacia, withdrawal seizures. Benzodiazepines: sedation, tolerance, dependence. Vigabatrin: irreversible visual field defects in 30 to 40 percent.

Interactions. Valproate raises lamotrigine and phenobarbital levels. Carbapenem antibiotics lower valproate levels sharply; do not combine. Phenobarbital and primidone are strong enzyme inducers. Opioids and alcohol add respiratory depression to benzodiazepines and barbiturates.

Special groups.

• Pregnancy: avoid valproate and phenobarbital; if exposure is unavoidable, give folic acid 5 mg daily and use the lowest dose in divided portions.
• Men: counsel about a possible small risk to children after paternal valproate exposure.
• Breastfeeding: phenobarbital and benzodiazepines cause infant sedation; valproate is acceptable.
• Children: phenobarbital 3 to 5 mg/kg daily; avoid valproate under 2 years with multiple drugs.
• Older adults: avoid phenobarbital and long-acting benzodiazepines.
• Liver impairment: avoid valproate; reduce phenobarbital.

Monitoring. Valproate: liver enzymes, platelets and weight; ammonia if drowsy; levels if adherence or toxicity in doubt. Vigabatrin: visual fields every 6 months. Phenobarbital: levels, bone health.

Referral and escalation. Jaundice, vomiting and abdominal pain on valproate (hepatotoxicity or pancreatitis), unexplained drowsiness, or any pregnancy on valproate need urgent specialist review.