Prucalopride

• Chronic Idiopathic Constipation
• Functional Constipation
• Colonic Motility Disorders

Prucalopride is a selective serotonin 5-HT4 receptor agonist used to treat chronic idiopathic constipation (CIC) in adults who have not responded adequately to laxatives. It stimulates gut motility through a targeted mechanism that enhances coordinated colonic contractions.

Mechanism of Action

Prucalopride works through serotonin receptor activation in the gastrointestinal tract:

• High-affinity 5-HT4 receptor agonist: Selectively binds to 5-HT4 receptors in the gut wall
• Stimulates peristalsis: Activates ascending excitatory and descending inhibitory neural pathways
• Enhances colonic motility: Increases high-amplitude propagating contractions (HAPCs)
• Accelerates colonic transit: Promotes coordinated propulsive bowel movements

Unlike older 5-HT4 agonists (such as cisapride and tegaserod), prucalopride has high selectivity for 5-HT4 receptors without significant binding to hERG cardiac potassium channels, providing an improved cardiovascular safety profile.

Available Formulations

Prucalopride is available as oral tablets:

• 1 mg tablets
• 2 mg tablets (Motegrity)

Medical Uses

FDA-Approved Indication:

• Chronic idiopathic constipation in adults who have not responded adequately to laxatives

Prucalopride is appropriate for patients who have tried lifestyle modifications and over-the-counter laxatives without adequate relief.

Dosing Guidelines

Adults:

• 2 mg orally once daily

Severe Renal Impairment (CrCl <30 mL/min):

• 1 mg once daily

Administration:

• Take with or without food
• Can be taken at any time of day, but consistent timing is recommended

Important Safety Information

Contraindications:

• Known hypersensitivity to prucalopride or any component
• Intestinal perforation or obstruction due to structural or functional disorder
• Obstructive ileus
• Severe inflammatory conditions of the intestinal tract (Crohn's disease, ulcerative colitis, toxic megacolon/megarectum)

Warnings and Precautions:

• Suicidal ideation and behavior: Cases of depression, suicidal ideation, and completed suicide have been reported; monitor patients for new or worsening depression or suicidal thoughts
• Severe or persistent diarrhea: May occur; consider dose reduction or discontinuation
• Cardiovascular history: Use with caution in patients with arrhythmias or ischemic heart disease
• Not for opioid-induced constipation: Efficacy not established for this indication

Drug Interactions

Prucalopride has low potential for drug interactions:

• Not significantly metabolized by cytochrome P450 enzymes
• P-glycoprotein (P-gp) inhibitors (cyclosporine, verapamil, quinidine, ketoconazole): May modestly increase prucalopride exposure
• P-glycoprotein inducers: May decrease prucalopride exposure

Special Populations

• Renal Impairment: 1 mg once daily for CrCl <30 mL/min
• Hepatic Impairment: No adjustment for mild to moderate; severe impairment not studied
• Elderly: Start with 1 mg daily if renal function unknown; increase to 2 mg based on efficacy and tolerability
• Pregnancy: Limited human data; use only if potential benefit justifies potential fetal risk
• Lactation: Present in breast milk; consider developmental benefits of breastfeeding
• Pediatric: Safety and efficacy not established in patients under 18 years