Phenobarbital

Mechanism

Chemical and Commercial Profile

Common trade names: Luminal, Luminaletas.
Group: First generation antiepileptic, derived from barbituric acid.

Mechanism of Action

Phenobarbital acts by allosterically and directly facilitating inhibitory neurotransmission mediated by the GABA_A receptor. It binds to a specific binding site on the beta subunit of the receptor, increasing the duration of the opening of the Chloride channel (Cl^-) in response to GABA binding (unlike benzodiazepines, which increase the opening frequency). At high concentrations, it secondarily blocks L- and N-type calcium currents and antagonizes excitatory AMPA-type glutamate receptors.

Pharmacokinetics

Pharmacokinetics

• Absorption: Complete but very slow orally; bioavailability is 95%. The plasma peak is reached after 2-8 hours.
• Distribution: Moderate binding to plasma proteins (40-60%). Its volume of distribution is 0.5-0.6 L/kg. It crosses the BBB slowly but spreads widely with continued use.
• Metabolism: Hepatic oxidative catalyzed mainly by the isoenzyme CYP2C9 (60%) and CYP2C19. It generates the inactive metabolite p-hydroxyphenobarbital, which is subsequently conjugated with glucuronic acid.
• Excretion: Renal, eliminating 25-30% of the total dose unchanged. This excretion can be accelerated by urinary alkalinization in case of acute overdose.
• Half-life (t_1/2): Extremely long: 80-120 hours in adults; 60-80 hours in children. It favors a stable state of balance and reduces the risk of acute inter-dose withdrawal, but is associated with systemic accumulation.

Indicators and dose

Indications

• Generalized tonic-clonic seizures.
• Complex and simple motor focal seizures.
• First-line treatment in neonatal seizures due to perinatal asphyxia.
• Intravenous refractory status epilepticus (as advanced rescue therapy).

Dosage and Settings

• Adult Population (Maintenance): 60-150 mg/day in a single nightly intake.
• Pediatric Population: 3-6 mg/kg/day (divided into one or two doses).
• Neonatal Loading Dose (IV): 20 mg/kg infused slowly at a controlled rate.
• Target Plasma Range: 15-40 mcg/mL.
• Renal Failure: Adjust dose by reducing the regimen by 25-50% in patients with Cl_Cr < 30 ml/min due to unaltered renal elimination.
• Liver Failure: Decrease the dose by 50% in Child-Pugh B; contraindicated in Child-Pugh C due to the high risk of hepatic coma or secondary encephalopathy.

Security

Contraindications

• Acute intermittent porphyria (absolute contraindication due to potent induction of the delta-aminolevulinate synthase enzyme, which can trigger lethal acute crises).
• Severe respiratory failure or obstructive sleep apnea syndrome (OSA).
• Severe decompensated liver failure.

Adverse Effects (ADR)

Safety Alert · Risk of Respiratory Depression IV

Rapid intravenous administration of phenobarbital in the setting of rescue status has an extremely high risk of inducing **severe arterial hypotension, cardiac bradycardia and central respiratory depression with respiratory arrest**. It requires continuous hemodynamic monitoring, endotracheal intubation available at the patient's bedside, and an infusion rate that should never exceed 60 mg/minute.

• CNS: Marked sedation, somnolence, ataxia, paradoxical hyperactivity reactions (exclusively in children and the elderly, presenting with psychomotor agitation and destructive behaviors), global cognitive impairment with chronic use.
• Dermatological: Maculopapular rash (1-3%). Rare cases of erythema multiforme or Stevens-Johnson Syndrome.
• Osteomuscular: Progressive osteomalacia and bilateral Dupuytren's contracture of the hands with chronic use.

Clinical Interactions

• Potent multienzyme inducer: Massively induces the transcription operons of CYP3A4, CYP2C9, CYP2C19, and UGT. It markedly reduces the effectiveness of contraceptives, warfarin, cyclosporine, antidepressants, corticosteroids, and the vast majority of other antiepileptics (such as valproate, carbamazepine, and lamotrigine).

Pregnancy and Breastfeeding

FDA Category: D. Demonstrated risk of major fetal malformations (microcephaly, cardiac closure defects, facial dysmorphia) and severe neonatal abstinence syndrome after delivery. Supplementation with vitamin K1 recommended in the last month of pregnancy to prevent hemorrhagic disease of the newborn. Breastfeeding: Relatively contraindicated due to the long half-life and accumulation in the infant, causing lethargy and poor weight gain.