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

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2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.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