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INTRODUCTION

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The most common intravenous benzodiazepines administered in the perioperative setting are midazolam, diazepam, and lorazepam. Benzodiazepines produce hypnosis, sedation, anxiolysis, anterograde amnesia, anticonvulsion, and centrally produced muscle relaxation. They do not provide any analgesia. Benzodiazepines are primarily used for premedication and sedation and also for induction of general anesthesia in high doses. Benzodiazepines may be associated with higher risk of postoperative cognitive dysfunction in the elderly.

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The chemical structure of this class of drugs consists of a benzene ring with a seven-member diazepine ring. Substitutions at various positions on the rings distinguish the drugs. The imidazole ring of midazolam allows for water solubility at a low pH (3.5) and preparation in an aqueous solution. At physiologic pH, midazolam increases its lipid solubility by an intramolecular rearrangement. Intravenous diazepam and lorazepam solutions contain propylene glycol (associated with venous irritation) due to their water insolubility.

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MECHANISM OF ACTION

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Benzodiazepines act by enhancing inhibitory neurotransmission through their interaction with the gamma-aminobutyric acid (GABA) receptors. These drugs enhance the efficiency of coupling between the chloride ion channel and the GABA receptor, leading to enhanced inhibition via cellular hyperpolarization. Different GABA receptor subtypes mediate each clinical effect. Alpha-1 receptors modulate sedation, anterograde amnesia, and anticonvulsion. Alpha-2 receptors modulate anxiolysis and muscle relaxation. Central nervous system (CNS) effects depend on each drug’s particular stereospecific affinity for a receptor subtype as well as their degree of binding. The order for receptor affinity is lorazepam>midazolam>diazepam. Effects are dose dependent. Receptor saturation can produce a ceiling effect. Flumazenil reverses the effects of benzodiazepines by acting as an antagonist on these same receptors.

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PHARMACOKINETICS

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Benzodiazepines may be administered orally, intramuscularly (not diazepam), or intravenously. Diazepam and lorazepam are well absorbed from the gastrointestinal tract. Midazolam undergoes first-pass effect, requiring an increase in its oral dosing.

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Due to high lipid solubility with intravenous administration, both diazepam and midazolam readily cross the blood–brain barrier with onset of CNS effects within 2-3 minutes. Moderately lipid-soluble lorazepam has a slightly longer onset of action. Effects of a single dose are terminated by redistribution with awakening, which occurs within 3-10 minutes. The elimination phases of these drugs are dependent upon their metabolism.

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METABOLISM

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Hepatic metabolism via oxidation and glucuronide conjugation transforms benzodiazepines into water-soluble end products which are excreted in the urine. The phase I metabolite of diazepam, desmethyldiazepam, is an active compound with a long half-life. Enterohepatic circulation of diazepam produces a secondary peak in plasma concentration at 6-12 hours with possible resedation. Midazolam results in an active metabolite, hydroxymidazolam, which has mild CNS effects and can accumulate in renal failure.

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Hepatic clearance for midazolam is 5 times that of lorazepam and 10 times that of diazepam. Elimination half-lives vary from 2 hours for midazolam, 11 hours for lorazepam, and 20 hours for diazepam. Midazolam has ...

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