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THE MECHANISM OF ACTION OF ANTICHOLINESTERASE DRUGS
Author(s) -
BURGEN A. S. V.
Publication year - 1949
Publication title -
british journal of pharmacology and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0366-0826
DOI - 10.1111/j.1476-5381.1949.tb00540.x
Subject(s) - citation , action (physics) , clinical pharmacology , mechanism (biology) , medicine , library science , computer science , pharmacology , philosophy , physics , epistemology , quantum mechanics
During the past few years much new work on anticholinesterase substances-has been published as a result of the new interest in the subject produced by the discovery of diisopropylfluorophosphonate (DFP) by McCombie and Saunders (1946). Many discrepancies of detail between the behaviour of individual cholinesterase inhibitors have been noted and have occasioned serious doubts as to the validity of the hypothesis that the physiological action of these substances is solely a consequence of cholinesterase inhibition. One source of error was greatly clarified by Mendel and his co-workers (Mendel, Mundell, and Rudney, 1943; Mendel and Rudney, 1943 and 1944; Hawkins and Gunter, 1946; Hawkins and Mendel, 1947), who showed that the term " cholinesterase " has been applied in the past to enzymes of two, and possibly more (Augustinsson, 1948), distinct enzymological Species-termed' by them "true" and " pseudo" cholinesterases, distinguishable by specific substrates. They have shown that these enzyme types differ strikingly in their distribution, their sensitivity to inhibitory agents, and their optimum substrate concentrations, and that the appearance of the pharmacological effects of anticholinesterases is related to inhibition of the " true" cholinesterase. Only# when the physiological response measured is that to acetylcholine carried by the blood stream does the pseudocholinesterase in the plasma seem to be important (Heymans, Verbeke, and Votava, 1948) in determining the magnitude of acetylcholine responses. Despite this very important advance many anomalies remain to be explained, and it is the purpose of this paper to discuss the kinetics of cholinesterase inhibition by various agents and the light this sheds on our interpretation of cholinesterase inhibition under strictly physiological conditions. Some aspects of the kinetics of cholinesterase activity and inhibition have been considered by a number of workers (Straus and Goldstein, 1943; Goldstein, 1944; Mazur and