EVOLVING CONCEPTS OF DRUG ACTION: AN INTEGRATIVE REVIEW OF DRUG-RECEPTOR INTERACTION MODELS

Resumen

This review synthesized the evolution of the major theoretical models of drug action and drug–receptor interactions, based on searches conducted in PubMed/NCBI, SciELO, and the Virtual Health Library (BVS-BIREME/PAHO/WHO), complemented by authoritative reference works. From Langley’s proposal of “receptive substances” and Ehrlich’s principle that drugs exert their effects through binding to specific molecular targets, pharmacodynamics has progressively developed quantitative models of drug action. The Law of Mass Action established the reversibility of drug–receptor binding and its dependence on affinity, expressed by the dissociation constant (Kd). Clark’s receptor occupancy theory linked pharmacological responses to receptor occupancy; however, subsequent evidence demonstrated that receptor occupancy alone cannot account for the variability of pharmacological effects. Ariëns and Stephenson introduced the concepts of intrinsic activity and efficacy, distinguishing receptor binding from receptor activation and providing a framework for understanding full and partial agonists, antagonists, and spare receptors. Subsequent models incorporated receptor conformational flexibility, replacing static paradigms with dynamic approaches. Two-state and multistate models, together with macromolecular perturbation theory, account for constitutive activity, inverse agonism, and biased signaling. Thus, modern pharmacology views drug action as a dynamic process dependent on affinity, efficacy, receptor conformation, and signaling pathways across different cellular contexts.