Interactions between drugs and occupied receptors

Abstract

This review has two parts. Part I deals with isobolographic procedures that are traditionally applied to the joint action of agonists that individually produce overtly similar effects. Special attention is directed to newer computational procedures that apply to agonists with dissimilar concentrationeffect curves. These newer procedures are consistent with the isobolographic methods introduced and used by Loewe, however the present communications provides the needed graphical and mathematical detail. A major aim is distinguishing super and sub-additive interactions from those that are simply additive. The detection and measurement of an interaction is an important step in exploring drug mechanism and is also important clinically. Part II discusses a new use of isoboles that is applicable to a single drug or chemical whose effect is mediated by two or more receptor subtypes. This application produces a metric that characterizes the interaction between the receptor sub types. The expansion of traditional isobolographic theory to this multi receptor situation follows from the newer approaches for two-drug combination analysis in Part 1. This topic leads naturally to a reexamination of competitive antagonism and the classic Schild plot. In particular, it is shown here that the Schild plot in the multi-receptor case is not necessarily linear with unit slope. Both parts of this review emphasize the quantitative aspects rather than the many drugs that have been analyzed with isobolographic methods. The mathematical exposition is rather elementary and is further aided by several graphs. An appendix is included for the reader interested in the mathematical details. KeywordsIsobole; Synergism; Additivity; Receptor interaction; Schild plot; Knockout animals; Muscarinic receptors I. Drug Combinations IntroductionThe simultaneous presence of two or more drugs is a common occurrence in clinical settings and in numerous experimental designs aimed at studying mechanism. When two drugs (or chemicals) that produce overtly similar effects are simultaneously present it is important to detect and characterize any interaction that leads to either exaggerated or reduced effects. That characterization requires measurement, i.e., quantitation yielding a metric that distinguishes between the expected and the actual effect magnitudes. Obtaining that metric is an important step in the exploration of mechanism. Even when a single drug is administered to a living system it is present in a sea of endogenous chemicals. Thus, studies of drug action are enhanced by models that apply to drug combination situations. Interactions between drugs can be ronald.tallarida@temple.edu, (phone) (FAX) 215-707-7068 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Plea...

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