A23: Antidotes in Depth

INTRODUCTION

Benzodiazepines are used as first-line anticonvulsants for virtually all xenobiotic induced seizures; as sedatives of choice for most forms of xenobiotic induced agitation; as muscle relaxants for diverse disorders such as serotonin toxicity, neuroleptic malignant syndrome, and poisoning from strychnine or black widow spider envenomation; and as ­sedatives for withdrawal from ethanol, γ-hydroxybutyric acid, and other ­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.

HISTORY

Most ancient texts make reference to the use of some plant or natural substance for sedation. By the mid to late 1800s, many of the natural sedatives were replaced by alcohol and chloral hydrate.¹⁷ The search for better sedatives with fewer side effects led to the development of barbiturates in the early 1900s followed by numerous others such as meprobamate, glutethimide, and ethchlorvynol (Chap. 74). Since the introduction of chlordiazepoxide in 1960,⁷⁷ benzodiazepines have gained acceptance as safe and effective drugs for a large variety of clinical indications. Over the intervening years, the number of benzodiazepines has increased, with each new drug demonstrating unique and complex pharmacology.

CHEMISTRY

All benzodiazepines share a common chemical structure, shown in Fig. A23–1. 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. The pyrazolopyrimidines (zolpidem, zopiclone, and zaleplon) lack the typical benzodiazepine structure but have similar pharmacologic effects.²⁸ 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 Chap. 74.

γ-AMINOBUTYRIC ACID TYPE A RECEPTORS

Benzodiazepines target the γ-aminobutyric acid type A (GABA_A) receptor, which is a ligand-gated chloride channel, but have no appreciable binding to GABA_B. When GABA is present on its GABA_A receptor, benzodiazepines increase the frequency of channel opening, resulting in enhanced flow of negatively charged chloride ions into the cell with resultant hyperpolarization.⁸³ However, in the absence of GABA, benzodiazepines have no effect on chloride conductance. The GABA_A receptor is assembled from five subunits that span the cell membrane in a circular fashion to create the chloride channel.⁵⁸ These subunits are ...