Summary
Synthetic antidiarrheal agents like diphenoxylate and loperamide are characterized by strong opiate-like constipating activity with an almost complete lack of central morphinomimetic effects. The present investigation examines the pharmacological mechanisms underlying the action of such compounds.
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1.
In the radioreceptorassay, antidiarrheal agents competitively inhibited the stereospecific binding of opiates, having affinities comparable to those of strong narcotic nnalgesics. Binding was increased in the absence of sodium. No differences in the affinities of these compounds to central and peripheral opiate receptors, respectively, were found.
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2.
Antidiarrheal agents inhibited the electrically induced contractions of the isolated longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum. This effect was completely antagonized by the narcotic antagonist naloxone; however, it was impossible to reverse drug action by washing the preparation. To obtain pharmacological effects on the isolated organ, up to 70-fold lower concentrations were necessary in case of the antidiarrheals than was calculated from their affinities in the radioreceptorassay.
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3.
The pharmacokinetic behaviour of 3H-loperamide was tested in mice after i.v. injection. Compared to morphine, loperamide was rapidly eliminated from the general circulation and only small concentrations reached the CNS. This phenomenon provides an explanation for the fact, that opiate-like antinociception could only be obtained with antidiarrheal agents after application of subtoxic or toxic dose levels.
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4.
Up to 2 h after i.v. administration of 3H-loperamide, an increase in radioactivity in the wall of the small intestine was found. Accumulation in the gastrointestinal tract might be related to distinct physicochemical properties of the compound. The surface tension lowering effect is a common characteristic by which all antidiarrheals differed from narcotic analgesics and could be related to the peculiar behaviour of these substances in vitro and in vivo.
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Wüster, M., Herz, A. Opiate agonist action of antidiarrheal agents in vitro and in vivo—Findings in support for selective action. Naunyn-Schmiedeberg's Arch. Pharmacol. 301, 187–194 (1978). https://doi.org/10.1007/BF00507036
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DOI: https://doi.org/10.1007/BF00507036