Sedatives

Positive GABAA Receptor Modulators

Prior to the development of benzodiazepines, barbiturates were the most commonly used sedative/hypnotic drugs in medical practice. Barbiturates such as butabarbital, pentobarbital, phenobarbital, and secobarbital were commonly used to induce sedation and to treat insomnia. Barbiturates bind to GABAA receptors and activate the receptors (i.e., promote chloride flux through the membrane channel) through direct binding and through the facilitation of GABA binding to the receptor. Barbiturates are still used in medical practice to produce sedation prior to procedures that require anesthesia; however, the use of barbiturates for the outpatient [Page 717]treatment of insomnia has become uncommon as a result of the availability of drugs with better safety profiles such as the benzodiazepines.

Like barbiturates, benzodiazepines also bind to GABAA receptors, but they bind at a different site than do the barbiturates. Benzodiazepines facilitate the binding of GABA to GABAA receptors, but unlike barbiturates, they do not activate the receptor directly. This difference is thought to account for the greater safety profile of the benzodiazepines as compared to the barbiturates. For example, benzodiazepine overdose is not usually fatal unless another drug such as a barbiturate, opioid, or alcohol has been taken together with the benzodiazepine. As a result of the improvement in safety profile over the barbiturates, benzodiazepines are currently the most widely prescribed sedative/hypnotic drugs in the United States.

The same pharmacological mechanism of action (facilitation of GABA binding to GABAA receptors) and sedative effects appear to be shared by all of the benzodiazepines. However, only some of the benzodiazepines are U.S. Food and Drug Administration (FDA)-approved for the treatment of insomnia (e.g., estazolam, trade name ProSom; flurazepam, trade name Dalmane; quazepam, trade name Doral; temazepam, trade name Restoril; and triazolam, trade name Halcion). The most important clinical differences between different benzodiazepines appear to involve differences in pharmacokinetic effects such as the duration of action of individual drugs.

Another class or subclass of drugs that also bind to the benzodiazepine site on GABAA receptors (or a site nearby in the case of eszopiclone) and facilitate the binding of GABA, but do not have benzodiazepine chemical structures are the “Z-drugs,” which include zolpidem (trade name Ambien), eszopiclone (trade name Lunesta), and zaleplon (trade name Sonata). In addition to differences in chemical structure, the Z-drugs also differ from the traditional benzodiazepines in that they bind preferentially to a subset of GABAA receptors that contain an a1 subunit (as compared to most of the benzodiazepines that bind non-selectively to GABAA receptors that contain a1, a2, a3, or a5 subunits). The preferential binding of the Z-drugs to a1 subunit-containing GABAA receptors have been purported to result in greater sedative/hypnotic effects and lesser anxiolytic (i.e., anxiety decreasing) effects of these drugs compared to the benzodiazepines; however, the effects of the Z-drugs are very similar and often indistinguishable from the traditional benzodiazepines. The relatively short half-lives of the Z-drugs (one to six hours) might be one of the most clinically relevant differences between these non-benzodiazepine positive GABAA receptor modulators and the more traditional benzodiazepines for their use in the treatment of insomnia.

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