Phenobarbital (DB01174): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Phenobarbital is a long-acting barbituric acid derivative, classified as a sedative-hypnotic and anticonvulsant, that has occupied a significant, albeit evolving, role in clinical medicine for over a century. Its primary mechanism of action involves positive allosteric modulation of the gamma-aminobutyric acid type A (GABAA​) receptor, where it prolongs the opening of the associated chloride ion channel, leading to potent, nonselective depression of the central nervous system (CNS). This fundamental action underlies its broad-spectrum efficacy in the management of generalized tonic-clonic and partial seizures, making it one of the oldest and most enduring anti-seizure medications still in clinical use.

Therapeutically, Phenobarbital is indicated for various seizure disorders, status epilepticus, and short-term sedation. It also has critical, though often off-label, applications in the management of neonatal seizures, withdrawal syndromes from alcohol and other CNS depressants, and certain types of hyperbilirubinemia. Despite its proven efficacy and low cost—factors that have secured its place on the World Health Organization's List of Essential Medicines—its clinical utility is significantly constrained by a challenging safety and tolerability profile. Key limitations include a narrow therapeutic index, a high potential for physical dependence and severe withdrawal reactions, and a profound propensity for drug-drug interactions. As a potent inducer of hepatic cytochrome P450 (CYP450) enzymes, Phenobarbital accelerates the metabolism of numerous co-administered drugs, frequently leading to therapeutic failure of those agents. Furthermore, its use is associated with significant CNS adverse effects, including sedation and cognitive impairment, as well as rare but life-threatening hypersensitivity reactions. Its status as a globally controlled substance