J.M. Monti¹, D. Warren Spence², S.R. Pandi-Perumal³, Salomon Z. Langer⁴ and R. Hardeland⁵

¹Dept. of Pharmacology and Therapeutics, School of Medicine, Clinics Hospital, Montevideo 11300, Uruguay. ²Sleep and Alertness Clinic, 750 Dundas Street West, Toronto, ON M6J-3S3, Canada. ³Somnogen Inc, 8790 112th Street, New York, NY 11418, U.S.A. ⁴Euthymia Ltd, 8 H. Rosenblum St., apt. 4650, Tel Aviv 69379, Israel. ⁵Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, Göttingen, Germany.

Abstract

The imidazopyridine drug zolpidem (N,N,6-trimethyl-2[4-methyl-phenyl]imidazo[1,2-a]pyridine-3-acetamide) is a sedative/hypnotic with relative selectivity for α₁ subunits of the GABA_A receptor/chloride channel complex. Because of this selectivity and regional receptor distribution, zolpidem is less generalized in its CNS depressive actions than benzo- diazepines and largely devoid of their major, undesired side- and after-effects, at recommended doses. Zolpidem is rapidly taken up and distributed, binds extensively to plasma proteins, and is readily inactivated by hepatic cytochrome P₄₅₀ mono-oxygenases, especially CYP3A4. Zolpidem is thus a rapidly acting agent which provides effective facilitation of sleep onset. However, plasma levels of the immediate release (IR) formulation frequently decline too quickly for effective sleep maintenance. To address this problem zolpidem extended release (ER) has been developed. At age-specific dosages, it increases, in middle-aged and elderly patients, total sleep time and reduces the number of nocturnal awakenings. Both zolpidem IR and ER have favorable toxicological profiles. Adverse effects are moderate, frequently in the incidence range of placebos, and certainly less frequent and severe than those of benzodiazepines. Zolpidem IR and ER are practically devoid of next-day hangover effects and only infrequently cause rebound insomnia of usually short duration. Both variants of zolpidem have a limited potential for dependence and abuse.