Antisecretory Drugs for Diarrheal Disease

Acute diarrhea is a major cause of morbidity and mortality worldwide. Infants and pre-school children are the most vulnerable in whom there are 2–3 million deaths each year as a result of the associated dehydration and acidosis. Although oral rehydration therapy has reduced mortality during the past 30 years ago, the search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce faecal losses in patients with high-volume watery diarrhea has continued for more than 20 years. A variety of potential targets for antisecretory agents have been explored which include loci within the enterocyte (the chloride channel, calcium-calmodulin) and other sites such as enteric nerves and endogenous mediators (such as 5-HT, prostaglandins). Although the potential of calcium-calmodulin inhibition has as yet not been realised, preliminary studies suggest that there are chloride channel blockers under development that will find a place in the management of secretory diarrheas. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of acute diarrhea. Potentiation of the effects of endogenous enkephalin activity by enkephalinase inhibition has already produced a safe, effective anti-secretory drug, racecadotril. Speculative early work indicates that there may be a role for antagonists of 5-HT, substance P, and VIP receptors. There now seems to be a real possibility that antisecretory therapy will become more widely available in the future.