Systematic review: Cardiovascular safety profile of 5-HT 4 agonists developed for gastrointestinal disorders

J. Tack, M. Camilleri, L. Chang, W. D. Chey, J. J. Galligan, B. E. Lacy, S. Müller-Lissner, Eamonn Martin Quigley, J. Schuurkes, J. H. De Maeyer, V. Stanghellini

Research output: Contribution to journalReview articlepeer-review

249 Scopus citations


Background The nonselective 5-HT 4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT 4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT 4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT 4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT 1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT 4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT 4 agonists with no hERG or 5-HT 1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT 4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT 4 receptors. Selectivity for 5-HT 4 over non-5-HT 4 receptors may influence the agent's safety and overall risk-benefit profile. Based on available evidence, highly selective 5-HT 4 agonists may offer improved safety to treat patients with impaired GI motility.

Original languageEnglish (US)
Pages (from-to)745-767
Number of pages23
JournalAlimentary Pharmacology and Therapeutics
Issue number7
StatePublished - Apr 2012

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology
  • Pharmacology (medical)


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