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Brotizolam

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy as an Hypnotic

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Summary

Synopsis

Brotizolam is a new thienotriazolodiazepine derivative with a pharmacological profile similar to that of benzodiazepines. it is indicated for use as an hypnotic in the management of insomnia, although it also has anticonvulsant, antianxiety and muscle relaxant properties in animals.

In clinical trials brotizolam 0.125 to 0.5mg improved sleep in insomniacs similarly to nitrazepam 2.5 and 5mg, flunitrazepam 2mg and triazolam 0.25mg, whilst brotizolam 0.5mg was shown to be superior to flurazepam 30mg in some studies. Brotizolam is an effective hypnotic for hospital patients awaiting surgery, in whom it also reduces anxiety.

Brotizolam has an elimination half-life of about 5 hours, which is ‘intermediate’ compared with the shorter-acting hypnotic, triazolam, and longer-acting benzodiazepines. Consequently, it is able to induce sleep without producing early morning rebound insomnia, and can also maintain sleep throughout the night. Brotizolam at dosages below 0.5mg at night usually produced minimal morning drowsiness; no residual impairment of psychomotor performance occurs following dosages within the recommended range of 0.125 to 0.25 mg/kg. No serious side effects have been reported to date and the most frequently observed adverse experiences are drowsiness, headache and dizziness. Mild rebound insomnia may occur in some patients when treatment is stopped.

Thus, brotizolam is a useful hypnotic which can be used in patients who have difficulty in falling asleep and also in patients who are troubled by night-time awakenings. Used in the recommended dosage it may be particularly useful for patients in whom daytime impairment of performance is unacceptable.

Pharmacodynamic Studies

Brotizolam binds with high affinity to benzodiazepine receptor sites, and in animal studies it demonstrated anticonvulsant, antianxiety and muscle relaxant properties similar to those of nitrazepam and other benzodiazepines. In healthy volunteers and insomniacs, brotizolam 0.2 to lmg increases total sleep time and reduces total wake time by both hastening sleep onset and reducing the number and duration of nocturnal awakenings. Stage 2 sleep is increased, particularly in insomniacs. Rapid eye movement (REM) sleep was usually reduced in patients with insomnia receiving brotizolam 0.5mg at night (a dose of 0.25mg did not affect REM sleep) but was not significantly altered in healthy volunteers who received doses of 0.1 to lmg at night. Following abrupt withdrawal of brotizolam therapy, rebound insomnia has been reported in some individuals. Brotizolam at dosages of less than 0.3mg in the morning caused minimal changes in acute psychometric function tests, whereas higher dosages were associated with a more significant impairment of attention, concentration and psychomotor performance. Following nighttime doses of brotizolam up to 0.5mg minimal residual effects have been noted the next morning; however, a dose of 0.6mg caused impairment of visuomotor performance for up to 14.5 hours. Animal studies suggested that brotizolam is unlikely to produce physical dependence at normal therapeutic dosages.

Pharmacokinetic Studies

Maximum plasma concentrations of brotizolam usually occur within 2 hours of single oral 0.25 to 1mg doses, and there appears to be a linear relationship between dose and mean maximum plasma concentration for dosages up to 1.5mg. After administration of brotizolam 0.5mg orally its bio-availability was calculated to be 70%. Brotizolam rapidly distributes throughout the body and animal studies have shown that it passes into breast milk and crosses the placenta. The apparent volume of distribution of brotizolam was 0.66 L/kg after administration of 0.25mg intravenously to healthy volunteers. Brotizolam is extensively bound to human plasma proteins (89 to 95%).

Brotizolam is rapidly and almost completely metabolised in the liver by oxidation, the primary metabolites being 1-methylhydroxy and 4-hydroxy derivatives. These have some pharmacological activity, but are further metabolised to inactive conjugates of glucuronic or sulphuric acid and eliminated via the kidneys. Excretion of a single dose is complete within 4 days. Brotizolam has a short elimination half-life (about 5 hours) which is increased in elderly subjects (mean values of up to 9.8 hours have been reported). Renal insufficiency does not affect the elimination of brotizolam. In contrast, elimination half-life is longer in patients with liver cirrhosis and this was associated with decreased clearance and increased volume of distribution. Currently there is no evidence that either brotizolam or its metabolites accumulate with repeated administration.

Therapeutic Trials

In non-comparative trials of up to 26 weeks’ duration, brotizolam 0.125 to 0.5mg was found to be an effective and well tolerated hypnotic. A number of double-blind trials compared the efficacy of brotizolam with placebo in outpatients with insomnia, and usually doses of 0.25 and 0.5mg significantly reduced the time taken to fall asleep, reduced nocturnal awakenings and improved sleep quality. Nightly doses of brotizolam 0.125mg adequately increased the duration and quality of sleep in elderly patients.

In short term comparative studies, brotizolam dosages of 0.125 and 0.25mg at night were found to be equal or superior to nitrazepam 2.5 and 5mg in improving the sleep performance of general practice outpatients, hospital inpatients and geriatric patients. No clinically significant differences were documented in double-blind clinical trials comparing brotizolam 0.25mg with flurazepam 15mg, flunitrazepam 2mg or triazolam 0.25mg. However, in one study brotizolam 0.5mg was significantly better than flurazepam 30mg in improving the sleep of hospital inpatients with insomnia.

As an hypnotic for patients the night before surgery brotizolam was generally more effective than flunitrazepam 2mg and, in 1 study, was preferred by a greater proportion of patients. Brotizolam 0.5mg administered 2 hours prior to surgery significantly reduced the dose of thiopentone (297vs 319mg, p < 0.02) required to produce the same level of anaesthesia, compared with placebo.

Preliminary studies suggest that brotizolam may be a useful hypnotic for subjects with disrupted sleep cycles (intercontinental travellers, shift or night workers, etc.) and further investigations in this setting are warranted.

Side Effects

Brotizolam has generally been well tolerated in clinical trials to date and discontinuation of therapy has rarely been necessary. Its side effect profile is similar to that of the shorter acting benzodiazepines, with drowsiness, dizziness and headache being the most frequently reported adverse experiences. Isolated instances of tinnitus, visual disturbances, difficulty in concentrating, dry mouth and nausea have been documented. Brotizolam did not affect cardiovascular or respiratory function and there have been no significant adverse biochemical or haematological reactions.

In some patients withdrawal of brotizolam has led to a degree of rebound insomnia on the first night without treatment, but usually the symptoms were not severe. Similar symptoms were noted after discontinuation of nitrazepam.

Dosage and Administration

The recommended oral dosage of brotizolam is 0.25mg taken before retiring, although this may be increased to 0.5mg in selected patients. Elderly patients should initially receive 0.125mg. No reduction of dose is necessary for patients with renal insufficiency.

Elimination of brotizolam is significantly impaired in patients with liver cirrhosis and so it should be avoided or used with extreme caution in these circumstances. As with other hypnotic drugs, patients should be cautioned about the possible effects of taking other depressant drugs and alcohol.

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    Mark S. Langley & Stephen P. Clissold

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  2. Stephen P. Clissold

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