Phenobarbitone

Usage

Phenobarbitone is primarily prescribed for the prevention and treatment of seizures, including generalized tonic-clonic seizures, partial seizures, and status epilepticus. It’s also used as a sedative, a hypnotic (for short-term treatment of insomnia), and preoperatively. It’s classified as a barbiturate and an anticonvulsant. The drug enhances inhibitory neurotransmission, primarily by potentiating the effects of gamma-aminobutyric acid (GABA) at the GABA_A receptor.

Alternate Names

Phenobarbitone is also known as phenobarbital. Brand names include Solfoton, Luminal, and others.

How It Works

Pharmacodynamics: Phenobarbitone enhances GABA-mediated inhibition in the central nervous system. It binds to a specific site on the GABA_A receptor, distinct from the GABA binding site and the benzodiazepine binding site. This binding increases the duration of chloride channel opening, leading to hyperpolarization and reduced neuronal excitability. It also reduces the release of excitatory neurotransmitters like glutamate.

Pharmacokinetics: Phenobarbitone is well-absorbed orally. Peak plasma concentrations are reached in 8-12 hours. It has a long half-life (53-118 hours in adults, 21-72 hours in children), allowing for once-daily dosing. The drug is metabolized in the liver, primarily by CYP450 enzymes, with a small portion excreted unchanged in the urine. It induces several CYP450 enzymes.

Dosage

Standard Dosage

Adults:

• Sedation: 30-120 mg/day PO divided into 2-3 doses.
• Hypnotic: 100-320 mg/day PO or IV/IM as a single dose. Use should not exceed two weeks.
• Anticonvulsant: Initial: 1-3 mg/kg/day PO or IV divided into 1-2 doses. Adjust based on serum levels and response to maintain within the therapeutic range (20-40 mcg/mL). Maximum dose: 600mg/day.

Children:

• Sedation: 2 mg/kg PO three times/day or 60 mg/m² PO three times/day.
• Anticonvulsant: Neonates (<28 days): 3-5 mg/kg/day PO or IV divided into 1-2 doses. Infants: 5-6 mg/kg/day PO or IV divided into 1-2 doses. Children (1-5 years): 6-8 mg/kg/day PO or IV divided into 1-2 doses. Children (6-12 years): 4-6 mg/kg/day PO or IV divided into 1-2 doses.

Special Cases:

• Elderly Patients: Start with a lower dose and titrate cautiously due to increased sensitivity to CNS depressant effects.
• Patients with Renal Impairment: Reduce the dose based on the degree of impairment as phenobarbitone is partially excreted by the kidneys.
• Patients with Hepatic Dysfunction: Reduce the dose due to impaired metabolism. Phenobarbitone also induces hepatic enzymes.
• Patients with Comorbid Conditions: Use with caution in patients with respiratory disease, cardiovascular disease, hyperthyroidism, diabetes mellitus, or myasthenia gravis.

Clinical Use Cases

• Intubation: Phenobarbitone is not typically used for intubation.
• Surgical Procedures: Preoperative sedation: 100-200 mg IV/IM 60-90 minutes prior to surgery. Pediatric: 1-3 mg/kg IV/IM.
• Mechanical Ventilation: Not typically used in this context.
• Intensive Care Unit (ICU) Use: Primarily used for seizure control. Dosage adjustments are based on individual patient needs.
• Emergency Situations (e.g., status epilepticus): Adult: Loading dose: 10-20 mg/kg IV. Pediatric: Loading dose: 20 mg/kg IV (may repeat with 10 mg/kg after 15 minutes if needed). Maintenance dose should be started 8-12 hours after the loading dose.

Dosage Adjustments

Dose modifications are required for patients with renal or hepatic impairment. Therapeutic drug monitoring is recommended to optimize therapy and minimize adverse effects. Genetic polymorphisms affecting drug metabolism may also necessitate adjustments.

Side Effects

Common Side Effects:

Drowsiness, dizziness, headache, nausea, vomiting, constipation, agitation, confusion, and fatigue. “Hangover” effect, ataxia, nightmares, nervousness, and psychiatric disturbances may also occur.

Rare but Serious Side Effects:

Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, severe skin rashes, hepatotoxicity, megaloblastic anemia (with chronic use), respiratory depression, hypotension, bradycardia, and syncope.

Long-Term Effects:

Osteoporosis, vitamin D deficiency, decreased libido, and dependence can occur with prolonged use.

Adverse Drug Reactions (ADR):

Agranulocytosis, aplastic anemia, and paradoxical excitement (especially in children and the elderly) require immediate intervention.

Contraindications

Absolute contraindications include hypersensitivity to phenobarbitone, manifest or latent porphyria, severe respiratory depression, and severe hepatic impairment.

Drug Interactions

Phenobarbitone is a potent inducer of CYP450 enzymes. It interacts with numerous medications, including:

• Commonly prescribed medications: Oral contraceptives (reduced efficacy), warfarin (decreased efficacy), doxycycline, corticosteroids, tricyclic antidepressants, and other anticonvulsants.
• Over-the-Counter (OTC) drugs and supplements: Antihistamines (increased sedation).
• Food and lifestyle factors: Alcohol (increased CNS and respiratory depression).

Pregnancy and Breastfeeding

Phenobarbitone is a Pregnancy Category D drug. It can cause fetal harm, including congenital malformations and bleeding disorders. It’s excreted in breast milk and can cause drowsiness and feeding problems in infants. Safer alternatives should be considered during pregnancy and breastfeeding.

Drug Profile Summary

• Mechanism of Action: Enhances GABAergic neurotransmission, leading to decreased neuronal excitability.
• Side Effects: Drowsiness, dizziness, headache, nausea; rarely, Stevens-Johnson syndrome, respiratory depression.
• Contraindications: Porphyria, severe respiratory depression, severe hepatic impairment.
• Drug Interactions: Numerous; potent CYP450 inducer.
• Pregnancy & Breastfeeding: Avoid; Pregnancy Category D.
• Dosage: Varies depending on indication and patient factors.
• Monitoring Parameters: Serum phenobarbitone levels, liver function tests, complete blood count.

Popular Combinations

Phenobarbitone is sometimes used in combination with other anticonvulsants for refractory epilepsy.

Precautions

• General Precautions: Evaluate liver and kidney function before and during therapy. Assess for respiratory disease.
• Specific Populations: Avoid in pregnancy and breastfeeding. Use with caution in children and the elderly.
• Lifestyle Considerations: Avoid alcohol. Caution with operating machinery or driving.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Phenobarbitone?

A: Dosage varies based on the indication and patient-specific factors. For adults, the usual sedative dose is 30-120 mg/day PO, hypnotic dose is 100-320 mg/day, and anticonvulsant dose starts at 1-3 mg/kg/day. Pediatric doses vary by age and indication. Elderly patients require lower doses.

Q2: How does phenobarbitone work in the body?

A: It primarily enhances the inhibitory effects of GABA by increasing the duration of chloride channel opening at the GABA_A receptor.

Q3: What are the common side effects of phenobarbitone?

A: Drowsiness, dizziness, headache, nausea, and cognitive impairment are common side effects.

Q4: Can phenobarbitone be used during pregnancy?

A: It’s generally avoided due to the risk of fetal harm.

Q5: What are the major drug interactions with phenobarbitone?

A: Phenobarbitone interacts with numerous drugs, including oral contraceptives, warfarin, and other anticonvulsants. It’s a potent CYP450 inducer, so its co-administration with CYP450 substrates requires careful consideration.

Q6: What is status epilepticus, and how is phenobarbitone used in its management?

A: Status epilepticus is a prolonged seizure lasting longer than five minutes or recurrent seizures without recovery of consciousness between them. Phenobarbitone is used as a second-line agent after benzodiazepines, given intravenously.

Q7: Can phenobarbitone be used for long-term seizure control?

A: Yes, it can be used long-term, but tolerance may develop, requiring dosage adjustments. Monitoring serum levels is crucial.

Q8: How is phenobarbitone metabolized?

A: Primarily metabolized by hepatic CYP450 enzymes, with a small portion excreted unchanged in the urine.

Q9: What should patients know about taking phenobarbitone?

A: Take as prescribed, do not stop abruptly, avoid alcohol, and be cautious with operating machinery or driving. Report any unusual symptoms to your doctor immediately.

Q10: Are there any contraindications for phenobarbitone use?

A: Yes, including porphyria, hypersensitivity, severe respiratory or liver diseases.