Pentobarbital (Nembutal)

Central Nervous System Depressant - Short-Acting Barbiturate

Overview

Pentobarbital is a short-acting barbiturate first synthesized in 1928 and FDA-approved in 1930 for sedation, anesthesia, and seizure control. Originally marketed as Nembutal, it was widely used for insomnia treatment and surgical anesthesia but has largely been replaced by safer alternatives due to its narrow therapeutic window and high abuse potential. Currently, pentobarbital remains clinically important primarily for refractory status epilepticus, barbiturate coma induction for intracranial pressure management, and euthanasia procedures in veterinary medicine and human medical aid-in-dying where legally permitted. Its rapid onset, reliable effects, and dose-dependent progression from sedation to anesthesia to respiratory arrest have made it both therapeutically valuable and inherently dangerous.

Mechanism of Action

Pentobarbital enhances GABA-mediated neurotransmission by binding to the GABA-A receptor complex and prolonging chloride channel opening, resulting in neuronal hyperpolarization and CNS depression. At higher concentrations, pentobarbital can directly activate GABA receptors independent of GABA and also blocks voltage-gated sodium and calcium channels, explaining its greater toxicity compared to benzodiazepines. The drug primarily affects the reticular activating system, producing dose-dependent effects from mild sedation to surgical anesthesia and ultimately respiratory and cardiac depression. Pentobarbital also reduces cerebral blood flow and intracranial pressure, making it valuable for neuroprotection in brain injury, though it significantly suppresses REM sleep and can cause rebound hyperexcitability upon discontinuation.

Indications

  • Insomnia: Short-term treatment of insomnia when other treatments are ineffective (rarely used due to safety concerns).
  • Preoperative Sedation: Sedation and anxiolysis before surgical or diagnostic procedures.
  • Emergency Anticonvulsant: Control of acute seizures and status epilepticus when other agents have failed.
  • Anesthesia Induction: General anesthesia induction in combination with other agents.
  • Refractory Status Epilepticus: Third-line agent for status epilepticus unresponsive to benzodiazepines and phenytoin.
  • Barbiturate Coma: Induced coma for severe traumatic brain injury with elevated intracranial pressure.
  • Medical Aid in Dying: Component of physician-assisted death protocols where legally permitted.
  • Barbiturate Withdrawal: Cross-tolerance allows substitution during withdrawal from other barbiturates.
  • Intractable Agitation: Severe agitation unresponsive to other sedatives (last resort).

Dosing and Administration

Indication Route Adult Dose Pediatric Dose
Insomnia PO 100-200 mg at bedtime 2-6 mg/kg at bedtime
Preoperative Sedation PO/IM 150-200 mg 2-6 mg/kg (max 100 mg)
Status Epilepticus IV 10-15 mg/kg loading, then 0.5-3 mg/kg/hr 10-20 mg/kg loading, then 1-3 mg/kg/hr
Barbiturate Coma IV 3-5 mg/kg loading, then 1-3 mg/kg/hr 3-5 mg/kg loading, then 1-4 mg/kg/hr
Anesthesia Induction IV 100-200 mg 3-5 mg/kg
  • IV Administration: Inject slowly (≤50 mg/minute) to prevent respiratory depression and hypotension.
  • Continuous Monitoring: Requires continuous cardiac, respiratory, and neurological monitoring during IV use.
  • Duration Limits: Oral use should not exceed 2 weeks due to tolerance and dependence development.
  • Extravasation: IV infiltration can cause tissue necrosis; ensure proper IV placement before administration.
  • Elderly: Reduce dose by 50%; increased sensitivity to CNS depression and higher fall risk.
  • Hepatic Impairment: Contraindicated in severe disease; reduce dose by 50-75% in mild-moderate impairment.
  • Renal Impairment: Dose adjustment generally not required but monitor for prolonged effects.
  • Pregnancy: Category D; crosses placenta readily; can cause neonatal respiratory depression and withdrawal.
Clinical Pearl: For status epilepticus, pentobarbital is typically reserved for refractory cases when benzodiazepines, phenytoin, and levetiracetam have failed - requires ICU monitoring.

Pharmacokinetics

Parameter Details
Absorption Rapidly absorbed orally; peak levels in 30-60 minutes
Bioavailability High oral bioavailability (>95%)
Onset of Action IV: 1-5 minutes; PO: 15-60 minutes
Metabolism Hepatic via CYP2C19 and CYP2C9; significant first-pass effect
Half-Life 15-50 hours (average 22 hours); prolonged in elderly
Duration of Action 3-4 hours for sedation; longer for anticonvulsant effects
Excretion Urine (99% as metabolites, <1% unchanged)
Clinical Pearl: The long elimination half-life (22 hours) means accumulation occurs with repeated dosing, increasing the risk of prolonged sedation and respiratory depression.

Side Effects

  • Central Nervous System: Drowsiness (very common), dizziness, ataxia, confusion, hangover effect, cognitive impairment.
  • Gastrointestinal: Nausea, vomiting, constipation, abdominal pain.
  • Cardiovascular: Hypotension, bradycardia, especially with IV administration.
  • Local (IV): Pain at injection site, phlebitis, potential tissue necrosis with extravasation.
  • Other: Headache, weakness, blurred vision, skin rash.

Incidence data from FDA prescribing information and clinical studies (2021).

  • Respiratory Depression: Dose-dependent and potentially fatal, especially with IV administration or drug combinations.
  • Cardiovascular Collapse: Severe hypotension and cardiac depression with rapid IV administration.
  • Physical Dependence: Can develop within 1-2 weeks; withdrawal includes life-threatening seizures.
  • Laryngospasm/Bronchospasm: Paradoxical respiratory complications, particularly in patients with asthma.
  • Severe Skin Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis (rare).
  • Paradoxical Excitement: Hyperactivity, agitation, particularly in children and elderly.
Clinical Pearl: Respiratory depression is the primary cause of death in pentobarbital overdose - onset can be rapid and requires immediate mechanical ventilation support.

Interactions

  • CNS Depressants: Alcohol, benzodiazepines, opioids - potentially fatal additive respiratory depression and sedation.
  • CYP Enzyme Induction: Pentobarbital induces CYP3A4, CYP2C9, CYP2C19 - reduces levels of many drugs.
  • Warfarin: Significantly reduces warfarin effectiveness; may require dose doubling and frequent INR monitoring.
  • Oral Contraceptives: Reduces contraceptive efficacy through enzyme induction; backup contraception essential.
  • Corticosteroids: Accelerated metabolism may require steroid dose increases.
  • Phenytoin: Complex bidirectional interaction; monitor phenytoin levels closely.
  • MAO Inhibitors: Prolonged barbiturate effects; avoid concurrent use.
Clinical Pearl: Pentobarbital is a potent enzyme inducer - many drug interactions involve reduced efficacy of co-administered medications rather than increased pentobarbital toxicity.

Contraindications and Warnings

  • Hypersensitivity: Known allergy to pentobarbital or other barbiturates.
  • Porphyria: All barbiturates can precipitate life-threatening acute porphyric attacks.
  • Severe Respiratory Disease: Severe COPD, respiratory depression, airway obstruction.
  • Severe Cardiovascular Disease: Marked hypertension, severe heart failure, shock.
  • Severe Hepatic Impairment: Significantly impaired drug metabolism increases toxicity risk.
  • High Abuse Potential: Schedule II controlled substance; monitor for signs of misuse and diversion.
  • Respiratory Monitoring: Requires continuous monitoring during IV use; resuscitation equipment must be available.
  • Withdrawal Risk: Abrupt discontinuation after regular use can cause fatal withdrawal seizures.
  • Injection Site Care: IV extravasation can cause severe tissue necrosis requiring surgical intervention.
  • Tolerance Development: Rapid tolerance requires dose escalation, increasing overdose risk.
  • Elderly Sensitivity: Extreme caution in elderly due to increased sensitivity and fall risk.

Evidence and Guidelines

  • Status Epilepticus: Effective as third-line therapy for refractory status epilepticus (85% seizure control rate in ICU studies).
  • Barbiturate Coma: Mixed evidence for improved outcomes in traumatic brain injury; requires careful risk-benefit analysis.
  • Anesthesia Studies: Reliable anesthesia induction but higher complication rates compared to modern agents.
  • Withdrawal Studies: Fatal withdrawal seizures documented in 15% of cases without medical supervision.
  • Neurocritical Care Society: Recommended as third-line agent for super-refractory status epilepticus.
  • Brain Trauma Foundation: May consider for refractory intracranial hypertension when other measures fail.
  • American Academy of Sleep Medicine: Not recommended for insomnia due to safety profile.
  • DEA Scheduling: Schedule II controlled substance due to high abuse potential and dependence risk.

Monitoring Parameters

  • Respiratory Function: Continuous monitoring of respiratory rate, depth, and oxygen saturation during IV use.
  • Cardiovascular Status: Blood pressure, heart rate, and cardiac rhythm monitoring, especially during IV administration.
  • Neurological Assessment: Level of consciousness, pupil response, and seizure activity monitoring.
  • IV Site Monitoring: Frequent assessment for infiltration, phlebitis, or signs of extravasation.
  • Drug Levels: Serum pentobarbital levels for prolonged use (therapeutic range: 1-5 mg/L for sedation).
  • Liver Function: Baseline and periodic LFTs, especially with prolonged use or hepatic risk factors.
  • Withdrawal Assessment: Monitor for tremor, anxiety, insomnia, and seizure activity during discontinuation.

Patient Education

  • ICU Setting Only: IV pentobarbital requires intensive care monitoring; never administer outside hospital setting.
  • Short-Term Use: Oral forms should only be used for very short periods (days) due to rapid dependence development.
  • Avoid Alcohol: Never combine with alcohol - this combination can be rapidly fatal.
  • Driving Prohibition: Do not drive or operate machinery; impairment can last 12-24 hours after administration.
  • Gradual Discontinuation: Never stop abruptly after regular use; requires medical supervision for safe withdrawal.
  • Drug Interactions: Inform all healthcare providers; pentobarbital affects the metabolism of many other medications.
  • Secure Storage: Store securely away from others; high potential for abuse and accidental overdose.
  • Emergency Signs: Seek immediate help for slow or absent breathing, blue lips/fingernails, or inability to wake up.