Mechanism of action
Zaleplon is a high-selectivity,[25] high-affinity ligand of positive modulatory benzodiazepine sites on GABAA receptors. Zaleplon binds preferentially at benzodiazepine sites on α1-containing GABAA receptors (previously known as BZ1/Ω1 receptors), which largely mediate the sedative effects of benzodiazepines.[26] However, unlike zolpidem, zaleplon binds with appreciable affinity to benzodiazepine sites on some α2 and α3-containing GABAA receptors, which are implicated in the anxiolytic and muscle relaxant effects of benzodiazepines. Zaleplon demonstrates greater selectivity at these sites than lorazepam or zopiclone.[27][28]
Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the normal sleep architecture.[29]
A meta-analysis of randomized, controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone, and eszopiclone has found few clear and consistent differences between zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.[30]
Zaleplon should be understood as an ultrashort-acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the δ-frequency band and a decrease in the energy of the θ-frequency band.[31][32] In contrast to non-selective benzodiazepine drugs and zopiclone, zaleplon does not increase power in the β-frequency band.[33]
Pharmacokinetics
The ultrashort 1hr half-life gives Zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills.[34][35]
Zaleplon is primarily metabolised by aldehyde oxidase into 5-oxozaleplon, and its half-life may be affected by substances which inhibit or induce aldehyde oxidase. According to urine analysis, about 9% of zaleplon is metabolized by CYP3A4 to form desethylzaleplon, which is quickly metabolized by aldehyde oxidase to 5-oxodesethylzaleplon.[3][2] All of these metabolites are inactive.[2] When taken orally, zaleplon reaches maximum concentration in about 45 minutes.[2]
