An update on prucalopride in the treatment of chronic constipation

Abstract

Chronic constipation (CC) is a highly prevalent and often under-appreciated gastrointestinal disorder associated with significant impairment in quality of life. Symptoms of constipation are typically present for a number of years prior to a patient seeking help. Lifestyle modifications followed by, or coupled with, over-the-counter laxatives represent the initial treatment option; however, relief for many is limited and dissatisfaction rates for these approaches remain high. Over recent years, therefore, considerable effort has been exerted on the development of novel pharmacological approaches. Two major targets have emerged, motility and secretion. Research on the former led to the development of a number of prokinetic agents capable of stimulating colonic motility and, thus, accelerating colonic transit. Of these, earlier prototypes such as cisapride and tegaserod, though effective, were ultimately withdrawn due to cardiovascular adverse events due in part to receptor nonselectivity. Highly selective serotonergic receptor agonists have since emerged which appear to be equally effective in stimulating gut motility but are devoid of cardiac side effects. One such agent is prucalopride, which has now been approved for the management of chronic idiopathic constipation in several countries, but not in the United States. Multiple multicenter, randomized placebo-controlled clinical trials have demonstrated superiority for prucalopride compared to placebo in the short to medium term in relieving the major symptoms of constipation in both men and women across a broad spectrum of ages, ethnicities and geographic locations. To date, prucalopride has enjoyed a favorable safety profile and there have been no signals to suggest arrythmogenicity. Efficacy over longer periods of treatment remains to be confirmed. Evidence for efficacy in other forms of constipation, such as opioidinduced constipation and that related to Parkinson's disease is beginning to emerge; its status in the management of constipation-predominant irritable bowel syndrome or foregut motility disorders, such as gastroparesis, remains to be established.

Luminal 5‐HT4 receptors—A successful target for prokinetic actions

“…In particular, prucalopride, used by Shokrollahi et al to demonstrate prokinetic effects on propulsive motor patterns in rabbit proximal colon, has emerged as a popular and effective therapeutic agent for promoting gut motility. Prucalopride displays high‐affinity binding to human 5‐HT 4(a) and 5‐HT 4(b) receptor isoforms which is consistent with its clinical success since these isoforms are expressed in the human colon (Table ). Other high‐affinity agonists have also been developed including naronapride (ATI‐7505), velusetrag (TD‐5108), and YH12852.…”

Pathophysiology and Treatment of Gastrointestinal Motility Disorders in the Acutely Ill

“…Cisapride markedly accelerates gastric emptying in the critically ill . However, cisapride is not a selective serotonin agonist and also stimulates the cardiac ether a‐go‐go potassium channels, which prolong the QT interval leading to cardiac dysrhythmia . This effect resulted in cisapride being withdrawn from the market.…”

“…Cisapride markedly accelerates gastric emptying in the critically ill. 96,97,102,103 However, cisapride is not a selective serotonin agonist and also stimulates the cardiac ether a-go-go potassium channels, which prolong the QT interval leading to cardiac dysrhythmia. 101 This effect resulted in cisapride being withdrawn from the market. The non-selective 5-HT Tegaserod was also evaluated in off-label audits and was reported to reduce GRVs in the critically ill. 104 However, it was withdrawn from the market, also due to concerns about adverse cardiovascular effects.…”

Practical management approach to gastroparesis

“…It is predominately excreted in urine unchanged, and does not interact with cytochrome P450 system. 37 The most frequent adverse effects associated with prucalopride are diarrhoea, headaches, nausea and abdominal discomfort. 37…”

“…Cisapride has been extensively studied in gastroparesis, and compared with metoclopramide, cisapride causes a greater increase in gastric emptying. 38 Cisapride appears to have a direct effect on the hERG encoded potassium channels in cardiac myocytes 37 and has been associated with cardiac arrhythmias, including cardiac sudden death. Cisapride is heavily restricted for this reason.…”