Some Aspects of the Pharmacology of Metoclopramide

Abstract

Aspects of the pharmacology of metoclopramide have been investigated by experiments using laboratory animals and isolated tissues, The purpose of this study being to examine peripheral actions of this drug which might contribute towards an understanding of its clinical effectiveness in stimulating gastrointestinal motility. Metoclopramide did not affect the gastric emptying rate or intestinal transit in the conscious rat. It did not modify gastric emptying in anaesthetised rats or gastric volume and relaxation responses in anaesthetised or decerebrate rats. Studies on the cardiovascular system of rats and cats revealed that metoclopramide evoked pressor responses at low doses, probably by a vasoconstrictor action, and hypotensive responses at higher doses, by cardiac depressant and vasodilator actions. No adrenolytic or sympatholytic effects of metoclopramide were observed butit was shown to possess potent dopamine-receptor blocking activityin both species. Low concentrations of metoclopramide had stimulant and sensitising effects on isolated preparations of gastrointestinal tissue but depressant effects on nerve and muscle activity at high concentrations. The sensitising effects of metoclopramide were non specific and required functioning nervous tissue, but were not mediated by blockade of sympathetic or non-adrenergic inhibitory nerves, anticholinesterase activity, release of acetylcholine, or prostaglandin synthesis, The findings suggest that these effects may not result from tryptaminergic-receptor blockade but possibly from blockade of inhibitory dopamine-receptors in the gut. Possible interactions between metoclopramide and gastrointestinal hormones were investigated and secretin and glucagon were found to have cardiovascular dopamine-receptor stimulant properties which were antagonised by metoclopramide. Secretin and glucagon produced inhibitory effects on isolated intestinal tissue and on gastric motility in vivo which were prevented by metoclopramide in a manner suggesting pharmacological rather than physiological antagonism. These experimental findings are discussed in relation to current understanding of the pharmacology of metoclopramide and the physiology of the gut.