Serotonin 5-ht4 receptor agonists

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Information about Serotonin 5-ht4 receptor agonists

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approved for use in the United States, but both were found to have significant serious adverse effects and have been withdrawn (cisapride) or placed under restricted use (tegaserod).

Liver safety of Serotonin 5-ht4 receptor agonists

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.

Mechanism of action of Serotonin 5-ht4 receptor agonists

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 Cisapride was approved in the United States, but was subsequently withdrawn after multiple reports of life threatening arrhythmias associated with prolonged QTc syndrome.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.

Antidiarrheal agents

Antidiarrheal agents include bulk forming agents, hydroscopic agents, bile acid resins, bismuth, inhibitors of intestinal motility, non-absorbed antibiotics and hormones. Bulk forming agents include methylcellulose; hydroscopic agents include pectin and kaolin; bile acid resins are cholestyramine, colestipol and colesevalam; inhibitors of intestinal motility include opioids such as diphenoxylate and loperamide. Antibiotics include rifamycin and rifaximin which are non-absorbed and are used for travelers' diarrhea. Hormones with antidiarrheal activity include octretide and somatostatin. Most antidiarrheal agents are active locally in the small intestine and colon and are largely not absorbed. Some, however, have been implicated in rare causes of liver injury (senna, cascara, cholestyramine). Telotristat is a relatively new agent that inhibits the synthesis of serotonin and is used specifically for the diarrhea of carcinoid syndrome.

Antiemetics are a diverse group of medications that act at different points in the pathways that regulate nausea and vomiting. These include antihistamines, anticholinergic agents, phenothiazines, serotonin type 3 receptor blockers, centrally acting benzamides, cannabinoid receptor agonists, substance P antagonists and miscellaneous.

Anticholinergic Agents


Cannabinoid Receptor Agonists

Serotonin 5-HT3 Receptor Antagonists

Substance P/Neurokinin 1 Receptor Antagonists


Acid peptic disease/antiulcer agents that include antacids, the histamine type 2 receptor blockers (H2 blockers), and the proton pump inhibitors (PPIs). These agents are some of the most commonly taken medications and are very well tolerated, most being available both by prescription and over-the-counter. While many of these drugs are approved for use in duodenal and gastric ulcer disease, their major use is for acid reflux and indigestion.

Histamine H2 Receptor Antagonists (H2 Blockers) Cimetidine, Famotidine, Nizatidine, Ranitidine

Proton Pump Inhibitors

Cathartics, laxatives or agents for constipation include bulk forming agents, osmotic agents, stool wetting agents, nonspecific stimulants, prokinetic agents and agents that increase fluid secretion. Many of these therapies are not systemically absorbed and none are considered particularly hepatotoxic. Naldemedine and naloxegol are opioid antagonists and are used to treat the constipation associated with opioid use.

Inflammatory bowel disease encompasses several disorders, most commonly ulcerative colitis and Crohn colitis. Agents can be classified as 5-aminosalicyclic acid (5-ASA) based agents, immunosuppressive drugs, antitumor necrosis factor agents, corticosteroids, antibiotics and miscellaneous.

5-Aminosalicyclic Acid (5-ASA) Derivatives

Immunosuppressive Agents

Tumor Necrosis Factor Antagonists


Irritable Bowel Syndrome Agents Antimuscarinics/Antispasmodics [See Anticholinergic agents

Prokinetic Agents - See Serotonin 5-ht4 receptor agonists Alosetron, Cisapride, Domperidone, Linaclotide, Lubiprostone, Metoclopramide, Plecanatide, Prucalopride, Tegaserod


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