Pharmacotherapeutic Principles for Hypnotic Medications

Abstract

The mechanism of action and the pharmacokinetics of hypnotic drugs are key determinants of their clinical effects in patients with primary or comorbid insomnia. Accordingly, the sedation and sleep-promoting properties of drugs acting as positive allosteric modulators of the GABA A receptor depend upon their selective binding to the α 1 receptor subtype. The additional binding to other receptor subtypes conditions the occurrence of adverse events. The absorption rate has been emphasized as a determinant of onset of action, and the elimination half-life ( t 1/2 ) and distribution as key factors of duration of action of hypnotic drugs in clinical use. Benzodiazepine and nonbenzodiazepine hypnotics improve sleep induction, and depending on their t 1/2 and presence of active metabolites, they improve sleep maintenance. In this respect, the pyrazolopyrimidine derivative zaleplon does not affect total sleep time. On the other hand, the increase of total sleep time that follows the administration of the benzodiazepine and imidazopyridine derivatives midazolam, triazolam, and zolpidem immediate-release, is limited to the first half of the night. In order to circumvent this limitation, a zolpidem extended-release preparation has been made available. The benzodiazepine hypnotics, temazepam, flunitrazepam, and flurazepam, and the cyclopyrrolone derivatives, zopiclone and eszopiclone, increase total sleep time beyond the first half of the night. The effect of the melatonin agonist ramelteon on sleep variables is limited to a decrease of the latency to sleep onset. The benzodiazepine derivatives induce a further reduction of slow-wave sleep (SWS) and rapid eye movement (REM) sleep in patients with an insomnia complaint. Furthermore, during the administration of the nonbenzodiazepine derivatives, zaleplon, zolpidem, zopiclone, and eszopiclone, and the melatonin agonist ramelteon, SWS and REM sleep do not regain normal levels or can even be further suppressed.