Since the introduction of chlordiazepoxide in 1960,53 benzodiazepines have gained acceptance as safe and effective drugs for a large variety of clinical indications. Specifically in medical toxicology, benzodiazepines are used as the first-line anticonvulsants for virtually all xenobiotic-induced seizures; as the sedatives of choice for most forms of xenobiotic-induced agitation; as muscle relaxants for diverse disorders such as serotonin syndrome, neuroleptic malignant syndrome, and poisoning from strychnine or black widow spider envenomation; and as sedative hypnotics for withdrawal from ethanol, γ-hydroxybutyric acid (GHB), and a variety of sedatives. Additional distinct indications for benzodiazepines can be found in overdose from chloroquine and possibly other quinine-derived antimalarials, and in patients with cocaine-associated myocardial ischemia and infarction.
This Antidotes in Depth provides a summary of the clinical pharmacology of benzodiazepines in order to provide the reader with the background necessary to administer these drugs as safely and effectively as possible.
All benzodiazepines share a common chemical structure shown in Figure A24–1. 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 some pharmacologic characteristics. The pyrazolopyrimidines (zolpidem, zopiclone, and zaleplon) lack the typical benzodiazepine structure, but have similar pharmacologic effects.20 Since these pharmaceuticals are largely unstudied for the antidotal indications described above, they are not discussed in depth here. A discussion of the manifestations and treatment of overdose of benzodiazepines and similar xenobiotics can be found in Chapter 74.
Generic structure of benzodiazepines.
Benzodiazepines target the γ-aminobutyric acid type A (GABAA) receptor, which is a ligand-gated chloride channel (a24fg2see Chap. 13, Fig. 13-10), but have no appreciable binding to GABAB. In the absence of GABA, benzodiazepines have no effect on chloride conductance. However, when GABA is present on its GABAA receptor, benzodiazepines increase the frequency of channel opening resulting in enhanced flow of negatively charged chloride ions into the cell with resultant hyperpolarization.56
The GABAA receptor is assembled from five subunits that span the cell membrane in a circular fashion to create the chloride channel.40 These subunits are coded as α, β, γ, δ, ε, Φ, π, or ρ, and at least 19 isoforms of these subunits (such as α1, α2, α3, α4, and α5) are identified.12 If the isoforms of the known subunits could assemble randomly, several hundred thousand possible configurations of the GABAA receptor would be possible.58 However, it appears that a minimum of at least one α, one β, and either one γ or one δ subunit are required to form a functional chloride ...