Phenobarbital

Phenobarbital is a long-acting barbiturate used for focal and generalised tonic-clonic seizures, neonatal seizures and as a later-line drug in status epilepticus. It is cheap, effective and widely available, but it is sedating, a potent enzyme inducer, teratogenic and dependence-forming.

Mechanism. Prolongs opening of GABA-A chloride channels and reduces glutamate-mediated excitation.

Pharmacokinetics. Bioavailability is over 90% orally, protein binding about 50%, and half-life 70 to 140 hours in adults (shorter in children, longer in neonates). It is metabolised by cytochrome P450 2C9, 2C19 and 2E1, and about 25% is excreted unchanged, more in alkaline urine. Steady state takes 2 to 3 weeks.

First-line use. Focal and generalised tonic-clonic seizures where cost or supply limits other drugs, and first-line for neonatal seizures. Treatment is long term.

• Adults, oral phenobarbital: 60 mg at night, increased by 30 mg every 2 to 4 weeks to a usual 60 to 180 mg once daily at night (1 to 3 mg/kg daily). Maximum usual 240 mg daily.

• Children: 3 to 5 mg/kg daily in one or two doses, titrated by response and level. Maximum usual 8 mg/kg daily.

• Neonatal seizures: loading 20 mg/kg intravenously over 20 to 30 minutes, then 2.5 to 5 mg/kg daily. Refractory seizures may receive additional 10 to 20 mg/kg doses to a total of 40 mg/kg, under specialist care with ventilatory support available.

Emergency use. Status epilepticus after benzodiazepine, when phenytoin, levetiracetam or valproate are unavailable or have failed:

• Phenobarbital intravenous 15 to 20 mg/kg at not over 50 to 100 mg/min in adults, and at not over 1 mg/kg/min (maximum 30 mg/min) in children. Monitor airway, breathing and blood pressure continuously. Intramuscular use is possible without intravenous access but absorption is slow.

Kidney, liver, weight and age.

• Kidney: reduce the dose and extend the interval in severe impairment; haemodialysis removes about 30%, so give a supplement.

• Liver: reduce the dose; avoid in severe impairment, as it can precipitate coma.

• Older adults: lower starting dose; confusion, falls and paradoxical agitation are frequent.

Contraindications. Acute intermittent porphyria, severe respiratory depression, severe liver impairment and hypersensitivity.

Serious adverse effects. Respiratory depression and hypotension (especially intravenous and with benzodiazepines), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, megaloblastic anaemia, osteomalacia, dependence with withdrawal seizures, and foetal malformation.

Common adverse effects. Sedation, cognitive slowing, ataxia, mood change, and hyperactivity or irritability in children.

Interactions.

• Induction lowers warfarin, direct oral anticoagulants (avoid), hormonal contraceptives, corticosteroids, doxycycline, dolutegravir (needs 50 mg twice daily), efavirenz, protease inhibitors, artemether-lumefantrine and praziquantel. Rilpivirine is contraindicated.

• Valproate and chloramphenicol raise phenobarbital levels. Rifampicin lowers them. Alcohol, opioids and benzodiazepines add sedation.

Common prescribing errors. Giving it to someone with porphyria. Rapid intravenous rates. Adjusting the dose before steady state is reached. Missing interactions with antiretrovirals and contraceptives.

Special groups.

• Pregnancy: raises risk of cardiac malformations and clefts, and neonatal withdrawal. Give folic acid 5 mg daily before conception and vitamin K 1 mg to the newborn.

• Breastfeeding: infant sedation and poor feeding are likely because of accumulation; monitor closely, or choose an alternative.

• Regional: a controlled drug in many countries, and commonly one of the few antiseizure medicines available in primary care.

Formulations. Tablets 15, 30 and 60 mg. Elixir 15 mg/5 mL (some contain alcohol). Injection 200 mg/mL. Once daily dosing at night is adequate because of the long half-life.

Preparation. Dilute the injection at least 1 in 10 with water for injection or 0.9% sodium chloride and give slowly. The solution is highly alkaline, so avoid extravasation and subcutaneous use.

Monitoring. Respiratory rate, oxygen saturation, blood pressure and conscious level during intravenous use. Trough level 15 to 40 mg/L, checked 2 to 3 weeks after changes. Full blood count, liver function, calcium, vitamin D and folate in long-term use.

Stopping. Taper over several weeks to months, for example reducing by 15 to 30 mg every 2 to 4 weeks. Abrupt withdrawal can cause status epilepticus.

Referral and escalation. Refer for uncontrolled seizures, planned pregnancy, or dependence. Respiratory depression needs airway support and critical care.