phenobarbital
antiepileptic· Brands: Luminal, Gardenal, Phenobarbitone, SolfotonIMIVPO
Mechanism of action
Phenobarbital is a barbiturate that enhances the inhibitory action of GABA at GABA_A receptors, increasing the duration of chloride ion channel opening and hyperpolarising the neuronal membrane. It also reduces excitatory glutamate transmission, and at high concentrations may directly activate chloride channels. This results in a generalised depression of neuronal activity.
Pharmacokinetics
Phenobarbital is well absorbed after oral administration, with peak plasma concentrations reached in 2-4 hours. It is extensively metabolised in the liver by CYP450 enzymes, particularly CYP2C9, but also induces many hepatic enzymes, leading to drug interactions. The elimination half-life is long, approximately 80-120 hours, allowing once-daily dosing. The drug is excreted renally, partly unchanged, and requires dose adjustment in renal impairment.
Indications & dosing
Epilepsy (focal and generalized seizures)
Maintenance dose; can be taken once daily due to long half-life.
- adult · PO: 60–180 mg once daily · Maintenance dose; can be taken once daily due to long half-life.
Status epilepticus
Slow IV injection; repeat after 20 minutes if required.
- adult · IV: 10–20 mg/kg single dose · Slow IV injection; repeat after 20 minutes if required.
Neonatal seizures
Loading dose; maintenance is 3-5 mg/kg/day.
- neonatal · IV: 15–20 mg/kg single dose · Loading dose; maintenance is 3-5 mg/kg/day.
Prophylaxis of febrile seizuresoff-label
Consider when risk of recurrence is high; monitor serum levels.
- pediatric · PO: 3–5 mg/kg daily · Consider when risk of recurrence is high; monitor serum levels.
Contraindications & precautions
- Hypersensitivity to barbiturates · Include a history of rash or other allergic reactions to barbiturates.
- Porphyria · Barbiturates can precipitate an acute attack.
- Severe hepatic impairment · Metabolism is reduced; risk of toxicity.
- Respiratory depression or severe respiratory insufficiency · May worsen respiratory failure; use with caution.
- Monitor liver function and full blood count during long-term treatment.
- Do not withdraw abruptly; taper to avoid withdrawal seizures.
- Use with caution in patients with respiratory disease, renal impairment, or in the elderly.
- Phenobarbital induces hepatic enzymes; check for interactions with other drugs.
- Use in pregnancy may cause fetal harm; weigh benefits against risks.
- May cause drowsiness; advise patients to avoid driving or operating machinery.
Adverse effects
- Sedation and drowsiness
- Ataxia and incoordination
- Dizziness
- Respiratory depressionserious
- Skin rash, including Stevens-Johnson syndromeserious
- Hepatotoxicityserious
- Blood dyscrasias (e.g., agranulocytosis, thrombocytopenia)serious
- Dependence and withdrawal seizures on long-term useserious
Renal & hepatic adjustment
- eGFR 0+: Reduce dose in significant renal impairment (eGFR < 30). Monitor serum phenobarbital levels and consider alternative in severe impairment.
- Hepatic impairment (mild): Use with caution, no dose adjustment usually required.
- Hepatic impairment (moderate): Reduce dose by 25-50% and monitor serum phenobarbital levels.
- Hepatic impairment (severe): Avoid if possible; if necessary, use reduced dose with close monitoring. (avoid)
Monitoring, pregnancy & toxicity
- Serum phenobarbital concentration · First 2-4 weeks after starting or dose change, then at intervals; target 15-40 mg/L
- Adherence and seizure frequency · At each clinic visit
- Signs of CNS depression (sedation, ataxia, nystagmus) · Regularly
- Liver function tests · Baseline and periodically
- Bone health (calcium, vitamin D) in long-term use · Annually
- Pregnancy: Phenobarbital is teratogenic and may cause congenital malformations (e.g. cleft palate, cardiac defects). Use only if alternative antiepileptics are ineffective or contraindicated. Given the high risk of harm to the fetus, patients should be counselled about risks and benefits. If used, maintain monotherapy at the lowest effective dose, consider monitoring serum levels, and provide folic acid supplementation. Do not stop abruptly as this can precipitate seizures.
- Toxicity: Acute overdose: CNS depression, respiratory depression, hypotension, coma, and areflexia. · Maintain airway, breathing, and circulation; consider activated charcoal within 1 hour of ingestion; haemodialysis may be effective in severe cases due to the drug's small volume of distribution and low protein binding; monitor blood pressure and temperature.
- Toxicity: Chronic toxicity: sedation, confusion, ataxia, nystagmus, and skin rash. · Reduce dose gradually if possible; monitor serum levels and consider alternative therapy.
- Toxicity: Phenobarbital can cause severe skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis). · Withdraw the drug immediately and provide supportive care; seek dermatological consultation.
Clinical notes
Phenobarbital is used for the treatment of generalised tonic-clonic and partial seizures, and is also a first-line agent for status epilepticus when given intravenously. It has a long duration of action and is often used once daily. Sedation is a common side effect, and tolerance can develop. Abrupt discontinuation may precipitate withdrawal seizures, so the dose should be tapered. Therapeutic drug monitoring is recommended due to the narrow therapeutic index. Phenobarbital is a potent enzyme inducer, affecting the metabolism of many drugs including oral contraceptives and anticoagulants. Caution is needed in hepatic impairment and in the elderly.
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BNF; local formulary