Serotonin 5-HT4 Receptor Agonists

Publication Details



The serotonin type 4 (5-HT4) receptor agonists are potent prokinetic agents that act on serotonin receptors in the intestine and promote intestinal peristalsis, increase gastric emptying and decrease esophageal reflux. Two 5-HT4 receptor agonists have been developed and were approved for use in the United States, but both were found to have significant serious adverse effects and have been withdrawn (cisapride) or placed under restricted use (tegaserod). Both cisapride and tegaserod have been associated with a low rate of transient serum enzyme elevations during therapy, but neither has been implicated convincing in cases of clinically apparent liver injury with jaundice.


Serotonin plays a major role in the normal motility and secretory function of the intestine and is produced by specialized enterochromaffin cells in the mucosa of the gut. Serotonin (5-HT) is released in response to chemical and mechanical stimulation and acts through the type 4 receptors that are common in the intestinal mucosa to increase peristalsis and intestinal tone. 5-HT4 receptors are also found in the central nervous system, urinary bladder and atria of the heart, which may explain some of their adverse effects. Two 5-HT4 receptor agonists have been developed and used in clinical medicine: cisapride and tegaserod.

Cisapride (sis’ a pride) is a piperidinyl benzamide and a potent 5-HT4 receptor agonist that was developed as a therapy for gastroesophageal reflux disease (GERD) and diabetic gastroparesis. In several clinical trials, cisapride was found to improve symptoms of bloating and gastric distension in patients with gastroparesis and decrease symptoms of reflux in patients with GERD. Cisapride was approved in the United States, but was subsequently withdrawn after multiple reports of life threatening arrhythmias associated with prolonged QTc syndrome. Cisapride had been available in tablets of 10 and 20 mg under the brand name of Propulsid. The usual recommended dose was 10 to 20 mg 3 to 4 times daily. Cisapride is still available on a limited basis in Europe and elsewhere. It is also available for use in animals for treatment of gastrointestinal status and megacolon.

Tegaserod (teg” a ser’ od) is an aminoguanidine indole derivative of serotonin and a selective, partial 5-HT4 receptor agonist. It simulates the peristaltic reflex and increases intestinal and colonic motility resulting in hastened transit. It also reduces visceral sensation in response to distension. These features led to its development as therapy of irritable bowel syndrome and constipation. It was approved for use in the United States in 2002 and was available in tablets of 2 or 6 mg under the brand name of Zelnorm. The typically recommended dose was 2 to 6 mg twice daily. Tegaserod was withdrawn in 2007 because of adverse cardiovascular effects, postmarketing studies demonstrating an excess of severe adverse cardiovascular events in tegaserod treated patients (0.11%) compared to matched controls (0.01%). The association of tegaserod with adverse cardiovascular events has been contested but, currently, tegaserod is available only on an emergency basis and with prior authorization from the FDA.

Prucalopride (proo kal' oh pride) is a unique chemical entity, a benzofurancarboxamide derivative which is highly selective for the serotonin type 4 receptor and differs from cisapride and tegaserod in having minimal activity against for other serotonin receptors. In multiple clinical trials, prucalopride was found to aleviate symptoms of chronic idiopathic constipation in a proportion of patients and had minimal adverse effects. Importantly, cardiac arrhythmias and prolongation of the QTc interval were not increased in frequency in patients receiving prucalopride. Prucalopride was approved as therapy of chronic idiopathic constipation in 2018 and is now generally available. Prucalopride is described in its own record in LiverTox.


Both cisapride and tegaserod were linked to occasional instances of serum enzyme elevations during therapy (1% to 9%), but these elevations were generally mild and asymptomatic, resolving rapidly with or without discontinuing drug. While moderate serum enzyme elevations during 5-HT4 receptor agonist therapy have been described, there have been have been no convincing reports of clinically apparent acute liver injury with jaundice attributed to these agents. Plucalopride has not been linked to increased rates of serum enzyme elevations nor to instances of acute liver injury with jaundice, but experience with its long-term use has been limited.

Likelihood score: E (unlikely causes of clinically apparent liver injury).

Mechanism of Injury

Cisapride is metabolized in the liver, largely via CYP 3A4, and it must be used with caution in patients taking medications that inhibit CYP 3A4 activity. Tegaserod is metabolized by the liver largely by glucuronidation and has little effect on cytochrome P450 activity and few drug-drug interactions.

Drug Class: Gastrointestinal Agents, Prokinetic Agents

Other Drugs in the Subclass, Prokinetic Agents: Prucalopride



Cisapride – Generic, Propulsid®

Tegaserod – Zelnorm®

Prucalopride – Motegrity®


Gastrointestinal Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 25 April 2019

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