Barbiturates - Pharmacology

Note: Shanbhag's Review of Pharmacology is not available in this library. The following covers barbiturate pharmacology comprehensively as presented in Goodman & Gilman's The Pharmacological Basis of Therapeutics and Katzung's Basic & Clinical Pharmacology - the primary references Shanbhag's text is itself based on.

1. Chemistry / Structure

• Barbituric acid itself has no CNS depressant activity
• Activity is conferred by alkyl or aryl groups at position C5
• Replacement of O at C2 by sulfur gives thiobarbiturates (e.g., thiopental) - more lipid-soluble, faster onset, shorter duration

• Increased lipid solubility → decreased duration, decreased latency, faster metabolism, increased hypnotic potency
• Long-chain substitutions at C5 → anticonvulsant activity
• Phenyl group at C5 → anticonvulsant property (e.g., phenobarbital)
• N-methyl substitution → shorter action (methohexital)

2. Classification

3. Mechanism of Action

• They enhance GABA-mediated Cl⁻ influx by binding to a specific site (distinct from the benzodiazepine site)
• At low concentrations: they increase the duration of Cl⁻ channel opening (unlike benzodiazepines which increase frequency)
• At high/anesthetic concentrations: they can directly open Cl⁻ channels even without GABA (this explains their greater danger in overdose vs. benzodiazepines)
• They also inhibit AMPA receptors (glutamate-mediated excitatory neurotransmission), contributing to CNS depression
• All excitable tissues are reversibly depressed, but CNS is most sensitive

4. Pharmacokinetics (ADME)

• Oral administration: Na⁺ salts absorbed faster than free acids, especially from liquid preparations
• Onset: 10-60 min orally; delayed by food
• IM injection: must be deep into large muscles (superficial injection causes pain/necrosis)
• IV: reserved for status epilepticus (phenobarbital) or anesthesia induction (thiopental, methohexital)

• Wide distribution throughout the body
• Readily cross the placenta (teratogenic risk)
• Highly lipid-soluble agents (thiopental, methohexital): rapid redistribution to muscle/fat after IV injection → rapid awakening in 5-15 min despite long elimination half-life (redistribution kinetics, NOT metabolism, determines duration)

• Nearly complete hepatic metabolism (except phenobarbital and aprobarbital)
• Key biotransformation: oxidation of radicals at C5 - terminates biological activity
• N-glycosylation important for phenobarbital
• Other pathways: N-hydroxylation, desulfuration (thiobarbiturates → oxybarbiturates), ring opening, N-dealkylation (mephobarbital → phenobarbital, an active metabolite)
• Phenobarbital (~25%) and aprobarbital (nearly all): excreted unchanged in urine

• Renal excretion of phenobarbital can be greatly increased by:
  • Osmotic diuresis
  • Alkalinization of urine (phenobarbital is a weak acid, pKa ~7.2; alkaline urine ionizes it → traps in urine → ion trapping)
  • This is the basis for treating phenobarbital overdose with sodium bicarbonate

• Chronic barbiturate use markedly induces hepatic microsomal enzymes: CYP1A2, CYP2C9, CYP2C19, CYP3A4, glucuronyl transferase
• This accelerates metabolism of many drugs: warfarin, oral contraceptives, corticosteroids, other barbiturates, vitamin K and D, steroid hormones, cholesterol, bile salts
• Self-induction partly accounts for pharmacokinetic tolerance
• Also induces ALA synthase (mitochondrial) - dangerous in porphyria

5. Pharmacological Effects

Central Nervous System

• Dose-dependent CNS depression: sedation → hypnosis → anesthesia → coma → death
• Non-selective: depress all CNS functions (unlike benzodiazepines which have a ceiling effect)
• No analgesia - some barbiturates may actually lower pain threshold (hyperalgesia) - important point; pain can cause paradoxical excitement
• Reduce sleep latency; decrease REM sleep (REM rebound on withdrawal)
• EEG: increase beta waves at low doses; suppress EEG activity at anesthetic doses

• Decrease cerebral blood flow (CBF), cerebral blood volume (CBV), and intracranial pressure (ICP)
• Decrease cerebral metabolic rate (CMRO2) - dose-dependent, up to burst suppression
• Useful in management of raised ICP and space-occupying lesions
• Neuroprotection from focal cerebral ischemia (stroke, surgical)
• NOT effective for global ischemia (cardiac arrest)
• Anticonvulsant (except methohexital which activates epileptic foci - useful in ECT)

Cardiovascular System

• Depression of myocardial contractility (direct negative inotropic effect)
• Peripheral vasodilation → fall in systemic blood pressure
• Less baroreceptor reflex inhibition than propofol → compensatory tachycardia limits hypotension
• Rapid IV injection can cause cardiovascular collapse before anesthesia (apnea, laryngospasm)
• Risk greater with hypovolemia, cardiac tamponade, cardiomyopathy

Respiratory System

• Respiratory depressants: decrease minute ventilation (reduced tidal volume and rate)
• Decrease ventilatory response to hypercapnia and hypoxia
• Usual induction dose causes transient apnea
• Hypnotic doses contraindicated in pulmonary insufficiency
• Barbiturates do NOT produce muscle relaxation

Hepatic Effects

• Acute: inhibit CYPs and biotransformation of other drugs
• Chronic: induce smooth ER proliferation and CYP enzymes (see enzyme induction above)
• Trigger ALA synthase → absolutely contraindicated in acute intermittent porphyria and porphyria variegata

Renal Effects

• Severe oliguria or anuria in acute poisoning - secondary to marked hypotension

6. Therapeutic Uses

7. Adverse Effects

• Aftereffects (Hangover): Residual drowsiness, mood distortion, impaired fine motor skills, nausea, vomiting, vertigo - may persist next day
• Paradoxical excitement: Excitement/inebriation-like state instead of sedation; common in elderly, debilitated patients, and N-methyl barbiturates; also with pain (lower pain threshold)
• Hypersensitivity: Allergic reactions more common in asthma, urticaria, angioedema; localized edema (eyelids, cheeks, lips); erythematous dermatitis; rarely exfoliative dermatitis from phenobarbital (can be fatal, associated with fever, delirium, liver damage)
• Tolerance and Dependence: Both pharmacokinetic (enzyme induction) and pharmacodynamic tolerance develop; physical dependence causes severe withdrawal (more dangerous than opioid withdrawal - can be fatal with grand mal seizures)
• Abuse potential: High (Schedule IV/II drugs)
• Porphyria crisis: Absolutely contraindicated in acute intermittent porphyria

8. Tolerance and Dependence

• Pharmacokinetic tolerance: Enzyme induction → increased metabolism of barbiturate itself
• Pharmacodynamic tolerance: CNS adaptation at receptor level
• Physical dependence: Abrupt withdrawal after chronic use causes a dangerous abstinence syndrome:
  • Anxiety, insomnia, tremors, delirium, grand mal seizures, hyperthermia
  • Can be life-threatening (unlike opioid withdrawal)
  • Treatment: gradual dose tapering, substitution with long-acting barbiturate (phenobarbital)

9. Acute Barbiturate Poisoning (Overdose)

• Mild: drowsiness, slurred speech, ataxia, nystagmus, emotional lability
• Severe: stupor → deep coma → respiratory arrest
• Flaccid coma + small reactive pupils + hypothermia + hypotension - hallmark (few other causes)
• Respiratory depression is the primary cause of death

• Airway, breathing, circulation (supportive)
• Activated charcoal (if early)
• Alkalinization of urine (sodium bicarbonate) + forced diuresis → enhances excretion of phenobarbital
• Hemodialysis for severe cases
• No specific antidote (unlike benzodiazepines which have flumazenil)
• Caution: Rapid lowering of levels in chronic users can precipitate withdrawal seizures

10. Contraindications

1. Acute intermittent porphyria / porphyria variegata (absolute)
2. Pulmonary insufficiency (hypnotic doses)
3. Severe hepatic impairment
4. Rapid IV injection in hemodynamically compromised patients
5. Known hypersensitivity

11. Key Comparisons: Barbiturates vs. Benzodiazepines