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INTRODUCTION

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Barbiturates are derivatives of barbituric acid. The presence of oxygen in the pyrimidine nucleus at carbon 2 position makes the drug an oxybarbiturate (eg, methohexital). In contrast, thiobarbiturates (eg, thiopental) have a sulfur atom at the carbon 2 position. Substitutions at carbon 5 position with either aryl or alkyl groups produce hypnotic and sedative effects. Phenyl groups enable the potent anticonvulsant activity. Thiamylal and thiopental, both thiobarbiturates, have similar pharmacological profiles and are available as racemic mixtures. Methohexital is marketed as a racemic mixture of two alpha isomers. The beta-1 stereoisomer form of methohexital produces excessive motor responses.

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All of these barbiturates are available as sodium salts, and are mixed with either sodium chloride or sterile water to produce the solutions used for intravenous injection.

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Thiobarbiturates have about 2 weeks’ stability in solution, whereas methohexital has 6 weeks. Decreasing the solution’s alkalinity by mixing the barbiturate with acidic solutions, lactated Ringer’s solution, or water-soluble drugs can cause precipitation and occlusion of an intravenous line.

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INDICATIONS

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  • Alternative induction drug for a patient allergic to propofol.

  • Used for cerebral protection during incomplete brain ischemia.

  • Facilitates electroconvulsive therapy or during identification of epileptic foci during surgery (methohexital).

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CONTRAINDICATIONS

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  • Porphyrias (induces aminolevulinic synthetase and stimulates the formation of porphyrin).

  • Hypovolemia (may cause significant reductions in cardiac output and blood pressure).

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MECHANISM OF ACTION

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Barbiturates depress nerve synapses in the reticular activating system, the portion of the nervous system responsible for the level of consciousness. Cellular mechanisms include inhibition of excitatory neurotransmission (acetylcholine and N-methyl-D-aspartate [NMDA]) and enhancement of inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA).

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The GABA receptor is a chloride ion channel. When GABA binds to its receptor, chloride ion conductance increases. The cell membrane hyperpolarizes and increases the threshold for excitability. Thus, GABA is an inhibitory neurotransmitter and the principal one in the CNS. The GABA receptor consists of five subunits, each containing specific binding sites for GABA as well as for barbiturates. Barbiturates bind to the GABA receptor, and at lower concentrations, enhance the effects of GABA. The enhancement effect results from decreased GABA dissociation from the receptor with increased duration of activated-ion chloride channel openings. Higher barbiturate concentrations produces anesthesia from agonist binding of the barbiturate to a specific subunit of the GABA receptor. Barbiturates also inhibit excitatory neurotransmission via the NMDA glutaminergic system and suppression of acetylcholine release.

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PHARMACOKINETICS

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Barbiturates produce rapid (30-45 seconds) onset of unconsciousness following intravenous administration. Most barbiturates exist as a nonionized form and readily pass through the blood–brain barrier, leading to their fast onset of action. The degree of lipid solubility, nonionization state, and degree of protein binding affect the passage of barbiturates across the blood–brain barrier. Higher brain uptake occurs when there is a lowering of serum albumin ...

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