Considerations on pharmacodynamics and pharmacokinetics: Can everything be explained by the extent of drug binding to its receptor?

Abstract

It is frequently assumed that pharmacological responses depend solely on the extent of drug binding to its receptor according to the occupational theory. It is therefore presumed that the intensity of the effect is determined by drug concentration at its receptor site, yielding a unique concentration-effect relationship. However, when dependence, abstinence, and tolerance phenomena occur, as well as for pharmacological responses in vivo that are modulated by homeostatic mechanisms, the rate of drug input shifts the concentration-effect relationship. Hence, such responses cannot be explained on the sole basis of the extent of drug binding to its receptor. Information on the cellular and molecular processes involved in the generation of abstinence, dependence, and tolerance will undoubtedly result in the development of pharmacodynamic models allowing a satisfactory explanation of drug effects modulated by these phenomena. Notwithstanding, integrative physiology concepts are required to develop pharmacokinetic-pharmacodynamic models allowing the description of drug effects in an intact organism. It is therefore important to emphasize that integrative physiology cannot be neglected in pharmacology teaching and research, but should be considered as an equally valuable tool as molecular biology and other biomedical disciplines for the understanding of pharmacological effects.

The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects

“…However, when observing tolerance, sensitization, dependence, and abstinence, it is clear that pharmacological responses in vivo can be subjected to modulation by homeostatic mechanisms. Thus, an integrative physiological approach is needed to understand concentration-effect relationships [91]. …”

Seizure effects resulting from modification of GABAA-dependent inhibition: A computer simulation study

“…cesses of ligand-receptor interaction [ 1,4], and we tried to estimate the effects of the values of a concentration impulse of the transmitter on the probability for realization of an intercellular signal. Thus, when we form a neuronal network consisting of the interconnected populations of excitatory and inhibitory formal neurons [it is supposed that elements of such neuronal populations are interconnected either randomly (Poisson distribution) or in a uniform manner], we include pharmacologically active synapses of the GABA TS in the analysis.…”