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. 2012 Apr;35(7):745-67.
doi: 10.1111/j.1365-2036.2012.05011.x. Epub 2012 Feb 22.

Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders

J Tack  1 , M Camilleri, L Chang, W D Chey, J J Galligan, B E Lacy, S Müller-Lissner, E M M Quigley, J Schuurkes, J H De Maeyer, V Stanghellini
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Free PMC article

Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders

J Tack et al. Aliment Pharmacol Ther. 2012 Apr.
Free PMC article

Abstract

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UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.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.

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Figure 1
Figure 1
Molecular structure of 5-HT4 agonists.
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