Types of pharmacological action at autonomic ganglia / by W.D.M. Paton.

  • William Paton
Date:
1954
Catalogue details

Licence: In copyright

Credit: Types of pharmacological action at autonomic ganglia / by W.D.M. Paton. Source: Wellcome Collection.

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    it may be relieved by increasing the concentration of stimulant drug, and re-established by increasing in turn the dose of antagonist, so that one can proceed as though lacing a shoe with first one lace on top and then the other. There is always an upper limit to the process, when the stimulant drug seems to become relatively ineffective and even sometimes (in the presence of very large amounts of an antagonist) itself depressant, but usually several cycles can be demonstrated. This is still, however, only circumstantial evidence. Suppose one takes a model experiment in which one studies, for instance, the antagonism by a sympatholytic drug to the response of the nictitating membrane to an injection of nicotine; one could quite readily show that the drug would depress the effect of a small dose of nicotine as revealed by the contraction of the nictitating membrane. Then one could show that increasing the dose of nicotine would overcome the antagonism, and so on. To take another example, one might excite a nerve trunk electrically and show that a certain concentration of local anaesthetic applied further down the trunk reduced the effect of a certain sub-maximal stimulation, that by increasing the stimulus strength this antagonism could be overcome, and that by further increasing the concentration of the anaesthetic the antagonism could be re-established. In both these examples, the conditions of our working definition of competitive inhibition are met. But nobody would suggest that a specific sympatholytic competes with acetylcholine or that volts compete with local anaesthetics. Consideration of these rather elementary examples suggests that one has to be rather cautious in identifying an action as competitive. One’s confidence in such an identification can be increased in three further ways. First, by verifying so far as is feasible that agonist and antagonist are acting at the same site; second by requiring some chemical relationship between the two (and for this reason I have segregated drugs chemically resembling acetylcholine in this section); and third by showing that the antagonist in question has a relationship to the agonist in some other way. Thus nicotine in its second phase can be regarded as competing with acetylcholine (although one would hesitate to stress their chemical resemblance) because nicotine displays so many other actions also displayed by acetylcholine. Any discussion of a possible competitive action requires the mention of one further point. There are a number of observations where a drug is a more effective antagonist against some acetylcholine-like substance than against acetylcholine itself; as for instance the thiazole compounds against nicotine studied by Pick & Unna (1946), or atropine