What is the use of Prucalopride (Resolor) in treating chronic idiopathic constipation?

Prucalopride for Chronic Idiopathic Constipation

Prucalopride (Resolor/Motegrity) is a highly effective second-line treatment for chronic idiopathic constipation in adults who have failed to respond adequately to first-line treatments such as polyethylene glycol and lifestyle modifications. 1, 2

Mechanism of Action and Efficacy

• Prucalopride is a selective serotonin 5-HT4 receptor agonist that:
  • Promotes neurotransmission by enteric neurons
  • Stimulates the peristaltic reflex
  • Enhances intestinal secretions
  • Improves GI motility 2
• It induces and increases the amplitude of colonic high-amplitude propagated contractions, which effectively move colonic contents 1
• Clinical benefits include:
  • Increased complete spontaneous bowel movements (CSBMs) per week (0.96 more than placebo)
  • Higher responder rates (≥3 CSBMs per week) compared to placebo (RR 2.37) 2
  • Improved constipation symptoms and abdominal symptoms
  • Enhanced quality of life and treatment satisfaction 1

Dosing and Administration

• Standard adult dose: 2 mg once daily
• Reduced dose for severe renal impairment (creatinine clearance <30 mL/min): 1 mg once daily 1, 2, 3
• Can be taken with or without food 3
• Efficacy in elderly patients (≥65 years) is comparable to the overall population 1, 4

Patient Selection

Prucalopride is indicated for:

• Adults with chronic idiopathic constipation who have not responded adequately to first-line treatments 2, 3
• Effective across different age groups, BMI categories, and renal function levels (though less effective in obese patients and those with moderate renal impairment) 4

Contraindications

Prucalopride should not be used in patients with:

• Hypersensitivity to prucalopride
• Intestinal perforation or obstruction
• Severe inflammatory conditions of the intestinal tract (Crohn's disease, ulcerative colitis)
• Toxic megacolon/megarectum 1, 2, 3

Adverse Effects and Safety

• Common side effects (generally transient):
  • Headache
  • Abdominal pain
  • Nausea
  • Diarrhea
  • Dizziness
  • Vomiting
  • Flatulence
  • Fatigue 1, 2
• Most side effects occur within the first week of treatment and typically resolve within a few days 1
• Approximately 5% of patients discontinue prucalopride due to side effects 1
• No increased risk of cardiovascular adverse events compared to placebo 1, 2

Important Safety Considerations

• Monitor for unusual changes in mood, behavior, or suicidal ideation
  • The FDA label cautions about potential mood changes and suicidal ideation
  • However, a causal relationship has not been clearly established 1, 3
• Discontinue treatment if patients experience unusual mood changes or suicidal thoughts 2, 3

Treatment Algorithm

1. Start with first-line treatments:
   • Polyethylene glycol (PEG)
   • Lifestyle modifications (high-fiber diet, adequate fluid intake, physical activity)
   • Optimizing toileting position
2. If inadequate response after sufficient trial (typically 4-8 weeks):
   • Consider prucalopride 2 mg once daily
   • For patients with severe renal impairment, start with 1 mg once daily
3. Evaluate response after 4 weeks:
   • If effective with tolerable side effects, continue treatment
   • If ineffective or intolerable side effects, discontinue and consider alternative therapies 1, 2

Clinical Pearls

• Prucalopride directly stimulates colonic motility, differentiating it from osmotic or chloride secretagogues approved for chronic constipation 5
• Unlike earlier 5-HT4 receptor agonists (cisapride, tegaserod), prucalopride does not interact with cardiac hERG potassium channels or other serotonergic receptors in blood vessels 5
• Most clinical trials evaluated prucalopride for 4-24 weeks, with long-term safety and efficacy data beyond 12 weeks being more limited 2
• Prucalopride has shown efficacy in patients with severe chronic constipation in whom laxatives failed to provide adequate relief 6