Prokinetic Drugs: Mechanism and Clinical Applications
A prokinetic drug stimulates and coordinates gastrointestinal muscular contractions to facilitate the transit of intestinal contents through the digestive tract. 1 These medications enhance gut motility, accelerate transit time, and are primarily used to treat various gastrointestinal motility disorders.
Mechanism of Action
Prokinetic drugs work through several mechanisms:
Serotonergic (5-HT4) Pathway
- Drugs like prucalopride act as selective serotonin 5-HT4 receptor agonists
- Stimulate colonic peristalsis and high-amplitude propagating contractions (HAPCs)
- Increase bowel motility by facilitating acetylcholine release 2
Dopaminergic Pathway
- Agents like metoclopramide and domperidone antagonize D2 dopamine receptors
- Stimulate gastric emptying and small intestinal transit
- Enhance esophageal sphincter contraction strength 1
Motilin Pathway
- Macrolides like erythromycin act as motilin receptor agonists
- Particularly effective for gastric motility disorders 1
Clinical Applications
Prokinetics are recommended in several clinical scenarios:
1. Chronic Intestinal Motility Disorders
- Recommendation: A trial with prokinetics should always be attempted in patients with chronic gastrointestinal motility dysfunctions 1
- Key drugs: Metoclopramide, domperidone, erythromycin, octreotide, and neostigmine
- Efficacy: While not universally effective, they can benefit a subset of patients 1
2. Gastroparesis
- Primary treatment includes dietary manipulation and prokinetic agents 1
- First-line options: Metoclopramide, erythromycin (IV or oral)
- Alternative: Domperidone (available in Canada, Mexico, Europe but not FDA-approved in US) 1
3. Gastric Feeding Intolerance in Critical Care
- First-line therapy: Intravenous erythromycin (100-250 mg 3 times daily for 2-4 days) 1
- Alternative: Intravenous metoclopramide (10 mg 2-3 times daily) or combination therapy 1
- Duration: Effectiveness decreases after 72 hours; should be discontinued after 3 days 1
Specific Prokinetic Agents
Metoclopramide
- Mechanism: D2 receptor antagonist with acetylcholine-like effects
- Caution: Risk of extrapyramidal side effects and tardive dyskinesia
- Limitation: Not recommended for long-term use due to neurological side effects 1
Domperidone
- Mechanism: Selective peripheral D2 receptor antagonist without central effects
- Caution: QTc prolongation risk; requires ECG monitoring for long-term use
- Note: Acts as a prokinetic by stimulating gut motility 3
Erythromycin
- Mechanism: Motilin receptor agonist
- Advantage: Particularly effective for gastric motility disorders
- Limitation: Tachyphylaxis (decreased effectiveness after 72 hours) 1
Prucalopride
- Mechanism: Highly selective 5-HT4 receptor agonist
- Advantage: Does not affect QT interval at therapeutic doses
- Effect: Stimulates colonic peristalsis and accelerates colonic transit time by 12 hours 2
Monitoring and Precautions
- QT Interval: Monitor in patients taking domperidone or other prokinetics with cardiac effects
- Contraindication: Avoid prokinetics in patients with suspected gastrointestinal obstruction 3
- Duration: Be aware of tachyphylaxis with certain agents (particularly erythromycin)
- Drug Interactions: Significant interactions may occur when domperidone is co-administered with CYP3A4 inhibitors like erythromycin or ketoconazole 3
Clinical Decision Algorithm
- Identify the affected GI segment (esophagus, stomach, small bowel, colon)
- Select appropriate agent based on:
- Location of dysmotility
- Patient comorbidities (cardiac, neurological)
- Potential drug interactions
- Start with short trial (2-4 days for IV erythromycin, up to 3 months for metoclopramide)
- Assess response and adjust or discontinue based on efficacy and side effects
- Consider combination therapy for refractory cases
By enhancing gastrointestinal motility through various receptor-mediated mechanisms, prokinetic drugs play an important role in managing patients with functional gastrointestinal disorders, particularly those with impaired transit.