Metoclopramide affects the gastrointestinal (GI) tract via cholinergic and dopaminergic action, which leads to relaxation of the esophageal and pyloric sphincters, increased gastric and duodenal peristalsis, and thus decreased transit time. This was the first prokinetic agent available with the potential to affect constipation-dominant irritable bowel syndrome (IBS). However, the combination of low effect on colonic function and an adverse-effect profile – including extrapyramidal movement, depression, and sedation – resulted in unfavorable results overall.
Cisapride increases gastrointestinal (GI) motility via an indirect or a combined 5-HT4 agonist/5-HT3 antagonistmediated stimulation of acetylcholine release and may contribute to the coordination and normalization of intestinal contractions. Low doses have been studied for IBS.
Van Outryve et al studied constipation-dominant IBS patients with associated pain. Cisapride was started at 5 mg three times daily for four weeks. The dosage was adjusted to between 2.5 to 10 mg three times daily for the next eight weeks based on response. Stool frequency and consistency were improved with initial treatment and, at study end, these results remained statistically significant. Decreases in pain severity at weeks 8 and 12 and pain frequency at weeks 4, 8, and 12 were significant; improvement in flatulence and abdominal distension was noted in both the cisapride and placebo groups from baseline and in the cisapride group as compared to the placebo group.
A later study conducted by Farup et al in patients with constipation-variant IBS contrasts the results of the previous study. In this cohort, cisapride was initiated at 5 mg three times daily and after four weeks was increased to 10 mg only in patients who did not respond to the lower dosage. The mean global rating scores for bowel symptoms showed a nonstatistical preference towards placebo over cisapride. No statistical differences in abdominal pain, stool frequency or consistency, bloating, defecation patterns, or general well-being were observed. The investigators’ evaluation of effect favored placebo.
Cardiac arrhythmias, such as torsades de pointes and ventricular fibrillation, with resultant fatalities are the most serious adverse effects with cisapride. These have occurred primarily in patients taking medications concomitantly that inhibit cisapride metabolism by the CYP3A4 isoenzyme, leading to elevated cisapride serum levels. Similar adverse events also occurred in patients predisposed to QT-interval prolongation or medicated with agents that themselves prolong QT-interval. The FDA instructed the manufacturer to cease active marketing of cisapride and to enlist a controlled distribution system restricted to carefully screened patients with refractory gastrointestinal disease. Diarrhea was a frequent side effect of cisapride, sometimes resulting in dehydration. Other adverse effects in more than 1% of patients included abdominal pain, nausea, constipation, flatulence, dyspepsia, rhinitis, cough, urinary tract infection, rash, pruritus, arthralgia, and abnormal vision.