Phenobarbital
Phenobarbital
Generic Name
Phenobarbital
Mechanism
Phenobarbital is a barbiturate that potentiates γ‑aminobutyric acid (GABA) neurotransmission.
• GABA_A receptor agonism: Opens chloride channels → hyperpolarization of neuronal membranes.
• Inhibition of voltage‑dependent sodium channels: Reduces neuronal excitability, lowering seizure threshold.
• Metabolism to active 5-phenyl-5‑(p‑hydroxyphenyl)-1,3,3‑trihydroxy‑1‑phenyl‑2,3‑dihydro‑2‑pyrrolidone (p‑hydroxyphenobarbital) which retains the same pharmacologic activity.
This dual action yields potent anticonvulsant and sedative effects.
Pharmacokinetics
| Parameter | Value |
| Absorption | Rapid (peak plasma 2–4 h after oral dose). Complete oral bioavailability. |
| Distribution | High plasma protein binding (~90 %, mainly albumin). Large volume of distribution (~0.6‑1 L/kg). Lipid‑soluble → crosses placenta, penetrates CNS, and accumulates in adipose tissue. |
| Metabolism | Hepatic glucuronidation (main pathway) and CYP450‑mediated oxidation (CYP2C9, CYP2C19). Metabolite is pharmacologically active. |
| Elimination | Renal excretion of metabolites. Half‑life: 3‑10 days in adults; longer in the elderly or with hepatic impairment. No dose adjustment required for renal disease due to extensive hepatic metabolism. |
| Special Populations | In pregnancy: reduces maternal seizure risk but may cause fetal withdrawal. In neonates: higher clearance; use lower doses (see Dosing). |
Indications
- Acute and chronic seizure disorders (e.g., generalized tonic‑clonic, absence, partial).
- Tetany, hypocalcemia‑induced seizures (high‑dose “safety‑drug” approach).
- Pre‑operative sedation (low‑dose infusion).
- Miscellaneous: Idiopathic pulmonary hypertension (rare), as a sedative in anesthetic protocols (in resource‑limited settings).
Contraindications
- Allergic reaction to phenobarbital or other barbiturates.
- Severe hepatic dysfunction (increased toxicity risk).
- Thyroid disease?: Mild hyperthyroidism may increase metabolism → dose adjustment.
- Pregnancy (especially >25 weeks): risk of fetal hypoglycemia, seizures, and withdrawal; use only if benefit outweighs risk.
- Concurrent use with antipsychotics or other CNS depressants → enhanced sedation/pneumonia risk.
- Caution in elderly, renally impaired, or with baseline QTc prolongation (potential arrhythmias).
Dosing
| Population | Initial Dose | Maintenance | Administration |
| Adults | 150 mg PO once daily → titrate 50‑250 mg/day to effect | 100‑200 mg/day orally (divided) | Oral capsules/tablets or IV (1‑5 mg/kg over 15‑30 min) |
| Children | 10–25 mg/kg/day (max 400 mg/day) | 10‑25 mg/kg/day | Oral suspension; 30 mg/kg IV if seizure control needed |
| Neonates | 50 mg/kg/day (max 200 mg/day) | 50 mg/kg/day | Oral or induced IV (1‑5 mg/kg) |
| Pregnancy | 30 mg/kg/day | 30–50 mg/kg/day | Oral; may increase dose after first trimester for seizure control. |
• Titration: Increase by 50–100 mg/day every 48–72 h until clinical response (usually within 2–4 weeks).
• Load dose may be given (500–1 000 mg IV) for uncontrolled seizures; monitor for residual sedation.
Adverse Effects
- Common
- drowsiness, dizziness, ataxia
- constipation, decreased appetite
- sedation‑related respiratory depression (particularly with high dosing or combos)
- rash/dermatitis (rare)
- Serious
- serotonin syndrome when combined with serotonergic agents
- hepatic injury (↑ALT, AST)
- hypoglycemia (especially in neonates) → seizures
- QTc prolongation (rare)
- paradoxical agitation/anxiety
- withdrawal syndrome if abrupt discontinuation: seizures, tremor, nervousness
Monitoring
- Baseline: Liver function tests (ALT, AST), CBC, electrolytes, lipid profile.
- During therapy:
- Seizure frequency & EEG changes
- Blood phenobarbital levels (100–200 μg/mL goal for controlled seizures).
- QTc interval (baseline, then after starting or dose increased).
- Liver enzymes (every 3–6 months).
- Plasma glucose (especially in infants).
- When switching drugs: Monitor for withdrawal, adjust dosing accordingly.
Clinical Pearls
- ‘Phenobarbital loading dose’: A single 500–1 000 mg IV dose can bring plasma levels into therapeutic range within hours, invaluable in status epilepticus when oral administration is impossible.
- Metabolism to active metabolite: Phenobarbital’s anticonvulsant effect persists because the glucuronide metabolism yields the same active compound; therefore, even after hepatic inhibitors, efficacy remains relatively stable.
- Pregnancy caution: Start low, increase slowly, and entirely discontinue before delivery if possible to avoid neonatal withdrawal.
- Drug‑drug interactions: Phenobarbital induces CYP450 (esp. CYP2C9), lowering efficacy of many oral contraceptives, anticoagulants, and antidiabetic agents—monitor therapeutic levels.
- Use in neonatal hypocalcemia: High‑dose phenobarbital blocks tetany by binding β‑subunits of voltage‑gated calcium channels—a useful adjunct in severe neonatal hypocalcemia.
- Tolerance & dependence: Chronic use leads to tolerance; abrupt withdrawal can precipitate seizures, so taper over 2–6 weeks.
> Remember: Phenobarbital is a first‑line anticonvulsant when drug cost, availability, or need for long‑term therapy outweighs newer agents—particularly in low‑resource settings. Its long half‑life allows once‑daily dosing but demands careful monitoring for cumulative sedation and hepatic toxicity.