Introduction
Phenobarbital is a long-acting barbiturate derivative that has been used clinically since 1912. It remains one of the most widely available antiepileptic drugs worldwide due to its efficacy, low cost, and established safety profile. As a Schedule IV controlled substance, phenobarbital is primarily used for seizure disorders but also has applications in other neurological and psychiatric conditions.
Mechanism of Action
Phenobarbital exerts its pharmacological effects primarily through potentiation of gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission. It binds to the GABA-A receptor complex at the barbiturate-binding site, increasing the duration of chloride channel opening. This hyperpolarizes the neuronal membrane and reduces neuronal excitability. At higher concentrations, phenobarbital directly activates GABA-A receptors and inhibits excitatory glutamate responses through AMPA receptors.
Indications
- FDA-approved indications:
- Treatment of generalized tonic-clonic and partial seizures - Emergency control of acute convulsive episodes (status epilepticus)
- Off-label uses:
- Neonatal seizures - Febrile seizures prevention - Alcohol withdrawal syndrome - Sedation in critical care settings - Essential tremor
Dosage and Administration
Adults (Epilepsy):- Initial dose: 60-100 mg/day orally in divided doses or single bedtime dose
- Maintenance: 60-200 mg/day
- Maximum dose: 400 mg/day
- Initial: 3-5 mg/kg/day in divided doses
- Maintenance: 3-8 mg/kg/day
- Loading dose: 15-20 mg/kg IV at rate ≤60 mg/min
- Maintenance: 1-3 mg/kg/day
- Hepatic impairment: Reduce dose by 25-50%
- Renal impairment: Reduce dose by 25-50%
- Elderly: Initiate at lower end of dosing range
Pharmacokinetics
- Absorption: Well absorbed orally (80-90% bioavailability)
- Distribution: Widely distributed throughout tissues; Vd: 0.5-0.6 L/kg
- Protein binding: 20-45%
- Metabolism: Hepatic via cytochrome P450 system (primarily CYP2C9, CYP2C19)
- Elimination: Renal excretion (20-50% unchanged); half-life: 53-118 hours
- Steady-state: Reached in 2-3 weeks
Contraindications
- Hypersensitivity to barbiturates
- History of porphyria
- Severe respiratory depression
- Severe hepatic impairment
- Pregnancy (except for life-threatening seizures uncontrolled by other agents)
Warnings and Precautions
- Boxed Warning: Risk of habit formation, abuse, and dependence
- Suicidality: Antiepileptic drugs increase risk of suicidal thoughts/behavior
- Respiratory depression: Especially with rapid IV administration or concomitant CNS depressants
- Withdrawal syndrome: Abrupt discontinuation may cause status epilepticus
- Hepatic effects: May induce hepatic enzymes; monitor LFTs
- Osteomalacia: Long-term use associated with vitamin D deficiency and bone disease
Drug Interactions
- Enzyme induction: Significantly induces CYP3A4, CYP2C9, CYP2C19, UGT
- Oral contraceptives: Reduced efficacy due to enzyme induction
- Anticoagulants: Warfarin effect reduced; monitor INR closely
- Other CNS depressants: Additive sedation with alcohol, opioids, benzodiazepines
- Valproic acid: Complex interaction; may increase phenobarbital levels
- Antidepressants: Reduced levels of tricyclics and SSRIs
Adverse Effects
Common (≥10%):- Sedation, drowsiness
- Cognitive impairment
- Ataxia, nystagmus
- Vertigo, dizziness
- Stevens-Johnson syndrome
- Drug reaction with eosinophilia and systemic symptoms (DRESS)
- Agranulocytosis
- Hepatic necrosis
- Megaloblastic anemia
- Hypersensitivity reactions
Monitoring Parameters
- Efficacy: Seizure frequency and characteristics
- Toxicity: Serum levels (therapeutic range: 15-40 mcg/mL)
- CBC with differential: Baseline and periodically
- Liver function tests: Baseline and every 6-12 months
- Vitamin D levels: Annually with long-term use
- Bone density: Consider DEXA scan with prolonged therapy
- Mental status: Monitor for depression/suicidal ideation
Patient Education
- Take medication exactly as prescribed; do not stop abruptly
- Avoid alcohol and other CNS depressants
- Use effective contraception (phenobarbital reduces efficacy of hormonal methods)
- May cause drowsiness; avoid driving or operating machinery until effects known
- Report any signs of infection, unusual bleeding, skin rash, or mood changes
- Regular follow-up with healthcare provider essential
- Wear medical alert identification indicating epilepsy diagnosis and medication
References
1. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Currents. 2016;16(1):48-61.
2. Brodie MJ, Kwan P. Current position of phenobarbital in epilepsy and its future. Epilepsia. 2012;53 Suppl 8:40-46.
3. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239-1276.
4. Lexicomp Online. Phenobarbital: Drug Information. Wolters Kluwer Clinical Drug Information, Inc. 2023.
5. Johannessen SI, Tomson T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed? Clin Pharmacokinet. 2006;45(11):1061-1075.
6. FDA Prescribing Information: Phenobarbital Tablets. Revised 2022.