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Thursday, May 19, 2011

Non-benzodiazepine hypnotics

Non-benzodiazepine hypnotics
These drugs comprise the barbiturates, alcohols and a new class of cyclopyrrolone hypnotics. Because of the severity of their side effects and their dependence potential, the barbiturates should not be used to treat insomnia. The alcohol type of hypnotics include the chloral derivatives, of which chloral hydrate and chlormethiazole are still occasionally used in the elderly, and ethchlorvynol. Chloral hydrate is metabolized to another active sedative hypnotic trichlorethanol. These drugs all have a similar effect on the sleep profile. They are short half-life drugs (about 4–6 hours) that decrease the sleep latency and number of awakenings; slow-wave sleep is slightly depressed while the overall REM sleep time is largely unaffected, although the distribution of REM sleep may be disturbed. Chloral hydrate and its active metabolite have an unpleasant taste and cause epigastric distress and nausea. Undesirable effects of these drugs include lightheadedness, ataxia and nightmares, particularly in the elderly. Allergic skin reactions to chloral hydrate have been reported. Chronic use of these drugs can lead to tolerance and occasionally physical dependence. Like the barbiturates, overdosage can lead to respiratory and cardiovascular depression. Therapeutic use of these drugs has largely been superseded by the benzodiazepines.
Any new hypnotic should induce and maintain natural sleep without producing residual sedative effects during the day; it should not cause dependence or interact adversely with other sedatives, including alcohol. The ideal hypnotic should not cause respiratory depression or precipitate cardiovascular collapse when taken in overdose. So far no drug fulfils all these criteria. Several new anxiolytic and sedative drugs act at the benzodiazepine receptor site, or one of the subsets that comprise this receptor site even though the chemical structure of these molecules differs substantially from the benzodiazepines. One of the first of these compounds to be developed was the cyclopyrrolone zopiclone. A structurally somewhat similar moleculezolpidem, an imidazopyridine, has also been marketed recently as has the beta-carboline abercarnil. Of the newer benzodiazepines, the tetracyclic 2,4 benzodiazepine bretazenil has also been introduced as a short-acting sedative–hypnotic.

The therapeutic profile and adverse effects of the non-benzodiazepine sedative–hypnotics Zopiclone was the first of the new sedative–hypnotics to be launched in the late 1970s and has been shown to be equi-effective with the standard sedative–hypnotic benzodiazepines such as flurazepam and temazepam.
There is evidence that zopiclone may cause less ‘‘hang-over’’ effects than the conventional benzodiazepines but some studies have shown that this drug does produce performance decrement when this is tested shortly after treatment. A similar profile has been reported for zolpidem while abercarnilhas been reported to cause a performance decrement for the first few days of treatment that then largely disappears. Bretazenil has been shown to cause dose-related disruptions in psychomotor performance, but these effects are not as prominent as occurs following an equivalent dose of diazepam or alprazolam. A somewhat unusual side effect has been described by patients taking zopiclone – a bitter, unpleasant taste and a dry mouth. The cause of these effects is presently unknown. Regarding abuse liability, to date there have been only few studies in which newer sedative–hypnotics have been investigated. Nevertheless there is some evidence that those with a history of sedative abuse preferred high doses of triazolam and zopiclone to placebo. There is some evidence that bretazenil has a lower abuse potential than the benzodiazepines. Abuse liability of these novel sedative hypnotics has also been evaluated in primates. Abercarnil causes a lower incidence of withdrawal effects than conventional benzodiazepines. This may be due to the differences in the intrinsic efficacy rather than the bioavailability of these drugs for the brain. However, zopiclone and bretazenil did lower the seizure threshold to electroshock-induced seizures in mice whereas the seizure threshold was unaffected by zolpidem, tracozalate and C1 218,872. In baboons zolpidem may cause physiological dependence; similar studies in monkeys show that mild withdrawal effects occur after the abrupt withdrawal of zopiclone, whereas withdrawal from diazepam caused severe symptoms. It may be concluded that sedative–hypnotic drugs with a limited efficacy such as bretazenil and zolpidem are also limited in their ability to cause physiological dependence.
In human studies, there is some evidence that withdrawal signs such as nervousness, anxiety and vertigo occur following sub-chronic administration of zopiclone but the frequency and intensity of the withdrawal effects are greater after conventional 1, 4-benzodiazepines. No rebound effects have been seen in patients with insomnia who received zolpidem daily for 7–180 days. By contrast, after 3 weeks of abercarnil treatment of patients with generalized anxiety disorder possible signs of withdrawal resulted, the incidence of these withdrawal effects being related to doses of abercarnil administered. From the published clinical studies, it would appear that the partial agonists bretazenil and abercarnil are less likely to cause physiological dependence, have lower reinforcing effects and a lower incidence of subjective effects associated with abuse liability than the conventional 1, 4-benzodiazepine sedative–hypnotics. It is presently unclear whether the full agonists for the GABA-A receptor, zolpidem and zopiclone, offer a real advance in the treatment of insomnia although their adverse effect profiles and abuse liability may be lower than that of the conventional benzodiazepines.

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