New Approaches to Antidiarrheal Therapy

Recent studies of the pathophysiology of diarrhea have resulted in both increased understanding of how existing antidiarrheal drugs work and a rational approach to the development of new antidiarrheal therapies. No longer can one assume that all antidiarrheal medicines are effective solely by virtue of their effects on intestinal smooth muscle with prolongation of intestinal transit time. The concept has emerged that diarrhea most often represents an increase in stool water excretion and that most diarrheal disorders are associated with changes in intestinal fluid and electrolyte movement (1). Thus, it is not surprising that antidiarrheal therapy can also be considered in relation to intestinal fluid and electrolyte movement. By definition, successful antidiarrheal therapy will result in a decrease in stool fluid output, which may result either from (a) an increase in intestinal fluid and electrolyte absorption or (b) an inhibition of intestinal fluid and electrolyte secretion (Fig. 1). What are the mechanisms by which an antidiarrheal agent increases fluid and electrolyte absorption? Antidiarrheal agents may affect fluid and electrolyte absorption either directly or indirectly. This classification is used to distinguish between direct stimulation of the absorptive process and one in which the absorptive process is not directly affected by the antidiarrheal drug. In the latter circumstance, it is generally recognized that some antidiarrheal agents affect intestinal motor function, resulting in retention of luminal contents with a decrease in the distal flow of fluid (2). As a consequence, there will be an increase in the time in which luminal contents are in contact with intestinal mucosa. This increase in contact time combined with a normal rate of fluid and electrolyte absorption by mucosal epithelial cells results in an increase in absorption. Thus, the overall absorptive process becomes more efficient. In contrast to this indirect stimulation of fluid and electrolyte absorption, studies in recent years provide considerable evidence that some antidiarrheal drugs act by directly stimulating the absorptive process (3-5). The first demonstration of this phenomenon was the observation that glucose increases fluid and electrolyte absorption (6,7). Although there has been modest controversy regarding the actual mechanism by which glucose augments water and sodium absorption, there is no doubt that the observed increase in fluid absorption is directly linked to glucose absorption. The demonstration that in clinical and