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Use of the biological stimulus in determining parameters of drug action, and its relationship to the drug effect A contribution to the theory of drug action

1977; Elsevier BV; Volume: 69; Issue: 2 Linguagem: Inglês

10.1016/0022-5193(77)90135-7

1095-8541

Alexander Gerö, Ronald J. Tallarida,

Mass Spectrometry Techniques and Applications

Drug action is considered a function of the biological stimulus, which in turn is proportional to the receptor occupancy; but the nature of the functional relationship is unknown, as is also the magnitude of the drug-receptor affinity and of the efficacy (the proportionality constant of the stimulus-occupancy relationship). Methods exist to determine the receptor affinity of (a) a drug of high efficacy provided it is possible to block part of the receptor irreversibly, or (b) a drug of low efficacy provided it can be observed together with a drug of high efficacy acting on the same receptor. The former method is generally accepted, the latter is shown to rest on a questionable simplification. An improvement of method (b) is presented which avoids all simplifying assumptions: making use of the affinity constant of the high-efficacy drug determined by method (a), and of the thesis that identical biological stimuli correspond to identical effects, it is shown that the equations of theoretical pharmacology yield the affinity constant of the low-efficacy drug. A more general version of the method allows to calculate the affinity constants of any two drugs acting on the same receptor, without previous knowledge of anything but the dose-response curves of the two drugs. In both cases, the relative efficacies of the two drugs can also be calculated and so can the stimuli corresponding to each drug concentration, so that it is possible to find empirically the nature of the functional relationship between the calculated stimulus and the observed drug effect.