Tegaserod is a serotonin 5-HT4 partial agonist that has high affinity for 5-HT4 receptors but no appreciable binding to 5-HT3 or dopamine receptors. Tegaserod was approved for the treatment of patients with chronic constipation and IBS with predominant constipation. It has since been withdrawn. Prucalopride is a high-affinity 5-HT4 agonist that is available in Europe (but not in the USA) for the treatment of chronic constipation in women. In contrast to cisapride and tegaserod, it does not appear to have significant affinities for either hERG K+ channels or 5-HT1B receptors. In three 12-week clinical trials of patients with severe chronic constipation, it resulted in a significant increase in bowel movements compared with placebo. The long-term efficacy and safety of this agent require further study.
Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea. However, these agents should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition. They should be discontinued in patients whose diarrhea is worsening despite therapy. Antidiarrheals are also used to control chronic diarrhea caused by such conditions as IBS or inflammatory bowel disease (IBD).
As previously noted, opioids have significant constipating effects (see Chapter 31). They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements and the gastrocolic reflex. Although all opioids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most.
Loperamide is a nonprescription opioid agonist that does not cross the blood-brain barrier and has no analgesic properties or potential for addiction. Tolerance to long-term use has not been reported. It is typically administered in doses of 2 mg taken one to four times daily. Diphenoxylate is a prescription opioid agonist that has no analgesic properties in standard doses; however, higher doses have central nervous system effects, and prolonged use can lead to opioid dependence. Commercial preparations commonly contain small amounts of atropine to discourage overdosage (2.5 mg diphenoxylate with 0.025 mg atropine). The anticholinergic properties of atropine may contribute to the antidiarrheal action.
Eluxadoline is a prescription opioid agonist with high affinity for the mu receptor (as well as low affinity for the delta receptor). When taken orally, eluxadoline binds to gut opioid receptors, resulting in slower colonic transit and increased fecal fluid absorption. Eluxadoline is approved for the treatment of patients with diarrhea-predominant IBS at a dose of 75–100 mg twice daily. In two randomized placebo-controlled trials, eluxadoline 100 mg twice daily led to significant improvement in abdominal pain and diarrhea in 30% of patients compared with 16% with placebo. Constipation may occur in 8% of patients. Approximately 1% of patients may experience sphincter of Oddi spasm (usually within the first week of therapy) resulting in abdominal pain, pancreatitis, and/or elevated pancreatic or liver enzymes. Eluxadoline should not be used in patients with a history of pancreatitis, alcoholism, or known sphincter of Oddi disease. Caution is advised in patients with prior cholecystectomy, in whom there is up to a 5% risk of complications due to sphincter of Oddi spasm. Eluxadoline 75 mg twice daily is recommended for patients with prior cholecystectomy, mild to moderate liver disease, or side effects at the higher dose.