Medical Pharmacology Chapter 12:  Anxiolytics and Sedative-Hypnotics

• Barbiturates

  • Mechanism of action 

    • Molecular: Barbiturates activate inhibitory GABA_A while inhibiting excitatory AMPA receptors.

    • AMPA receptors are the subtype of glutamate receptors sensitive to kainate or quisqualate.

    • Barbiturates interact differently than benzodiazepines at GABA receptors. For example, the γ (gamma)-subunit is not required for barbiturate activity.

    •  The combination of these receptor effects may result in the profound cns depression that occurs with higher barbiturate doses.

  • Pharmacokinetics/Redistribution

    • Barbiturates are usually orally administered and are rapidly and well absorbed.

    • Intravenous administration is used for:

      • Treatment of status epilepticus (phenobarbital)

      • Anesthesia induction/maintenance (methohexital (Brevital), thiopental (Pentothal)).

    • Barbiturates are highly lipid soluble and the i.v. barbiturate anesthesia induction agent are the most lipid soluble.

      • After i.v. injection these agents undergo rapid redistribution from the brain to other tissues.

    • Redistribution is the major mechanism  for termination of CNS action.

    • Most barbiturates undergo extensive hepatic metabolism prior to renal excretion.

    • Renal excretion is favored by osmotic diuresis and/or alkalinization of the urine.

    • Barbiturate metabolism is more rapid in young adults compared to children or the elderly.

    • Half-lives may be increased in pregnancy (due to increased volume of distribution)

    • Barbiturate half-lives can be increased in patients with chronic liver disease, such as cirrhosis.

  • Effects of barbiturates on major organ systems

    • Cardiovascular System

      • In sedative or doses for pharmacological hypnosis, barbiturates have minimal cardiovascular effects

      • When thiopental (Pentothal) is used in general anesthesia, following pre-anesthetic medication,  plasma renal flow, cerebral blood flow, and CSF pressure decrease.

      • Significant depression of myocardial contractility occurs in barbiturate poisoning

    • Central Nervous System

      •  Barbiturates depress respiratory drive.

        • At doses somewhat (three times) higher than required for pharmacological hypnosis, neurogenic drive is abolished and the hypoxic respiratory drive is reduced and the chemoreceptor drive is attenuated.

        • At still higher doses, the hypoxic drive is abolished.

    • Liver

      • Acutely, barbiturates combine with cytochrome P-450 and produce competitive inhibition of metabolism of a number of drugs and endogenous agents (such as steroids)

      • Chronically, barbiturates increase activities of cytochrome P-450 oxidases and glucuronyl transferases and therefore increase the metabolism (due to enzyme induction) of many drugs, steroids, vitamins K & D, cholesterol, bile salts.

        • The extent of the increase is about two fold

      • Part of barbiturate tolerance is due to increased hepatic metabolism of barbiturates, induced by barbiturates.

      • Non-microsomal enzyme system are also induced, including:

        •  d -aminolevulinic acid (ALA) synthetase. The effect of barbiturates on ALA synthetase that produces exacerbation in patients with intermittent porphyria.

        • aldehyde dehydrogenase

  • Barbiturate Overdosage/Adverse Effects

    • Adverse Effects:

      •  Drowsiness, impaired judgment, impaired motor skills

      •  Significant CNS/respiratory depression with high dosage.

      •  Paradoxical excitement

      •  If barbiturates are given for pain, restlessness, excitement, or delirium may result

      •  Hypersensitivity: allergic reaction in patients who are predisposed to angioedema, urticaria, and asthma

      •  Drug interactions: combination with other sedative agents can result in severe CNS depression.

    • Untoward effects:

      • Absolutely contraindicated in acute intermittent porphyria or porphyria variegata because barbiturates increase porphyrin synthesis.

      •  i.v. administration can produce cardiovascular collapse; overdosage can cause severe respiratory depression.

    •  Management of barbiturate poisoning

      • Severe intoxication is associated with coma and depressed respiration

      • Treatment is supportive with CNS stimulants contraindicated (increases mortality)

      • Hemodialysis or hemoperfusion may be needed

      • Complicating factors include:

        •  Circulatory collapse

        •  Shock

        •  Dehydration

        •  Renal failure.

  • Therapeutic Uses

    • IV anesthesia: Thiopental (Pentothal) and methohexital (Brevital)

    • Convulsions: emergency treatment (eclampsia, tetanus, status epilepticus), but benzodiazepines are preferable.

    • Epilepsy

    • Rarely used as a sedative due to the availability of safer benzodiazepine agents.

Hibbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 374-377.

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