Antidiarrhoeal — racecadotril
In health, the small and large intestines absorb water and electrolytes, but when the process is disturbed by bacterial toxins or enteropathogenic viruses, intestinal mobility may be excessive. This causes a marked loss of water and electrolytes, and the resulting diarrhoea and dehydration requires prompt treatment, particularly in young children, where the loss of fluid may be life-threatening. The standard treatment is with codeine and loperamide, which reduce fluid loss by slowing down the excessive rate of intestinal transport. A very different type of therapy involves enkephalinase inhibitors.
Enkephalins are endogenous opioids that activate delta receptors in the intestinal tract. They are normally degraded by enkephalinases, but in diarrhoea such degradation may be excessive. Some years ago, the enkephalinase inhibitor thiorphan was tried out as an antidiarrhoeal.1
Thiorphan is an acetylmercapto derivative, but further work has indicated that acetorphan, a deesterified prodrug of thiorphan, is more effective.2 Acetorphan, now referred to as racecadotril, is a potent inhibitor of enkephalinase, and appears to be of value in the control of severe diarrhoea by reducing the hypersecretion of water and electrolytes into the intestinal lumen. In randomised double-blind placebo-controlled clinical trials in children with acute diarrhoea, the drug was given in doses of 4.5mg daily, together with adjuvant dehydration therapy, and brought about a 50% reduction in stool output within 24hr, and a 70% reduction after treatment for 48hr.3 In adults, racecadotril in doses of 100–200mg daily caused a similar degree of symptomatic improvement.
The incidence of side-effects with racecadotril was low, and similar to those following placebo treatment. When compared to loperamide, post-treatment constipation was reduced. The drug represents a new and effective approach to the treatment of the old problem of acute diarrhoea. It is of interest that in cancer patients, racecadotril had no influence on the diarrhoea associated with the cytotoxic irinotecan.