Reversible competitive antagonism

The negative logarithm of the concentration of antagonist that causes a concentration ratio of x is commonly denoted by pA(. This term was introduced by H. O. Schild as an empirical measure of the activity of an antagonist. The value most often quoted is pA2, where 

To illustrate this notation we consider the ability of atropine to block the muscarinic receptors for acetylcholine. The presence of atropine at a concentration of only 1 nM makes it necessary to double the acetylcholine concentration required to elicit a given submaximal response of a tissue. Hence, pA2 = 9 for this action of atropine (-log(K) 9) = 9). 

The law of mass action was first applied to competitive antagonism by Clark, Gaddum, and Schild at a time before the importance of receptor activation by isomerization was established. It was assumed, therefore, that the equilibrium among agonist, antagonist, and their common binding site could be represented quite simply by the reactions  

As shown in Section 1.5.5, application of the law of mass action to these simultaneous equilibria leads to the following expression for the proportion of the binding sites occupied by agonist  

KA and KB are the dissociation equilibrium constants for the binding of agonist and antagonist, respectively. This is the Gaddum equation, named after J. H. Gaddum, who was the first to derive it in the context of competitive antagonism. Note that if [B] is set to zero, we have the Hill-Langmuir equation (Section 1.2.1). 

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To summarize to this point, reversible competitive antagonism has the following characteristics ... 

Practical Applications of the Study of Reversible Competitive Antagonism... 

Hi receptor antagonists block the actions of histamine by reversible competitive antagonism at the Hi receptor. They have negligible potency at the H2 receptor and little at the H3 receptor. For example, histamine-induced contraction of bronchiolar or gastrointestinal smooth muscle can be completely blocked by these agents, but the effects on gastric acid secretion and the heart are unmodified. 

Figure 6.6 Competitive antagonism, where both the agonist (AG) and the antagonist (ANT) compete to bind reversibly to the same subtype of receptor sites.

Antagonism occurs when the action of one drug opposes the action of another. The two drugs simply have opposite pharmacodynamic effects, e.g. histamine and adrenaline on the bronchi exhibit physiological or functional antagonism or they compete reversibly for the same drug receptor, e.g. flumazenil and benzodiazepines exhibit competitive antagonism. 

Similar effects were stated to occur with rabbit synaptosomes, levorphanol causing a reduction of K -stimulated ->Ca uptake in vitro (65). Once again this was a stereospecific, naloxone-reversible and non-competitive antagonism. Also, chronic levorphanol treatment of mice produce increases in K+-stimulated uptake compared with controls. In this case no effects were seen with resting levels of Ca flux at 5 mM K+ (3). Very similar results were reported by End et al. 

D-induced increase in the rate of herbicide detoxification by conjugation of diclofop to water-soluble metabolites a competitive antagonism between DM and 2,4-D on a common receptor site and a 2,4-D-induced reversal of the DM effects on transmembrane proton gradient. " ... 

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