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Comparative Pharmacokinetics and Pharmacodynamics of Short-Acting Hypnosedatives

Zaleplon, Zolpidem and Zopiclone

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Abstract

Benzodiazepines have historically been the mainstay of treatment for sleeping disorders, yet they have many shortcomings. A new group of sedative hypnotic agents has been developed for this purpose. Similar to the benzodiazepines, zaleplon, zolpidem and zopiclone have activity at the GABA receptor complex, yet they appear to have more selectivity for certain subunits of the GABA receptor. This produces a clinical profile that is more efficacious with fewer side effects. Zaleplon, zolpidem and zopiclone are structurally distinct. Due to variation in binding to the GABA receptor subunits, these three compounds show subtle differences in their effect on sleep stages, and as antiepileptics, anxiolytics and amnestics.

The duration of action of zaleplon, zolpidem and zopiclone can be related to their individual pharmacokinetic profile, which subsequently determines the time course of drug effect. Each of these compounds has a unique pharmacokinetic profile with different bioavailability, volume of distribution and elimination half-lives. Zaleplon has a rapid elimination so there are fewer residual side effects after taking a single dose at bedtime. By comparison, zolpidem and zopiclone have a more delayed elimination so there may be a prolonged drug effect. This can result in residual sedation and side effects but may be useful for sustained treatment of insomnia with less waking during the night. There are also differences in potency based on plasma concentrations suggesting that there are differences in binding to the GABA receptor complex. Although zaleplon has a much lower bioavailability (30%), the treatment dose is similar to zolpidem and zopiclone (bioavilaibility of 70%) because of the increased potency of zaleplon.

The pharmacokinetics and pharmacodynamics of zaleplon, zolpidem and zopiclone are significantly different from benzodiazepines. The new drugs are sufficiently unique from each other to allow customisation of treatment for various types of insomnia. While zaleplon may be best indicated for the delayed onset of sleep, zolpidem and zopiclone may be better indicated for maintaining a complete night’s sleep. Only the patient’s symptoms and response to treatment will dictate the best course of treatment.

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Acknowledgements

I thank Nancy Federspiel, Dr Steven Shafer and Dr Hong Cao for help in preparation of this manuscript. The author has no financial interest in any of the companies that produce any of the drugs discussed here, although he did participate in one study sponsored by Wyeth, the manufacturer of zaleplon, and has received funding from Wyeth for research on zaleplon. No sources of funding were used to assist in the preparation of this manuscript. The author has no conflicts of interest that are directly relevant to the content of this manuscript.

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  1. Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, 94305-5640, USA

    David R. Drover

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  1. David R. Drover
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Correspondence to David R. Drover.

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Drover, D.R. Comparative Pharmacokinetics and Pharmacodynamics of Short-Acting Hypnosedatives. Clin Pharmacokinet 43, 227–238 (2004). https://doi.org/10.2165/00003088-200443040-00002

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