Prucalopride Mechanism of Action
Prucalopride is a highly selective serotonin type 4 (5-HT4) receptor agonist that stimulates colonic peristalsis by promoting neurotransmission through enteric neurons, specifically triggering high-amplitude propagating contractions (HAPCs) that increase bowel motility. 1
Receptor Selectivity and Pharmacologic Action
Prucalopride demonstrates exceptional selectivity for 5-HT4 receptors, with no significant effects on 5-HT2A, 5-HT2B, 5-HT3, motilin, or CCK-A receptors at concentrations exceeding its 5-HT4 receptor affinity by 150-fold or greater 1
In isolated gastrointestinal tissues, prucalopride facilitates acetylcholine release from enteric neurons, which enhances the amplitude of colonic contractions and stimulates the peristaltic reflex 1, 2
This mechanism differentiates prucalopride from other constipation medications (which are exclusively osmotic agents or chloride secretagogues), as it directly stimulates colonic motility 3
Physiologic Effects on Colonic Function
Following a single 2 mg dose, prucalopride increases the number of high-amplitude propagating contractions (HAPCs) during the first 12 hours compared to osmotic laxatives 1
In animal models (rats and dogs), prucalopride stimulates gastrointestinal motility with contractions starting from the proximal colon and propagating to the anal sphincter 1
Clinical studies demonstrate that prucalopride 2 mg once daily reduces mean colonic transit time by 12 hours (from baseline of 65 hours to 53 hours) compared to placebo, which showed no meaningful change 1, 4
Critical Safety Distinction from Earlier 5-HT4 Agonists
Unlike cisapride and tegaserod (withdrawn 5-HT4 agonists), prucalopride does not interact with cardiac hERG potassium channels, avoiding the QT prolongation and cardiac arrhythmia risks that led to those drugs' withdrawal 5, 3
This cardiac safety profile exists because prucalopride has no significant action on 5-HT1B/D receptors or cardiac potassium channels 5
At doses up to 20 mg daily (10 times the maximum approved dose), prucalopride does not prolong the QT interval to any clinically relevant extent 1, 6
Clinical Translation of Mechanism
The selective 5-HT4 agonism translates to increased complete spontaneous bowel movements (CSBMs) per week, with a mean difference of 0.96 compared to placebo (95% CI 0.64–1.29) 2
Responder rates (achieving ≥3 CSBMs per week) are significantly higher with prucalopride, with a relative risk of 2.37 (95% CI 1.97–2.85) 2
The prokinetic effect improves not only stool frequency but also stool consistency, reduces straining, and increases the urge to defecate 4
Pharmacodynamic Considerations
Prucalopride's high affinity and selectivity for 5-HT4 receptors means it promotes neurotransmission specifically in the enteric nervous system without the extrapyramidal side effects seen with dopamine antagonists like metoclopramide 5, 2
The drug stimulates intestinal secretions in addition to motility, contributing to its overall prokinetic effect 2
Steady-state plasma concentrations are achieved within 3-4 days of once-daily dosing, with a terminal half-life of approximately 1 day 1