Review Article: The Role of Serotonergic Agents in the Treatment of Patients With Primary Chronic Constipation

B.D. Cash; W.D. Chey

Aliment Pharmacol Ther. 2005;22(11):1047-1060.

Conclusion

Our understanding of the pathophysiology of chronic constipation continues to evolve. Serotonin appears to play an important role in a number of physiological functions relevant to the symptoms of chronic constipation. As a consequence, drugs that accentuate the effects of serotonin, such as the 5-HT₄ receptor agonists, are attractive treatment candidates for patients with chronic constipation. Of the 5-HT₄ agonists that have been developed, tegaserod has been shown to accelerate gut transit and to improve the symptoms of chronic constipation while it retains an attractive safety profile in recent large, methodologically rigorous clinical trials. Although the exact mechanisms for these benefits remain unclear, it appears that the promotility effect of tegaserod, rather than its prosecretory effects or its amelioration of heightened visceral sensation, are largely responsible for the clinical effects of this medication. Although clearly superior to placebo, tegaserod improves symptoms in only a subset of patients with chronic constipation. This suggests that serotonin plays a critical role in some, but not all, patients with chronic constipation. Though unproven, it may be that patients with subtle or overt pelvic floor dysfunction are less likely to respond to serotonergic agents than patients with normal or delayed colonic transit. The roles of other serotonergic agents, including the 5-HT₃ agonists, the mixed 5-HT₃ antagonists/5-HT₄ agonists and agents that affect SERT, in the treatment of patients with chronic constipation remain to be determined.

CLICK HERE for subscription information about this journal.

1 2 3 4 5

Next Section

Acknowledgments

The authors would like to acknowledge the editorial assistance of Maribeth Bogush PhD and Sophia Shumyatsky, PharmD, in the preparation of this manuscript.

Funding information

This work was supported by an educational grant from Novartis Pharmaceuticals.

Reprint Address

Correspondence to: Dr W.D. Chey, Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA. E-mail: wchey@umich.edu

References

Serotonergic Agents and Targeted GI Conditions
Agent	Action	GI condition	Status
5-HT₃ receptor antagonists
MKC-733^[41] (substituted benzamide)	Delays liquid gastric emptying in association with relaxation of the proximal stomach, stimulates fasting antroduodenal migrating motor complex activity and accelerates small intestinal transit	Not yet determined	Under investigation
5-HT₄ receptor agonists
Prucalopride^[42] (benzofuran derivative)	Prokinetic: stimulates emptying of the stomach and the ascending colon and increases the rate of small and large bowel transit, potentially through the stimulation of high amplitude-propagating contractions and segmental contractions	IBS with constipation	Studies on hold (concerns about intestinal carcinogenicity and potential cardiac events)
Tegaserod^[39] (aminoguanidine indole)	Prokinetic: stimulates 5-HT₄ receptors, which are G protein-coupled receptors, and triggers release of additional neurotransmitters, including acetylcholine and calcitonin gene-related peptide, from sensory neurones leading to enhanced GI motility and intestinal secretion and to reduced visceral sensitivity	IBS with constipation Chronic idiopathic constipation	Approved by FDA for women with IBS-C men and women <65 with chronic idiopathic constipation
5-HT₃ receptor antagonists (these agents are contraindicated in patients with constipation)
Alosetron^[47] (methylimidazole analogue)	Activates 5-HT₃ receptors, which are ligand-gated cation-channels, resulting in neuronal depolarization that affects the regulation of visceral pain (reduces), colonic transit (slows) and small intestinal absorption (enhances)	IBS with diarrhoea	Approved by FDA for women with severe IBS-D for whom treatment with conventional agents has failed under restricted conditions of use, which include a risk management programme, a prescribing programme and a revised indication (above)
Cilansetron^[43] (methylimidazole analogue)		IBS with diarrhoea	'Not-approvable' action letter from FDA in March 2005 (more data needed)
Ondansetron^[48] (aminoimidazole carboxamide)	Antiemetic: centrally acting agents that prevent serotonin from initiating afferent transmission to the CNS through vagal and spinal sympathetic nerves; may also block serotonin stimulation at the chemoreceptor trigger zone and other CNS structures	CINV PONV RINV	Approved by FDA for CINV PONV RINV
Granisetron^[49] (aminoimidazole carboxamide)			Approved by FDA for CINV RINV
Dolasetron^[50] (aminoimidazole carboxamide)			Approved by FDA for CINV RINV
Ramosetron^[51] (thiazole monofumarate)			Not approved by FDA
Palonosetron^[52] (isoquinoline)			Approved by FDA for delayed emesis for patients receiving moderate emetogenic chemotherapy
5-HT₃ receptor antagonist/5-HT₄ receptor agonists
Cisapride (substituted piperidyl benzamide derivative)	Prokinetic with dual mechanism of action	Heartburn/GERD Gastroparesis IBS with constipation Constipation	Withdrawn from market [arrhythmogenic potential (QT internal prolongation)] Available in the United States only through a limited-access programme developed by Janssen Pharmaceutica and the FDA
	5-HT₃ receptor antagonist activity
	Antiemetic activity
	Accelerates gastric emptying in some species
	5-HT₃ receptor antagonist activity
	Prokinetic activity: enhances the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus, resulting in increased motility in the GI tract by full agonist activity at 5-HT₄ receptors
Mosapride^[44,45] (substituted benzamide)	Prokinetic: facilitates acetylcholine release from enteric cholinergic neurones of the myenteric plexus through stimulation of 5-HT₄ receptors, thereby increasing gastric emptying, stimulating gastric motor activity and increasing electrically evoked contractions	Non-ulcer dyspepsia Gastroparesis Gastric stasis Gastro-oesophageal reflux disease Constipation in Parkinson's disease	Not approved by FDA
Renzapride^[46] (substituted benzamide)	Prokinetic: does not alter gastric emptying or small bowel transit but does accelerate colonic transit and ascending colon emptying	IBS with constipation	Under investigation (phase III trials)

FDA, United States Food and Drug Administration; CNS, central nervous system; GI, gastrointestinal; IBS, irritable bowel syndrome; CINV, chemotherapy-induced nausea and vomiting; PONV, post-operative nausea and vomiting; RINV, radiation-induced nausea and vomiting; GERD, gastro-oesophageal reflux disease.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

Return to Article

Post as:

processing....

Review Article: The Role of Serotonergic Agents in the Treatment of Patients With Primary Chronic Constipation

Conclusion

Comments

Most Popular Articles

About

Membership

Apps

WebMD Network

Editions

Review Article: The Role of Serotonergic Agents in the Treatment of Patients With Primary Chronic Constipation

Conclusion

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Comments

Most Popular Articles

Email This

Feedback

Find Us On

About

Membership

Apps

WebMD Network

Editions