This hyperbolic relation resembles the mass action law that describes the association between two molecules of a given affinity. This resemblance suggests that drug agonists act by binding to (“occupying”) a distinct class of biologic molecules with a characteristic affinity for the drug. Radioactive receptor ligands have been used to confirm this occupancy assumption in many drug-receptor systems. In these systems, drug bound to receptors (B) relates to the concentration of free (unbound) drug (C) as depicted in Figure 2–1B and as described by an analogous equation: in which Bmax indicates the total concentration of receptor sites (ie, sites bound to the drug at infinitely high concentrations of free drug) and Kd (the equilibrium dissociation constant) represents the concentration of free drug at which half-maximal binding is observed. This constant characterizes the receptor’s affinity for binding the drug in a reciprocal fashion: If the Kd is low, binding affinity is high, and vice versa. The EC50 and Kd may be identical but need not be, as discussed below. Dose-response data are often presented as a plot of the drug effect (ordinate) against the logarithm of the dose or concentration (abscissa), transforming the hyperbolic curve of Figure 2–1 into a sigmoid curve with a linear midportion (eg, Figure 2–2). This
Drug effect (E) Emax Bmax ABEC50 Kd 1.0 0.5 1.0 0.5Receptor-bound drug (B)
FIGURE 2–1 Relations between drug concentration and drug effect (A) or receptor-bound drug (B). The drug concentrations at which effect or receptor occupancy is half-maximal are denoted by EC50 and Kd, respectively.
transformation is convenient because it expands the scale of the concentration axis at low concentrations (where the effect is changing rapidly) and compresses it at high concentrations (where the effect is changing slowly), but otherwise has no biologic or pharmacologic significance.
When an agonist occupies a receptor, conformational changes occur in the receptor protein that represent the fundamental basis of receptor activation and the first of often many steps required to produce a pharmacologic response. The overall transduction process that links drug occupancy of receptors and pharmacologic response is called coupling. The relative efficiency of occupancy-response coupling is determined, in part, at the receptor itself; full agonists tend to shift the conformational equilibrium of receptors more strongly than partial agonists (described in the text that follows). Coupling is also determined by “downstream” biochemical events that transduce receptor occupancy into cellular response. For some receptors, such as ligand-gated ion channels, the rela-
ABCDEEC50 (A) EC50 (C)EC50 (B) EC50 (D,E)  Kd 0.5 because the ion current produced by a drug is often directly proportional to the number of receptors (ion channels) bound. For other receptors, such as those linked to enzymatic signal transduction cascades, the occupancy-response relationship is often more complex because the biologic response reaches a maximum before full receptor occupancy is achieved.
Many factors can contribute to nonlinear occupancy-response coupling, and often these factors are only partially understood. A useful concept for thinking about this is that of receptor reserve
FIGURE 2–2 Logarithmic transformation of the dose axis and experimental demonstration of spare receptors, using different concentrations of an irreversible antagonist. Curve A shows agonist response in the absence of antagonist. After treatment with a low concentration of antagonist (curve B), the curve is shifted to the right. Maximal responsiveness is preserved, however, because the remaining available receptors are still in excess of the number required. In curve C, produced after treatment with a larger concentration of antagonist, the available receptors are no longer “spare”; instead, they are just sufficient to mediate an undiminished maximal response. Still higher concentrations of antagonist (curves D and E) reduce the number of available receptors to the point that maximal response is diminished. The apparent EC50 of the agonist in curves D and E may approximate the Kd that characterizes the binding affinity of the agonist for the receptor.