Pharmacodynamic Tolerance

Abstract

Definition Tolerance is a drug-induced reduction in subsequent drug effect. Pharmacodynamic tolerance refers to instances of tolerance that involve either (a) adaptive changes in receptor binding or (b) recruitment of processes that limit or oppose the effects of the drug on receptor-mediated signaling pathways. Impact of Psychoactive Drugs Overview Tolerance refers to a phenomenon in which the potency and/or maximal effectiveness of a drug to produce some effect is reduced after a regimen of prior exposure to that drug. Tolerance may be expressed as a reduced effect produced by a given drug dose, a requirement for higher drug doses to sustain a given effect, or a rightward and/or downward shift in a drug dose-effect curve. Tolerance may result from a variety of different mechanisms. Pharmacodynamic tolerance refers to instances of tolerance associated with pharmacodynamic mechanisms that are described below. It can be distinguished from pharmacokinetic tolerance (tolerance related to processes of pharmacokinetics: drug absorption, distribution, metabolism, and excretion) and behavioral tolerance (tolerance related to whole-organism learning processes). Pharmacodynamics is the study of drug action on a biological system, and pharmacodynamic mechanisms can be divided into two dissociable but complementary components of drug action: receptor binding and pharmacodynamic efficacy. Receptor binding quantifies the direct physical interaction between a drug and one or more target receptor(s). The degree of receptor binding produced by a given concentration of a drug is determined by the density of a given receptor type in a biological system (often expressed as Bmax, receptors per unit mass of tissue) and by the affinity of the drug for that receptor type (often expressed as Kd, the concentration of drug required to bind 50 % of the receptor population). Pharmacodynamic efficacy describes the degree to which a drug activates, inactivates, or otherwise modulates signaling pathways coupled to a receptor. These signaling pathways originate with changes in receptor conformation/function and are transduced into downstream changes in intra-and intercellular biochemistry, physiology, and behavior. Ago-nists stimulate these pathways, inverse agonists reduce constitutive activity in these pathways, and antagonists have no effect on their own but block effects of agonists and inverse agonists. Pharma-codynamic tolerance can be mediated by drug-induced changes in either receptor binding or receptor-mediated signaling. Moreover, these mechanisms are not mutually exclusive to each other or to nonpharmacodynamic mechanisms of tolerance. Rather, tolerance to a given effect of a given drug may involve multiple mechanisms, and mechanisms that underlie tolerance to one *