Terms and procedures used in the analysis of drug action: antagonists

Term Suggested Usage Notes
Competitive antagonism In competitive antagonism, the binding of agonist and antagonist is mutually exclusive. This may be because the agonist and antagonist compete for the same binding site or combine with adjacent sites that overlap (syntopic interaction). A third possibility is that different sites are involved but that they influence the receptor macromolecule in such a way that agonist and antagonist molecules cannot be bound at the same time. In practice, it is difficult to distinguish syntopic orthosteric antagonism from very strong allosteric antagonism (i.e., allosteric antagonism that is characterized by very high negative cooperativity between the orthosteric site and the allosteric site).
If the agonist and antagonist form only short-lasting combinations with the receptor, so that equilibrium between agonist, antagonist, and receptors is reached during the presence of the agonist, the antagonism will be surmountable over a wide range of concentrations (reversible competitive antagonism). In contrast, some antagonists, when in close enough proximity to their binding site, may form a stable covalent bond with it (irreversible competitive antagonism), and the antagonism becomes insurmountable when no spare receptors remain. More generally, the extent to which the action of a competitive antagonist can be overcome by increasing the concentration of agonist is determined by the relative concentrations of the two agents, by the association and dissociation rate constants for their binding, and by the duration of the exposure to each.
Noncompetitive antagonism Agonist and antagonist can be bound to the receptor simultaneously; antagonist binding reduces or prevents the action of the agonist with or without any effect on the binding of the agonist. Current usage should be limited to the action of blockers on the same receptor as the agonist (such as channel block of the nicotinic receptor). Prior use to describe the inhibition by adrenoceptor antagonists of the response to tyramine would be better termed indirect antagonism (Table 1).
Insurmountable antagonism A descriptive term indicating that the maximum effect of the agonist is reduced by either pretreatment or simultaneous treatment with the antagonist. This can encompass several distinct molecular mechanisms such as: (a) irreversible competitive antagonism; (b) noncompetitive antagonism; and (c) functional antagonism (see Table 1). The converse phenomenon surmountable antagonism is generally observed with reversible competitive antagonism though it may also occur with chemical antagonism, with irreversible antagonists in the case of spare receptors, or with certain forms of allosteric antagonism. In dissecting mechanisms of insurmountable antagonism, it is often helpful to distinguish between the locus of the action (competitive, noncompetitive, or indirect) and the kinetics of the action (reversible and irreversible). This can usually be done with appropriately designed time course or preincubation/blocking experiments.
Gaddum equation Embedded Image The relationship (Gaddum, 1937, 1943) that replaces the Hill-Langmuir equation (see Table 5) when two ligands, A and B, are in equilibrium with a common binding site. pAR is the proportion of the binding sites occupied by A; KA and KB are the equilibrium dissociation constants of A and B, respectively. Equating occupancies by an agonist first in the absence and then in the presence of a reversible competitive antagonist leads to the Schild equation (see below), and the terms Schild equation and Gaddum equation have sometimes been regarded as interchangeable.
The Schild equation Embedded Image The relationship (Schild, 1949) that would be expected to hold between the concentration ratio, r, and the concentration of a reversible competitive antagonist, B. KB is the equilibrium dissociation constant for the combination of B with the receptor. See also Gaddum equation (item above), Schild plot (item below), and (Section IV. B.).
The Schild plot A graph of log (r - 1) against log antagonist concentration, where r is the concentration ratio (see Table 4). This should yield a straight line of unit slope if the Schild equation is obeyed (Arunlakshana and Schild, 1959). The linearity and slope provide information about the nature of the antagonism. In practice, it is preferable to analyze agonist/antagonist interaction data by direct curve fitting to the Gaddum or Schild equations using computer-assisted nonlinear regression, but the Schild plot remains a useful graphical aid (see Section IV. B.).