Pharmacodynamics affinity constant

One frequently encounters the case where the equilibrium dissociation constant (iQ, see above) is defined by microconstants with Tast rates on and off the receptor. However, any change in potency in a chemical series (affinity) must represent an increase in the on (k+i) rate or a decrease in the off rate (fe i). Occasionally, either by accident or design, the off rate is altered dramatically enough to redefine the receptor kinetics of the compound such that the rates influence the actual pharmacodynam-... 

Tolerance Model For some drugs, pharmacodynamic parameters like max and ECsn may appear to vary over time, resulting in changes in pharmacological response despite the presence of constant concentrations at the effect site. Tolerance is characterized by a reduction in pharmacological response after repeated or continuous drug exposure. The complex mechanism of tolerance may involve receptor pool depletion, decrease in receptor affinity, and up- or down-regulation. 

Equilibrium as well as rate constants are related to free energy values AG by relationships of the type of eq. 11 (cliapter 1.2). Thus, only equilibrium constants (e.g. K values or at least IC50 values, not % inhibition at a certain concentration) and rate constants (e.g. log k values, not % absorption or % concentration in a certain compartment) are suited for QSAR studies, which means that all biological data have to be transformed in an appropriate manner before being used in quantitative analyses. In the case of complex biological data resulting from a sequence of several independent processes (in the worst case whole animal data), sometimes one effect predominates e.g. the bioavailability, the penetration of the blood-brain barrier, or the affinity to the receptor site. In other cases several effects overlap, which makes the QSAR analysis much more difficult. Due to the nonlinear characteristics of dose-response relationships, % effect values at a certain dose must not be used in QSAR equations. In each case they have to be transformed to equieffective molar doses (i.e. dose levels which produce or prevent a certain pharmacodynamic effect dose levels that increase the life span of animals to a certain extent dose levels which kill a certain percentage of the animals). 

Clark realized this, and said The action of acetylcholine depends on at least two separable factors, firstly the fixation of the drug by certain receptors, and secondly the power to produce its action after fixation (Clark, 1937). Further experimental work in Holland established these concepts firmly under the names affinity and intrinsic activity respectively (Ariens, 1954). An inhibitor (e.g. a chemotherapeutic drug, insecticide, or fungicide) requires only affinity but many pharmacodynamic drugs must have intrinsic activity as well, namely the ability to produce a natural physiological response as soon as combination between drug and receptor has occurred. The affinity is a measure of the attraction between the stimultant and the receptor numerically it is the reciprocal of the dissociation constant of the... 

---