[Pharmacological bases of therapeutic tolerance].
The purpose of this review paper is to describe the various mechanisms that may lead to a decrease in the effectiveness of drugs during long-term treatment (the so-called "tolerance" or "escape phenomenon"). In addition, some precise recommendations will be made. Tolerance may be due either to degradation of the active substance by enzyme induction, as is the case e.g. with barbiturates (pharmacokinetic drug tolerance) or to down-regulation of receptors (e.g. beta-adrenergic drugs and opiates) or exhaustion of the metabolic pathways involved in pharmacological activation, as with nitrates and other drugs (pharmacodynamic drug tolerance). Whatever its mechanism, tolerance can be prevented by intermittent drug administration despite the problems inherent in the therapeutic gaps thus created. Another, more rational approach is to replace the drug concerned by a more appropriate drug which permits, or induces the restoration of receptor density when their number is reduced by the physiopathological situation (e.g. H2 stimulation instead of beta-adrenergic stimulation) or which reproduces the action of first physiological messengers, such as the endothelium-derived relaxing factor (EDRF), without requiring metabolic activation (e.g. SIN-1 or molsidomine instead of nitrates).
Bassenge
E
E
Département de Physiologie appliquée, Université de Freiburg im Breisgau.
Grewe
R
R
D000818:Animals; D004361:Drug Tolerance; D006801:Humans; D008981:Molsidomine / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism; D010599:Pharmacokinetics; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism
D011955:Receptors, Drug; D008981:Molsidomine
Bases pharmacologiques de l'échappement thérapeutique.