Prokinetic drugs that stimulate 5-HT₄-serotonin receptors in the human atrium

Several gastrointestinal drugs like bromopride, cinitapride, cisapride, clebopride, felcisetrag, metoclopramide, mosapride, naronapride, prucalopride, renzapride, tegaserod, velusetrag, and zacopride are probably agonists at 5-HT₄-serotonin receptors in the intestine. Some of these drugs do not act selectively only on 5-HT₄-serotonin receptors. Instead, most of them also stimulate or inhibit other serotonin receptors. In addition, they sometimes stimulate or inhibit a wide variety of additional targets such as histamine receptors, adrenoceptors, dopamine receptors, monoamine transporters, or potassium channels. We review here to which extent these drugs are potent and/or effective agonists or antagonists at human cardiac 5-HT₄-serotonin receptors. We address the possibility that at therapeutic concentrations some of these drugs may induce cardiac side effects via 5-HT₄-serotonin receptors. Plasma concentrations of these drugs can sometimes be elevated by drug/drug interactions such that cardiac side effects become more likely. Moreover, we address the question whether such effects occur at the human cardiac atrium or at the human ventricle. We will focus on inotropic effects, but for completeness also address potential effects on the sinus node. We will present our view where there are remaining pre-clinical or clinical research needs. One may repurpose some of these drugs to act on cardiac 5-HT₄-serotonin receptors and discuss for which indications this may offer additional benefits.