Prokinetic Agents and QT Prolongation: A Familiar Scene with New Actors

Abstract

Prokinetic agents are a very large family of drugs with different mechanisms of action. Only QT prolongation by cisapride has made notable impact and deserved its partial restriction and/or withdrawal from the market. Postmarketing surveillance initially showed that cisapride was generally safe and well tolerated, but in the past decade, more recent data have shown some risk in the patient populations. QT prolongation by prokinetic agents can raised from different mechanisms: some involve increased plasma concentrations of cisapride due to increased bioavailability by inhibiting P glycoprotein, and inhibition of metabolism or deficit in the elimination. On the other hand, pharmacodynamic interactions can also enhance the arrhythmogenic effect of cisapride. The present article presents the mechanisms and reviews the main interactions studied so far, and the role of pharmacovigilance in the detection of rare clinical events. We emphasize the need for physicians to look for conditions (either clinical or not) prone to increase the risk of QT interval prolongation.

Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study

“…Safety issues related to this class of drugs that led to their marked withdrawal may have frustrated further attempts to study the potential of prokinetics in SSc-related enteric dismotility symptoms. However, it comes as a surprise that newer agents with no major cardiac issues have not been evaluated so far [12–14]. …”

“…As a prototypical representative of this class, cisapride has been shown to ameliorate gastric contractions and increase esophageal amplitude waves [9] and to reduce the colonic transit time in SSc patients [10]. Nonetheless, cisapride has been withdrawn from the global market due to safety concerns related to cardiac toxicity [11, 12]. These side-effects were linked to the lack of selectivity for the for the 5-HT 4 receptor and to the blockade of the human ether-a-go-go-related gene (hERG)-encoded K + channel.…”

“…These side-effects were linked to the lack of selectivity for the for the 5-HT 4 receptor and to the blockade of the human ether-a-go-go-related gene (hERG)-encoded K + channel. The consequences of this interaction are the prolongation of cardiac action potential repolarisation and, thus, QT interval, leading to a clinically significant arrhythmogenic potential [12, 13]. On the contrary, novel agonists that specifically interact with the 5-HT 4 receptor and possess GIT tissue-specific agonist activity, have a favorable cardiac profile and no major cardiac issues.…”

Treatment approaches of gastrointestinal dysfunction in Parkinson's disease, therapeutical options and future perspectives

“…A single report demonstrated tremor worsening in PD with cisapride treatment [78]. Due to its QT prolongation, cisapride has received partial restriction and withdrawal from the market [79].…”

The effects of serotonin on the electrophysiological properties of atrioventricular node during an experimental atrial fibrillation

“…An increase in reverse rate-dependent arrhythmic activity by 5-HT in the human atrium, acting through 5-HT 4 receptors, has been suggested to lead to atrial flutter and AF (Kaumann and Sanders 1994). Clinical evidence supporting this suggestion is rare, although cisapride (a partial 5-HT agonist) can elicit tachycardia in the human atrium by stimulating the sinoatrial 5-HT 4 receptor and thereby generating supraventricular arrhythmia (Keller and Di Girolamo 2010).…”