Classic receptor-occupancy theory

Pharmacodynamics describes the time course and the magnitude of pharmacological response of drugs. Based on the classic receptor-occupancy theory, after drug molecules reach the target biophase, it binds to the receptors to form the drug-receptor complex to exert pharmacological response (Fig. 2). 

Emax Model, ftmax model was originally derived from the classic drug-receptor occupancy theory. It is an empirical function for describing a non-linear concentration-effect relationship with the general form ... 

The various components of classical theory relating receptor occupancy to tissue response are shown schematically in Figure 3.5. It will be seen that this formally is identical to the equation for response derived in the operational model (see material following), where x = [Rt]e/p. 

FIGURE 3.5 Major components of classical receptor theory. Stimulus is the product of intrinsic efficacy (s), receptor number [R], and fractional occupancy as given by the Langmuir adsorption isotherm. A stimulus-response transduction function f translates this stimulus into tissue response. The curves defining receptor occupancy and response are translocated from each other by the stimulus-response function and intrinsic efficacy. 

The classical occupation theory of Clark rests on the assumption that drugs interact with independent binding sites and activate them, resulting in a biological response that is proportional to the amount of drug-receptor complex formed. The response ceases when this complex dissociates. Assuming a bimolecular reaction, one can write... 

In contrast to the assumption made in the classical occupation theory, the agonist in the two-state model does not activate the receptor but shifts the equilibrium toward the R form. This explains why the number of occupied receptors does not equal the number of activated receptors. 

The classical work of Clark (1937), based on the application of Langmuir s adsorption isotherm (see Section 8.1), assumed that the effect of a drug is proportional to the fraction of receptors occupied by drug molecules, and that a maximal effect is obtainable only when all receptors are occupied by the drug. As a statement of the action of inhibitors (so important for work in chemotherapy and agriculture) this simple occupation theory can hardly be bettered. However, it is inadequate to explain the kinetics of agents which elicit a positive response substances like the synaptic transmitter acetylcholine and innumerable artificial agonists. 

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