Pharmacology of the benzodiazepines; with special emphasis on alprazolam.
Different aspects on the structure-activity relationships, the pharmacokinetic and the pharmacodynamic properties of the benzodiazepines (BDZs) are briefly outlined, followed by a more thorough description of the current hypothesis on the mode of action of these drugs, focusing on the supramolecular GABA-BDZ-chloride-ionophore receptor complex. The existence of different synthetic ligands for the receptor exerting opposite effects is discussed together with the recent finding in mammals of an endogenous ligand with anxiogenic-like effects. The possibility of the anxiolytic effects of the BDZs being related to actions on monoaminergic systems is also briefly mentioned. A new group of BDZs, the triazolo-BDZs, is described. One of these compounds, alprazolam (APZ), exhibits a different clinical profile as compared to traditional BDZs. Apart from being effective in the treatment of generalized anxiety, it has been proven effective also in the treatment of panic disorder. Some studies also indicate anti-depressant effects of the compound. The reason for these apparent unique effects of APZ is not clear. A brief description of a commonly applied animal model (the Vogel conflict model) for the study of anxiety-related mechanisms is given and original animal data from experiments aiming at elucidating the mechanism behind the anti-panic effect of APZ are presented. The results indicate that tolerance to different pharmacodynamic effects of APZ and the traditional BDZ diazepam (DIZ) develop to different extents. Thus, tolerance development to the ataxic/sedative effects of APZ was pronounced, whereas no significant tolerance developed to the anxiolytic-like effects. For DIZ, however, tolerance development was pronounced to both the anxiolytic-like and the ataxic/sedative effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Söderpalm
B
B
Department of Pharmacology, University of Göteborg, Sweden.
D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D001008:Anxiety Disorders / Q000188:drug therapy; D001569:Benzodiazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D004361:Drug Tolerance; D006801:Humans; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000525:Alprazolam