Pharmacokinetic and clinical considerations in the choice of a hypnotic.

Abstract

Not only has insomnia become much more frequent in the last hundred years but its causes have also changed considerably. In the treatment of insomnia, benzodiazepines‐because of their additional anxiolytic effect‐offer substantial advantages over other sleep‐inducing agents. The residual fraction‐the quotient of plasma concentration at 12 h after drug intake to maximum plasma concentration‐makes it possible to differentiate between the benzodiazepines according to their suitability as anxiolytics or hypnotics. Midazolam has the lowest residual fraction of all known benzodiazepines and thus, administered in the appropriate dosage, also has the shortest duration of activity.

Midazolam: sleep and performance studies in middle age.

“…We tested the possibility that a trend toward impaired performance was present over the dose range, but no such trend was established. These observations are consistent with the rapid elimination of the drug and would be compatible with the observation that duration of activity is unlikely to be extended significantly by increasing the dose (Amrein et al, 1983).…”

“…However, elimination is not the only factor which determines the duration of action of an hypnotic (Amrein et al, 1983); the rate of absorption and of fall in plasma level during the distribution phase are also important. In this context midazolam, an imidazobenzodiazepine, has a very rapid elimination and this, together with fast absorption and distribution, suggests that it may be particularly short-acting (Heizemann et al, 1983).…”

Transient Insomnia and Rapidly Eliminated Hypnotics

“…The present and previous studies (6,7) suggest that the most appropriate role of midazolam is for sleeponset insomnia or for short periods of sleep, and this would support the analysis of Amrein et al (8). Indeed, the very rapid absorption of midazolam (9) indicates that relatively low doses of the drug would be appropriate, and the most useful dose may be ~7.5 mg. On the other hand, the somewhat slower elimination of brotizolam (0.125-0.25 mg) would appear to have the potential to sustain sleep (0) yet still be free of residual effects (11,12) and of accumulation on daily ingestion (3).…”

Risk factors for excessive benzodiazepine use in a working age population: a nationwide 5-year survey in Norway

“…Together with its one-compartment distribution (lack of fast decline in plasma concentration due to distribution) and medium long elimination half-life, oxazepam has repeatedly been suggested as a candidate drug when possible drug dependency is suspected in an individual in need of antianxiety treatment. On second thoughts, however, this finding might not be surprising at all as the first group might need higher doses (more DDDs) of oxazepam compared with other BZDs to achieve the same (initial kick) effect [ 19 , 20 ]. Starting on oxazepam at the recommended dosage (or even lower dosage due to cautiousness) might give an inadequate antianxiety effect initially and drive some individuals to seek a stronger antianxiety effect by increased dosage.…”

“…The finding of a higher risk of becoming an excessive user for first-time users of nitrazepam/flunitrazepam compared with diazepam was as expected given the plasma profiles with their “hit and run” pattern. Also, the finding of a non-significant but nominally increased risk for first-time users of hydroxyzine/buspirone compared with first-time diazepam users was unsurprising as the antianxiety effect of these drugs appears very slowly compared with, for example, diazepam [ 20 , 21 ].…”