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Barbiturates are a class of depressant drugs that slow down the central nervous system (CNS). They are used to treat anxiety, insomnia, seizures, and muscle spasms.

Mechanism of Action

Barbiturates cause postsynaptic enhancement of gamma-aminobutyric acid (GABA), interacting with alpha- and beta subunits of the GABA-A receptor. Barbiturates increase chloride ion flux, resulting in postsynaptic hyperpolarization and central nervous system (CNS) depression. Phenobarbital and pentobarbital affect the GABA-A receptors with a dose-dependent response. These drugs activate chloride channels at higher micromolar concentrations associated with anesthetic levels. Although both barbiturates and benzodiazepines interact with GABA-A receptors, they are unique because they potentiate GABA-A receptors while increasing chloride ion influx even with very low concentrations of the GABA neurotransmitter.

Classification of Barbiturates

Barbiturates are classified according to the duration of their action. The short- and intermediate-acting ones have effects lasting 2 to 6 hours, while long-acting barbiturates exert their effects for longer than 6 hours.

Ultra-short-acting: This category of barbiturates includes methohexital and thiopental.

Short-acting: This category of barbiturates includes pentobarbital and secobarbital.

Intermediate-acting: This category of barbiturates includes amobarbital and butalbital.

Long-acting: This category of barbiturates includes phenobarbital and primidone.

Pharmacokinetics

Absorption: Phenobarbital is rapidly absorbed with a time-to-peak concentration of 2 to 4 hours. The bioavailability of phenobarbital is approximately 90% in adults and less in neonatal populations. Sodium salts of barbiturates are absorbed more rapidly, and food delays the onset of action of orally administered barbiturates. The IV route is usually reserved for managing status epilepticus (phenobarbital sodium) or the induction or maintenance of general anesthesia(eg, methohexital or thiopental). Thiopental observes first-order kinetics in low doses of 5 mg/kg boluses. In high-dose or prolonged infusions, non-linear kinetics will occur due to the progressive saturation of enzyme systems.

Distribution: Highly lipid-soluble barbiturates cross the blood-brain barrier rapidly, but rapid redistribution from the CNS to peripheral tissues occurs. Thiopental and methohexital undergo rapid redistribution after IV injections into less-vascular tissues, particularly muscle and fat, decreasing the concentration of barbiturates in the plasma and brain. Terminating the effect of a single bolus IV injection of thiopental occurs by redistribution from the central compartment to peripheral compartments.

Metabolism: The oxidation of barbiturates is the most important biotransformation that terminates biological activity. In addition, n-glycosylation is important for the metabolism of phenobarbital. Phenobarbital is metabolized extensively by the cytochrome P450, and the maturation of this enzyme family mainly occurs during the neonatal period.

Repeated administration of phenobarbital decreases the half-life due to the induction of microsomal enzymes. The self-induced increase in barbiturate metabolism partially accounts for tolerance to barbiturates. In addition, with chronic administration, an increase in aminolevulinic acid (ALA) synthetase enzymes is detected. The effect of barbiturates on ALA synthetase can cause dangerous disease exacerbations in patients with porphyria. Primidone undergoes metabolism to phenylethylmalonamide and phenobarbital. The efficacy of primidone in treating essential tremor is not dependent on its phenobarbital metabolite.

Elimination: About 25% of phenobarbital is excreted unchanged in the urine. The renal excretion can be increased by osmotic diuresis or alkalinization of the urine. The metabolic elimination of barbiturates is more rapid in young people than in older people and infants. Age-related changes have been demonstrated in pharmacokinetics due to slower clearance in older patients, resulting in higher serum concentrations with smaller drug doses. In children, a shorter elimination half-time occurs due to greater clearance.The half-life of phenobarbital decreases by approximately 4.6 hours/day on chronic administration.

Adverse Effects

For women taking phenobarbital as monotherapy, the drug correlates with congenital defects in exposed infants.

When given in IV anesthetics, barbiturates produce a reduction in blood pressure and an increase in heart rate. Respiratory depression and apnea may occur.

Thiopental and thiamylal release histamine, while methohexital and pentobarbital have minimal histamine release.

Extravasation of thiopental (a vesicant) may cause severe tissue necrosis. If extravasation occurs, treatment measures include hyaluronidase and phentolamine. Case reports of successful treatment also include the topical application of a eutectic mixture of local anesthetics and the local injection of lidocaine.

Barbiturates such as butalbital can lead to withdrawal symptoms, including seizures. The recommended risk mitigation strategy is to taper off barbituates under supervision.

Hepatotoxicity

Barbiturates can cause allergic reactions and skin rashes associated with mild liver injury. Phenobarbital is predominantly linked with drug-induced liver injury. Phenobarbital-induced severe adverse drug reactions are DRESS (drug reaction with eosinophilia and systemic symptoms), Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Drug-Drug Interactions 

• Phenobarbital is an inducer of the cytochrome enzyme system, specifically the CYP1A2, 2B6, 2C9, and 3A4/5 isozymes that will reduce the efficacy of warfarin, steroids, psychoactive drugs, and immunosuppressants.

• Phenobarbital will also lower the plasma concentrations of other antiepileptic drugs, such as lamotrigine, oxcarbazepine, phenytoin, tiagabine, and valproate.

• Contraceptive failure can occur when systemic hormonal contraception drugs are administered with enzyme inducers like phenobarbital.

• Phenobarbital is a strong CYP3A4 inducer; avoid combination with hepatitis C drugs paritaprevir-ritonavir, ombitasvir, and dasabuvir.

• As primidone is a CYP3A4 inducer, combining it with apremilast is strictly contraindicated.

• When barbiturates are combined with other CNS depressants, such as benzodiazepines and opioids, they can cause oversedation and severe respiratory depression.