Barbiturates

Barbiturates constitute a class of central nervous system (CNS) depressants historically used for sedation, anesthesia, seizure management, and insomnia. Although their clinical utility has declined due to safety concerns—particularly regarding tolerance, dependence, and risk of overdose—certain barbiturates remain in use for specific medical indications. These agents act primarily through modulation of the GABAergic system, resulting in widespread inhibitory effects on neuronal activity. 

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1. Overview of Barbiturates

Barbiturates are derivatives of barbituric acid, a compound synthesized from malonic acid and urea. The core chemical structure is modified at position 5 to create various barbiturate derivatives with differing pharmacokinetic and pharmacodynamic profiles.

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2. Mechanism of Action

Barbiturates enhance the activity of gamma-aminobutyric acid (GABA) at the GABA-A receptor, which is a ligand-gated chloride ion channel.

• At low to moderate doses, barbiturates potentiate GABA-A activity, increasing the duration of chloride channel opening (distinct from benzodiazepines, which increase frequency).

• At high doses, barbiturates can directly activate GABA-A receptors even in the absence of GABA, contributing to their profound CNS depressant effects.

• They also inhibit AMPA receptors (a subtype of glutamate receptor), contributing to CNS depression.

The result is generalized neuronal inhibition, leading to sedation, hypnosis, anxiolysis, anesthesia, and in high doses, coma or death.

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3. Classification Based on Duration of Action

Barbiturates are categorized into four groups according to their onset and duration of action:

Class	Examples	Onset	Duration	Primary Use
Ultra-short-acting	Thiopental, Methohexital	Seconds	10–30 minutes	Induction of anesthesia, rapid sedation
Short-acting	Pentobarbital, Secobarbital	Minutes	3–4 hours	Sedation, preoperative anxiolysis
Intermediate-acting	Butabarbital	1 hour	6–8 hours	Sleep aid, pre-anesthetic
Long-acting	Phenobarbital	>1 hour	10–16 hours	Seizure control, sedation

4. FDA-Approved Barbiturates and Uses

Generic Name	Brand Name(s)	Approved Indications
Phenobarbital	Luminal	Seizure disorders (e.g., tonic-clonic, status epilepticus), sedation
Butabarbital	Butisol	Sedative, hypnotic (rarely used now)
Pentobarbital	Nembutal	Pre-anesthetic sedation, euthanasia (veterinary), status epilepticus (IV)
Secobarbital	Seconal	Insomnia (short-term), pre-op sedation
Thiopental (discontinued in U.S.)	Pentothal	Induction of anesthesia (IV)
Methohexital	Brevital	Induction of anesthesia, procedural sedation

5. Therapeutic Indications

Although barbiturate use has declined, they remain relevant for:

• Epilepsy and seizure management

  • Phenobarbital is still used, especially in pediatric populations and in low-resource settings.

  • Status epilepticus (second-line, after benzodiazepines).

• Pre-anesthetic sedation

  • Methohexital and pentobarbital for procedures and short surgical interventions.

• Induction of general anesthesia (mostly thiopental or methohexital).

• Insomnia (historical)—mostly replaced by benzodiazepines and Z-drugs due to safer profiles.

• Euthanasia or physician-assisted death (in certain jurisdictions), often with pentobarbital.

• Barbiturate coma induction in neurocritical care to reduce intracranial pressure.

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6. Pharmacokinetics

Property	Details
Absorption	Rapid oral absorption (except thiopental—IV only)
Distribution	High lipid solubility for short-acting agents; crosses blood-brain barrier
Metabolism	Hepatic via CYP450 (CYP2C9, 2C19); induces enzymes
Excretion	Renal elimination; alkaline urine increases excretion (especially in overdose)
Half-life	Phenobarbital: 80–120 hrs (prolonged); others shorter

Barbiturates induce hepatic enzymes, leading to auto-induction and interactions with other drugs metabolized by CYP enzymes.

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7. Adverse Effects

Common Adverse Reactions:

• Drowsiness, fatigue

• Dizziness, ataxia

• Respiratory depression

• Nausea and vomiting

Serious Reactions:

• Respiratory arrest (especially in overdose)

• Coma and death (narrow therapeutic index)

• Tolerance and dependence

• Withdrawal seizures (sudden discontinuation)

• Paradoxical excitement (especially in children)

• Hepatotoxicity (rare, mostly with chronic use)

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8. Contraindications

Barbiturates are contraindicated in:

• Porphyria (can precipitate attacks)

• Severe hepatic impairment

• Respiratory depression

• History of addiction to sedative-hypnotics

• Hypersensitivity to barbiturates

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9. Drug Interactions

Barbiturates are potent CYP450 inducers, especially CYP2C9, CYP2C19, and CYP3A4. As such, they lower plasma concentrations of:

• Warfarin

• Oral contraceptives

• Antidepressants (e.g., SSRIs, TCAs)

• Anticonvulsants

• Antiretroviral agents

• Immunosuppressants

Other interactions:

• Synergistic CNS depression with alcohol, opioids, benzodiazepines

• Reduced effect of some anticoagulants or antipsychotics

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10. Toxicology and Overdose

Clinical Features of Barbiturate Overdose:

• Profound CNS depression

• Hypotension

• Bradycardia

• Respiratory depression → apnea

• Hypothermia

• Coma

• Death (especially if mixed with alcohol or opioids)

Management:

• Supportive care: airway protection, oxygenation

• Activated charcoal if early ingestion

• Alkalinization of urine (sodium bicarbonate) to enhance elimination (especially for phenobarbital)

• No specific antidote

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11. Tolerance, Dependence, and Withdrawal

• Tolerance: develops rapidly to sedative and hypnotic effects

• Dependence: physical and psychological; similar to alcohol or benzodiazepines

• Withdrawal: potentially fatal; symptoms include:

  • Anxiety, tremors

  • Insomnia, agitation

  • Seizures, delirium

Tapering is essential after prolonged use to prevent withdrawal seizures.

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12. Barbiturates vs Benzodiazepines

Feature	Barbiturates	Benzodiazepines
GABA Modulation	↑ duration	↑ frequency
Overdose risk	High (fatal)	Lower (except with alcohol)
Antidote available	No	Yes (flumazenil)
Enzyme induction	Yes	No
Withdrawal severity	Severe	Moderate to severe
Current use	Limited	Widespread

13. Abuse and Recreational Use

Some barbiturates (especially Secobarbital, Pentobarbital) have been abused for their euphoric, sedative, and hypnotic effects. The street term “downers” refers to such use. Due to high risk of addiction and lethal overdose, these drugs are now classified as Schedule II or III controlled substances in the United States, depending on the specific agent.

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14. Veterinary and Euthanasia Use

• Pentobarbital is widely used in veterinary anesthesia, euthanasia, and capital punishment protocols.

• It induces deep sedation, coma, and death through respiratory arrest when used in high doses.

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15. Discontinued or Rarely Used Barbiturates

Some agents have been discontinued due to toxicity or availability of safer alternatives:

• Amobarbital (Amytal) – once used for “truth serum”

• Thiopental – formerly used for anesthesia, now largely unavailable in the U.S.

• Allobarbital, Aprobarbital, Talbutal – historic hypnotics