What are the specific indications for each prokinetic agent?

Specific Indications for Prokinetic Agents

Metoclopramide is the only FDA-approved prokinetic agent in the United States, indicated specifically for gastroparesis, while erythromycin serves as the most effective first-line agent for gastric intolerance in critically ill patients, and prucalopride is approved for chronic constipation refractory to laxatives. 1, 2, 3

FDA-Approved Agents

Metoclopramide

• Gastroparesis: The sole FDA-approved indication for any prokinetic in the United States 1, 3
• Dosing: 10 mg three times daily, taken 30 minutes before meals 3
• Critical limitation: Treatment must be restricted to less than 12 weeks due to black box warning for potentially irreversible tardive dyskinesia 1, 3
• Also effective for early satiety in cancer patients after treating constipation, though adverse CNS effects (somnolence, depression, hallucinations, extrapyramidal symptoms) limit use 1
• Feeding intolerance in sepsis/septic shock: Weak recommendation as second-line agent when enteral nutrition is interrupted 1
• Not recommended for routine use in pediatric GERD due to insufficient evidence 2, 3

Prucalopride (5-HT4 agonist)

• Chronic constipation in severe intestinal dysmotility refractory to traditional laxatives 2, 4
• Safer alternative for long-term therapy compared to dopaminergic agents, with no QT interval effects 2

Off-Label Agents Available in the United States

Erythromycin (Motilin Receptor Agonist)

• First-line agent for gastric intolerance in critically ill patients: Most effective prokinetic with superior evidence (RR 0.58, CI 0.34-0.98, p=0.04) 2
• Dosing: 100-250 mg IV three times daily 2
• Major limitation: Tachyphylaxis develops rapidly—effectiveness decreases to one-third after 72 hours, requiring discontinuation after 2-4 days 2
• Best reserved for acute exacerbations rather than chronic management 3
• May benefit postoperative ileus and colonic pseudo-obstruction 5

Domperidone (Dopamine D2 Antagonist)

• Not FDA-approved in the United States but available internationally 3
• Indicated for early satiety and upper GI motility disorders 1
• Advantage: Does not cross blood-brain barrier, resulting in fewer CNS side effects compared to metoclopramide 3
• Critical safety concern: Black box warning for QTc prolongation and risk of torsade de pointes, especially with IV bolus doses; requires ECG monitoring 1, 2
• Maximal effect in proximal GI tract; minimal efficacy for colonic disorders 5

Agents Withdrawn from Market

Cisapride (5-HT4 Agonist)

• Withdrawn due to fatal cardiac arrhythmias from QT interval prolongation 2, 3
• Historically most effective for GERD and showed promise for chronic constipation and postoperative ileus 5

Tegaserod (Partial 5-HT4 Agonist)

• Enhances gastric emptying but no confirmed efficacy in reducing gastroparesis symptoms 3
• Not approved for gastroparesis indication 3

Investigational Agents

Velusetrag (Selective 5-HT4 Agonist)

• Accelerated gastric emptying in phase 2 RCT for gastroparesis 1, 6
• Not yet FDA-approved 1

Indication-Specific Algorithm

For Gastroparesis:

1. Start metoclopramide 10 mg TID before meals (≤12 weeks maximum) 3
2. If ineffective or contraindicated, consider erythromycin for acute exacerbations only 3
3. Withdraw opioids and GLP-1 agonists first, as these directly impair motility 3

For Feeding Intolerance in Critical Illness/Sepsis:

1. First-line: Erythromycin 100-250 mg IV TID for 2-4 days maximum 2
2. Second-line: Metoclopramide 10 mg IV 2-3 times daily 1, 2

For Early Satiety in Cancer Patients:

1. Diagnose and treat constipation first 1
2. Consider metoclopramide or domperidone (if available), weighing CNS effects versus cardiac risks 1

For Chronic Constipation:

1. Prucalopride for severe intestinal dysmotility refractory to laxatives 2, 4

For Postoperative Ileus:

1. Supportive care remains primary treatment 7
2. Limited role for prokinetics; erythromycin may provide modest benefit 5, 7

Critical Safety Considerations

• Metoclopramide: 11-34% adverse event rate including extrapyramidal reactions; cumulative risk of irreversible tardive dyskinesia increases beyond 12 weeks 2, 3
• Domperidone: Requires ECG monitoring for QTc prolongation, particularly with long-term use 2
• Erythromycin: Rapid tachyphylaxis limits chronic use; does not affect pneumonia incidence 2
• All prokinetics: Should not be first-line without implementing dietary modifications (5-6 small, low-fat, low-fiber meals daily) 3