Barbiturates

Barbiturates Overview

  • Definition: Barbiturates are a class of drugs derived from barbituric acid.

  • Mechanism of Action:

    • Barbiturates are GABA A agonists that function as hypnotics by increasing chloride channel opening.

    • They depress the reticular activating system in the brainstem, resulting in controlled consciousness.

Types and Variants of Barbiturates

  • Thiobarbiturates:

    • Characterized by a sulfur atom in the second position of the molecule.

    • This configuration increases the lipid solubility and potency of the drug.

    • Examples: Thiopental and Thiamylal

  • Oxybarbiturates:

    • Contain oxygen in the second position.

    • Examples include methohexital and pentobarbital.

    • Adding a methyl group to nitrogen decreases the seizure threshold, thereby increasing potency.

      • Example is Methohexital:

      • Decreases seizure threshold, making it useful for electroconvulsive therapy (ECT).

      • Dosage: 1 to 1.5 mg/kg.

  • Phenobarbital:

    • Possesses a phenol group that introduces a carbon at the fifth position.

    • This modification enhances anticonvulsant effects.

Formulation & Administration

  • Barbiturate Solutions:

    • Generally, barbiturates are water-soluble with an alkaline pH of 9.

    • Solutions may precipitate when mixed with acidic solutions.

  • Administration Routes:

    • Venous Administration:

      • No venous irritation or pain occurs during administration.

    • Arterial Administration:

      • Intense vasoconstriction and crystal formation may lead to tissue necrosis which is detrimental.

Treatment for Complications

  • For complications arising from arterial administration:

    • Phentolamine and Phenoxybenzamine:

      • These medications induce vasodilation.

    • Stellate Ganglion and Brachial Plexus Block:

      • These procedures can cause sympathoectomy which assists in combating adverse effects.

Metabolism and Clearance

  • Barbiturates are cleared primarily by the liver and show redistribution upon awakening.

  • Repeated Dosing Effects:

    • Repeated doses can lead to tissue accumulation, resulting in prolonged wake-up time and hangover effects.

Key Facts About Thiopental

  • Chemical Name:

    • 5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid.

  • Dosage:

    • Adults: 2.5 to 5 mg/kg.

    • Children: 5 to 6 mg/kg.

  • Onset of Action:

    • Rapid onset, typically 30 to 60 seconds.

  • Duration of Action:

    • Lasts approximately 5 to 10 minutes.

  • Active Metabolite:

    • At high doses, thiopental is metabolized to pentobarbital.

Effects of Barbiturates on Body Systems

  • Cardiovascular Effects:

    • Hypotension results due to venodilation and decreased preload.

    • Secondary myocardial depression is noted.

    • Thiopental may cause non-immunogenic histamine release, leading to transient hypertension and bronchoconstriction—exercise caution in asthmatic patients.

    • Baroreceptor reflexes remain intact, aiding in maintenance of cardiac output.

  • Respiratory Effects:

    • Barbiturates induce respiratory depression characterized by a right shift in the CO2 dissociation curve.

  • Central Nervous System (CNS) Effects:

    • Cerebral Metabolic Oxygen Requirement decreases, leading to lowered cerebral blood flow and intracranial pressure (ICP).

    • Barbiturates can treat intracranial Hypertension.

    • EEG activity diminishes, potentially leading to burst suppression or isoelectric EEG patterns.

    • Analgesic Effects:

      • Barbiturates do not exhibit analgesic properties; low doses may even increase pain perception.

    • Neuroprotective during focal ischemia (e.g., carotid endarterectomy) but not effective for global ischemia (e.g., cardiac arrest).

Complications Associated with Barbiturates

  • Acute Intermittent Porphyria:

    • Inducible condition associated with a defect in heme synthesis, leading to accumulation of heme precursors.

    • Pathway: Succinyl CoA + Glycine leads to ALA synthase producing heme precursors.

    • Condition exacerbated by increased activity of ALA synthase due to emotional distress, prolonged fasting (NPO status), and induction by CYP450.

  • Drugs to Avoid:

    • To prevent acute forms, avoid:

      • Barbiturates

      • Etomidate

      • Ketorolac

      • Amiodarone

      • Certain calcium channel blockers

      • Birth control pills

      • Lidocaine (controversial)

Anesthetic Management in Acute Intermittent Porphyria

  • Management Strategies:

    • Administer fluids and glucose to decrease ALA synthase levels.

    • Heme Arginate: Administers to suppress ALA synthesis.

    • Ensure the patient remains normothermic to prevent hypothermia.

Conclusion

  • Barbiturates are multifaceted agents with critical implications across various physiological systems, and their use demands an understanding of potential complications and management strategies.