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INTRODUCTION

Benzodiazepines are a class of sedative–hypnotics that share similar chemical structures, receptor physiology, and clinical effects. Benzodiazepines are used broadly for a range of clinical indications, including xenobiotic-induced seizures, xenobiotic-induced psychomotor agitation, withdrawal from ethanol and other sedative–hypnotics, cocaine-associated myocardial ischemia, chloroquine overdose, and to induce muscle relaxation in serotonin toxicity, neuroleptic malignant syndrome, strychnine poisoning, and black widow spider envenomation. This Antidotes in Depth provides a summary of the clinical pharmacology of benzodiazepines and a review of their use in ­specific clinical scenarios, with an emphasis on specific drug selection and safe administration. A discussion of the manifestations and treatment of overdose of benzodiazepines and similar xenobiotics is found in Chap. 72.

HISTORY

The first benzodiazepine, chlordiazepoxide, was discovered serendipitously in 1957 as part of a quest to develop safer and more marketable sedatives.70 Before this, the most commonly prescribed sedative–hypnotics were the barbiturates, which by the 1920s had largely supplanted chloral hydrate, bromides, and opium as the sedatives of choice.71 Although safer than their predecessors, barbiturates were associated with dependence, abuse, and numerous overdose deaths, limiting their therapeutic use. Meprobamate, marketed in the 1950s as the first anxiolytic, was soon withdrawn from the market because of similar problems. The introduction of chlordiazepoxide in 1960 represented a major breakthrough in the field of psychopharmacology and ushered in an era of rapid development and widespread use of numerous other benzodiazepines. The improved safety profile of benzodiazepines as a class allowed them to become, for a time, the most widely prescribed drugs in the world.70

CHEMISTRY

All benzodiazepines share a common chemical structure, shown in Fig. A26–1. This structure links a benzene ring with a diazepine ring and gives rise to the name used to describe the drug class. The additional phenyl ring is present in all clinically important benzodiazepines and serves as a site of substitution that modulates certain pharmacologic characteristics. Modification of side chains of the ring structures leads to differences in lipophilicity, central nervous system (CNS) penetration, duration of action, potency, and rate of elimination. The majority of benzodiazepines are highly protein bound and lipophilic, entering the CNS via passive diffusion.48 The nonbenzodiazepine hypnotics (zolpidem, zopiclone, and zaleplon) lack the typical benzodiazepine structure but have similar pharmacologic effects.40 A discussion of the manifestations and treatment of overdose of benzodiazepines and other sedative–hypnotics is found in Chap. 72.

FIGURE A26–1.

Generic structure of benzodiazepines.

γ-AMINOBUTYRIC ACID TYPE A RECEPTORS

Benzodiazepines bind to a specific site on the postsynaptic γ-aminobutyric acid type A (GABAA) receptor. The GABAA receptor is a ligand-gated chloride channel that, when bound by the inhibitory neurotransmitter GABA, opens to allow an inward flux of negatively charged chloride ions. This results in ...

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