Mise à jour sur les considérations pharmacocinétiques, pharmacodynamiques et les interactions médicamenteuses dans le choix d’une benzodiazépine

Abstract

Over the past 50 years, significant clinical information has been obtained on numerous aspects of benzodiazepines, notably on their pharmacokinetics and pharmacodynamic properties, drug interactions and therapeutic usage. The main objective of this review is to determine which of these aspects a clinician should consider when choosing a benzodiazepine. Benzodiazepines can be distinguished by their half-lives and those with an intermediate half-life (6–12 h) are indicated for punctual usage and for initial insomnia while those with a longer half-life (over 12 h) are indicated for clinical situations requiring sustained therapeutic treatment. Benzodiazepines with longer half-lives are more at risk of causing side effects due to accumulation of the drug. Most, but not all, benzodiazepines are metabolized by the liver and should be used carefully in patients known to have a hepatic disease, in geriatric patients or in patients taking other medication modifying hepatic metabolism. In these cases, lorazepam, oxazepam or temazepam should be chosen because they are less dependant on hepatic metabolism. Most but not all benzodiazepines are metabolized by the intestinal and hepatic cytochrome P-450 3A4 system. A number of medication namely ketoconazole, erythromycin, corticosteroids, fluoxetine, fluvoxamine, sertraline, calcium channel blockers and grapefruit juice may increase plasma concentrations of some benzodiazepines by inhibiting P-450 3A4 cytochrome activity. Cigarette smoking has been reported to significantly increase the clearance of alprazolam. The mechanism of action of benzodiazepines consists in increasing the inhibitory effect of gamma-aminobutyrique acid (GABA) in the central nervous system. GABA receptor contains five sub-units organised in the form of a rosette. The canal in the centre of the rosette permits the entrance of chloride ions and the opening of the channel is modulated by GABA through changing the configuration of the proteins constituting the rosette. Benzodiazepines alone have no inhibitory activity on neurones but will potentiate the effect of GABA by binding to the sub-units α, β and γ of the rosette. Binding to the sub-unit α 1 localised mainly in the brain stem will increase sedation while binding to the sub-unit α 2 in the limbic system will confer anxiolytic properties to benzodiazepines. No differences among benzodiazepines have been reported concerning their binding to different sub-units. However, clonazepam does appear to modify serotoninergic transmission and this pharmacodynamic characteristic may increase clonazepam inhibitory properties and also stabilise mood in patient with unipolar depression. Benzodiazepines prolonged usage will modify the DNA expression and decrease synthesis m-RNA coding for sub-units α 1, α 2, α 3 and possibly β. These modifications in the composition of GABA receptors are thought to be a mechanism of autoregulation of the receptor and could explain tolerance which is observed in prolonged usage of benzodiazepines. Overall, pharmacokinetics properties and drug interaction remain the most important characteristics when choosing a benzodiazepine while pharmacodynamic properties have little relevance because differences are not significant within this class of medication.