One drug can overcome the effect of another or reduce the activity of an endogenously released and active substance such as a neurotransmitter, either by competing with that substance for its receptor site (receptor antagonism) or stimulating a different receptor to induce an opposing effect (physiological or functional antagonism), The former may be regarded as true antagonism for in the latter case both drugs are actually agonists, It is epitomised by the use in asthma of beta adrenoceptor agonists like salbutamol to dilate bronchi that have been constricted by a cocktail of local mediators such as
Figure 5.3 Drug antagonism, (a) Surmountable competitive antagonism. Dose-response curves are shown for an agonist alone and in the presence of increasing concentrations of the antagonist. The antagonism is surmountable because even in the presence of a large concentration of antagonist the agonist can still produce a maximal response and it is competitive because equal increments in the concentration of antagonist produces equal shifts in the DRCs. The shift is known as the dose ratio (r), and is the amount by which the dose of agonist must be increased in the presence of antagonist to produce the same response as in its absence, (b) A Schild plot. This shows dose ratio (r) measured as in (a) and plotted as log(r — 1) against log concentration of antagonist. In true competitive antagonism the graph should have a slope of 1 and its intercept with the abscissa gives pThe negative logarithm of this value is Schild's pA2 measure of drug antagonism. In the example shown a of 3.2 x 10"10 gives a pA2 of 9.5. (c) Unsurmountable irreversible antagonism. In the presence of low concentrations of antagonist the agonist can still produce a maximum response because the antagonist does not occupy all the receptors and there are sufficient 'spare receptors' available for the agonist. As the concentration of antagonist is increased fewer spare receptors remain and since the antagonist does not dissociate from the receptors (as its binding is irreversible) the agonist is unable to produce a full response, i.e. the antagonism is unsurmountable n
histamine, acetylcholine and kinins. In the CNS the inhibitory NT (GABA) could be regarded as the physiological antagonist of the excitatory NT (glutamate). When the agonist and antagonist compete for the same receptor the binding of the agonist and the response it produces are both reduced. Thus to obtain the same response in the presence, as in the absence of antagonist, the concentration of agonist must be increased and over a range of agonist concentrations this results in a parallel shift to the right in the position of its DRC (Fig. 5.3).
The degree of this shift, the amount by which the agonist concentration has to be increased in order to produce the same response in the presence as in the absence of the antagonist, is known as the dose ratio (r). The larger this ratio, the greater the shift in the DRC and the more potent is the antagonist. In fact if the antagonism is really competitive then the degree of shift of the DRC will be proportional to the increase in concentration of the antagonist used. From Fig. 5.3(a), it can be seen that increasing the antagonist concentration from 10—9 M to 10—8, 10—7, 10—6 M always produces the same tenfold increase in dose ratio (i.e. 10, 100, 1000). Also if the antagonism is competitive not only will the DRCs remain parallel but it should always be possible to restore the maximal response to the agonist by giving more of it, irrespective of the amount of antagonist present. This is known as reversible or surmountable competitive antagonism. Since both agonist and antagonist are continuously combining with and dissociating from the receptor the likelihood of either occupying it at any time will depend on their relative concentrations.
The dose ratio r = (XB/KB) + 1 where XB is the concentration of antagonist and KB its equilibrium constant. This can be expressed logarithmically as log (r - 1) = log Xb — log Kb and a plot of log (r — 1) against log XB (the Schild plot) should give a straight line with slope of 1, which intercepts the abscissa at the value — log KB (pKB) for the antagonist (Fig. 5.3(b)). This is frequently converted into a simple number by taking its negative logarithm, much as pH values represent hydrogen ion concentration, so that KBs of 10—7 or 3.2 x 10—7 mol/l become simply 7 or 6.5. This p^2 value was defined by Schild as the negative logarithm of the molar concentration of antagonist required to give a dose ratio of 2. Thus the larger the p^2 value, the smaller the concentration of antagonist needed and the greater its affinity and effectiveness. In practice full DRCs are rarely obtainable especially in studies on the CNS, or even necessary, provided that responses to two doses of agonist can be obtained at each concentration of antagonist. This will establish the position of the DRC and allow r to be calculated.
If the antagonist does not readily dissociate from the receptor, because it is bound firmly, then the agonist will not be able to displace it and restore a maximal response. At low concentrations of antagonist this may not be apparent. An agonist can often achieve a maximal response by activating only a small percentage of its receptors, so in the presence of low concentrations of a non-dissociating antagonist there may be sufficient spare receptors available for increased concentrations of the agonist still to achieve a maximal response. As the concentration of antagonist is increased, however, fewer unoccupied receptors are left and since the agonist cannot displace the antagonist a maximal response cannot be achieved (Fig. 5.3(c)). This is unsurmountable or irreversible competitive antagonism. It is still competitive because the drugs are competing for the same receptor. Sometimes an antagonist can inhibit the effect of an agonist not by occupying the same binding site on the receptor but some adjacent site or process necessary for the agonist's effect, such as the ion channel itself. This is noncompetitive antagonism which may, or may not, be reversible, depending on the action of the antagonist. There are a number of drugs with this action on the glutamate NMDA receptors (Chapter 10).
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