Benzodiazepine derivatives sedative effects

Flurazepam (15 to 30 mg p.o. at bedtime) is a benzodiazepine derivative sedative-hypnotic that is used in the management of insomnia. Flurazepam depresses the CNS at the limbic and subcortical levels of the brain. It produces a sedative effect by potentiating the effect of the neurotransmitter gamma-amino-butyric acid on its receptor in the ascending reticular activating system, which increases inhibition and blocks both cortical and limbic arousal (see also Figure 50). 

As already noted, there are drugs found among benzodiazepine derivatives that have expressed anxiolytic action and that lack or have poorly expressed sedative-hypnotic effects, which are called daytime tranquilizers. Medazepam, a representative of the daytime tranquilizers, is a drug that differs from diazepam only in the absence of a carbonyl group in the seven-membered azepine ring. 

The benzodiazepine derivatives class of antianxiety agents shares the property of binding to a benzodiazepine receptor, part of the GABA receptor-chloride channel complex whose function it modulates allosterically. Not only the anxiolytic effects of the benzodiazepines, but also the anticonvulsant, sedative, or muscle relaxant effects seem to be mediated by the GABA-related mechanism. Besides the direct involvement of the GABA system, in parallel or more downstream to this, several other neurotransmitters such as serotonin have been suggested to participate in different aspects of benzodiazepine action. 

It is generally accepted that the pharmacology of benzodiazepine derivatives is identical qualitatively but varies quantitatively. In other words, the sedative, hypnotic, anticonvulsant, muscle relaxant, and anxiolytic properties reside to various degrees in all of them. Nevertheless, they do exhibit pharmacological specificity, making it necessary to select a particular drug for its desired therapeutic effect. 

Clobazam, a 1,5-benzodiazepine derivative, is indicated in the management of ambulant patients with anxiety. Clobazam lacks sedative and amnestic effects, and does not cause impairment of psychomotor skills (see also Table 9). 

The pharmacology of benzodiazepine derivatives differs significantly from that of the neuroleptics, in that the benzodiazepines have no psychoplegic (antipsychotic) activity and cause no extrapyramidal, autonomic, or endocrine side effects. In addition, unlike the neuroleptics, which lower the seizure threshold, these substances are anticonvulsants. In addition, they are anxiolytics, muscle relaxants, and mild sedatives. Although the benzodiazepine derivatives do not produce pronounced autonomic or CV side effects, they can reduce or block the emotionally induced changes in cardiovascular functions, probably through actions on the limbic system. 

Many benzodiazepine derivatives have been reported to possess sedative and hypnotic activity in both animals and man. Flurazepam (l) has been found to possess useful hypnotic activity in man without producing significant "hangover" effects the following morning . In animals flurazepam was found to possess activity, in many tests systems, similar in potency and profile to diazepam . 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

---