Quazepam

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Abstract
Quazepam is a trifluoroethyl benzodiazepine hypnotic with a half-life of 27 to 41 hours, which has been shown to induce and maintain sleep in the short to long term (up to 4 weeks) treatment of patients with chronic or transient insomnia. Although its hypnotic efficacy has been well characterised against placebo, there are few clinical studies in comparison with established hypnotics, particularly over long term administration. However, preliminary evidence suggests that quazepam 15 to 30mg is as effective as flurazepam and triazolam in usual therapeutic doses, and causes minimal rebound insomnia following its withdrawal, unlike rapidly eliminated benzodiazepines such as triazolam. The lack of rebound phenomena is likely to be attributable to the ‘carryover’ effects occurring after discontinuation of quazepam, which has pharmacologically active metabolites with half-lives of elimination similar to or longer than that of the parent drug. Probably because of the long half-lives of quazepam’s metabolites, daytime sedation, fatigue and lethargy are the most frequently reported side effects. These side effects are most intense with the 30mg dose and least with the 7.5mg dose, which has not been studied extensively. Hence, quazepam is an effective hypnotic which may be particularly suitable for short or medium term use in patients in whom withdrawal effects or rebound insomnia may be especially bothersome. Further definition of certain characteristics of its profile — such as its long term use and potential for development of tolerance or dependence, effects on psychomotor skills, efficacy of the 7.5mg dose, and suitability in elderly patients and patients with chronic organic diseases — will assist in more clearly defining its ultimate place in therapy. In comparison with baseline established by the administration of placebo, quazepam in doses of 7.5 to 45mg decreases sleep latency and percentage of stage 1 sleep, and facilitates sleep maintenance as measured by reductions in number of awakenings, wake time after sleep onset and total wake time, and prolonged total sleep time. These effects are usually apparent following a single dose. The percentage of sleep spent in stage 2 increases, whereas that of rapid eye movement (REM) sleep and slow wave sleep (stages 3 and 4) is shortened. Comparative parallel group sleep laboratory studies reveal that the profile of sleep induction and maintenance with quazepam 15 and 30mg is similar to that of flurazepam. Unlike the more rapidly eliminated benzodiazepines triazolam and temazepam, the hypnotic effects of quazepam persist throughout the first night or more of drug withdrawal. Thus, rebound insomnia has not been shown to occur with quazepam, in contrast to the effects of the short acting benzodiazepines. To what extent, if any, that tolerance or dependence may occur with quazepam has not yet been established with certainty. A few studies in small numbers of volunteers in which the effects of single doses of quazepam on psychomotor performance have been investigated, suggest that the 15mg dose produces impairment to a similar extent as placebo and nitrazepam 5mg, but causes less deterioration than triazolam 0.25 to 1mg, nitrazepam 10mg and flunitrazepam 1mg. However, the effects of quazepam 30mg on psychomotor function appear to be equivalent to those of triazolam 0.5mg and nitrazepam 10mg. Animal studies demonstrate that quazepam possesses anxiolytic, anticonvulsant and muscle relaxant activity typical of the benzodiazepine profile, with low toxicity. In antagonising foot-shock aggression and pentylenetetrazol seizures in mice, quazepam was equipotent to flurazepam, but was more potent for inhibition of isoniazid-induced seizures. Selective binding by quazepam to the benzodiazepine receptor type I (BZ1 ) is characteristic of benzodiazepines with a trifluoroethyl moiety in position 1, and it has been postulated that the lack of ataxia seen with quazepam in animal studies may result from this property. While the biochemical events responsible for hypnotic activity are uncertain, evidence obtained in cats suggests that quazepam may act through facilitation of mechanisms in the lower brain which contribute to physiological EEG synchronisation and sleep induction. Following oral administration, peak plasma quazepam concentrations of about 30 µg/ L are attained within 2.5 hours, and may be subject to diurnal variation. The drug is distributed to most body tissues including the placenta, and is excreted in breast milk. The apparent volume of distribution of the central compartment is 5.0 L/kg after a nighttime dose; this is a reflection of the high lipophilicity of the drug. Quazepam is reported to be greater than 95% bound to plasma proteins. Extensive metabolism of quazepam by substitution of the sulphur group with oxygen yields 2-oxoquazepam (OQ), a pharmacologically active metabolite. OQ is further biotransformed by hydroxylation, or by N-dealkylation to N-desalkyl-2-oxoquazepam (DOQ), which is identical to N-desalkylflurazepam and is also pharmacologically active. The appearance of OQ in plasma is rapid and parallels the absorption of the parent drug. Although the concentration of DOQ is higher in brain than those of quazepam and OQ, in mice hypnotic activity is better correlated with the concentrations of the latter 2 compounds. Quazepam is excreted slowly in the urine and the faeces as metabolites; only trace amounts of the parent drug are recoverable unchanged. The half-lives of elimination of quazepam and OQ in young and elderly subjects are similar (about 27 to 40 hours). However, the half-life of DOQ (about 70 hours) is twice as long in the elderly. Several placebo-controlled studies involving mainly young or elderly outpatients taking single or repeated night-time doses of quazepam 15 or 30mg have clearly demonstrated...

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