Prucalopride: Selective 5-HT4 Agonist for Chronic Constipation
Prucalopride (Resolor, Motegrity) is a highly selective, high-affinity 5-HT4 (serotonin type 4) receptor agonist. Unlike older prokinetics (cisapride, metoclopramide), its high selectivity for 5-HT4 receptors avoids cardiac and CNS side effects.
Approved for chronic idiopathic constipation (CIC) in adults in whom laxatives fail to provide adequate relief. The first prokinetic in decades with a favourable cardiac safety profile (no QT prolongation).
Mechanism of Action
Stimulates 5-HT4 receptors on enteric neurons, activating the peristaltic reflex — promotes high-amplitude propagating contractions (HAPCs) in the colon, accelerating transit. Also reduces luminal fluid absorption in the colon. Minimal affinity for hERG channels (no QT prolongation).
Indications & Use
Chronic idiopathic constipation (CIC) when laxatives have been inadequate. Not for use as a general laxative or for constipation due to opioids (linaclotide preferred) or other specific causes. Once daily dosing.
Dosage
Standard: 2 mg once daily (take with or without food). Elderly ≥65 years: start 1 mg once daily (may increase to 2 mg). Renal impairment (GFR <30 mL/min): 1 mg once daily. Severe hepatic impairment: 1 mg once daily. Reassess if no benefit after 4 weeks.
Side Effects
Common (especially first day): headache, nausea, abdominal pain, diarrhoea — usually transient. Unlike older prokinetics, no QT prolongation and no CNS effects (does not cross BBB significantly). No cardiac arrhythmias reported.
Drug Interactions
No major CYP interactions. P-glycoprotein inhibitors (ketoconazole, verapamil): may increase prucalopride levels. Erythromycin: modest increase in prucalopride AUC. No clinically significant interactions with common medications.
Contraindications
Intestinal perforation or obstruction, severe inflammatory bowel disease (Crohn's, UC with toxic megacolon risk), severe renal impairment (dose adjustment needed, not absolute contraindication). Pregnancy (limited data — not recommended).
Frequently Asked Questions
How is prucalopride different from old prokinetics like cisapride?
Cisapride stimulated multiple serotonin receptor subtypes including 5-HT3 and 5-HT4, and also blocked hERG channels, causing fatal QT prolongation and arrhythmias — it was withdrawn from markets. Prucalopride is highly selective for 5-HT4 only, with minimal hERG binding — no QT prolongation.
How long does prucalopride take to work?
Most patients notice improvement in bowel habits within 1–4 weeks. If there is no significant improvement after 4 weeks, the medication should be reassessed. Treatment should continue as long as it is beneficial.
Can prucalopride be used long-term?
Yes. Studies up to 24 months show sustained efficacy and safety. No tolerance development has been observed. It is not a stimulant laxative and does not cause dependence.
References
- EMA Resolor SPC 2023
- Camilleri M et al. NEJM 2008
- NICE TA211: Prucalopride for chronic constipation 2010
Medical Disclaimer: This information is for educational purposes only and does not replace professional medical advice.