Zolpidem - Mechanism of Action

Mechanism of Action

Zaleplon and Zolpidem both are agonists at the GABA A ɣ 1 subunit. Due to its selective binding, Zolpidem has very weak anxiolytic, myorelaxant, and anticonvulsant properties but very strong hypnotic properties. Zolpidem binds with high affinity and acts as a full agonist at the α1-containing GABAA receptors, about 10-fold lower affinity for those containing the α2- and α3- GABAA receptor subunits, and with no appreciable affinity for α5 subunit-containing receptors. ω1 type GABAA receptors are the α1-containing GABAA receptors and ω2 GABAA receptors are the α2-, α3-, α4-, α5-, and α6-containing GABAA receptors. ω1 GABAA receptors are found primarily in the brain, whereas ω2 receptors are found primarily in the spine. Thus, zolpidem has a preferential binding for the GABAA-benzodiazepine receptor complex in the brain but a low affinity for the GABAA-benzodiazepine receptor complex in the spine.

Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α4 and α6 subunit-containing receptors. Zolpidem positively modulates GABAA receptors, it is presumed by increasing the GABAA receptor complex's apparent affinity for GABA without affecting desensitization or peak current. Like zaleplon (Sonata), zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep.

A meta-analysis of the randomised, controlled, clinical trials that compared benzodiazepines against Z-drugs such as zolpidem has shown few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.

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