All benzodiazepines interact with the γ-aminobutyric acid receptor (GABAA) and produce similar physiological and clinical effects.43,44 The anxiolytic effect, appears to be mediated by the alpha-2 subunit, of the receptor complex. Preferred terminology refers to these drugs as positive modulators since they do not have any effect in the absence of GABA. With chronic exposure, a number of molecular effects have been reported.43-45 Downregulation of binding sites with a reduction in the number of the GABAA receptors is one molecular phenomenon that has

been proposed as a Inhibitors,research,lifescience,medical mechanism for tolerance. Other changes that have been reported include changes in mRNA, a disturbance in the linking relationship between the benzodiazepine site and GABA, and perturbations in the

rate of turnover Inhibitors,research,lifescience,medical of subunits of the benzodiazepine receptor. Determinations of whether these findings can be OSI-027 manufacturer directly and causally linked to tolerance and discontinuation syndromes have been difficult, because of the differences in timing of the molecular and clinical phenomena.46,47 Molecular changes seem to occur more quickly than the development, of clinical tolerance. Although the benzodiazepines work via a common mechanism of action, there are definite pharmacokinetic and metabolic differences that affect, the presence and concentration of an active entity at the molecular site of action.48 These differences determine the clinical indications Inhibitors,research,lifescience,medical for which a given benzodiazepine Inhibitors,research,lifescience,medical is used, and they also result, in differences in clinical course once an administered medication is discontinued.49-51 The most important factors in this realm arc the speed at which the parent drug is cleared and the presence or absence of pharmacologically active metabolites (Table II). As an example, for a drug such as diazepam, the parent, drug is cleared slowly, and at least, three metabolically Inhibitors,research,lifescience,medical active compounds are generated during the course of its clearance. Some of these compounds are actually separate benzodiazepine entities available for prescription is their own right. After one 10 mg dose of diazepam,

pharmacologically active metabolites are detectable for at least 2 weeks. Hence, even with abrupt, discontinuation of diazepam, an intrinsic tapering process results (Figure 1). The potency of a given benzodiazepine Ketanserin parent drug at the site of activity is not a major determinant of clinical differences, since dosages are adjusted to produce a clinical effect, through the same molecular mechanism. Figure 1 Plasma concentrations of diazepam (blue circles) and its principal pharmacologically active metabolite, desmethyldiazepam (light-blue circles), in a healthy volunteer who took 2.5 mg of diazepam orally twice a day for 15 days. A Plasma levels are shown … Table II. Representative benzodiazepine derivatives in clinical use as antianxiety agents. The usual range of elimination half-life is shown in parentheses. * Prodrug, converted to desmethyldiazepam.