What are the different types of prokinetics?

Types of Prokinetic Agents

Prokinetic agents are medications that enhance gastrointestinal motility and can be classified into several distinct categories based on their mechanisms of action, with metoclopramide for short-term use (≤12 weeks) and itopride for longer-term management being the most recommended options. 1

Major Classes of Prokinetics

1. Dopamine Antagonists

• Metoclopramide: Acts as a D2 dopamine receptor antagonist and 5-HT4 agonist. It stimulates motility of the upper gastrointestinal tract by sensitizing tissues to acetylcholine, increasing gastric contractions, relaxing the pyloric sphincter, and increasing peristalsis of the duodenum and jejunum 2. Limited to short-term use (≤12 weeks) due to risk of irreversible tardive dyskinesia 1.

• Domperidone: A selective peripheral D2 dopamine receptor antagonist that does not cross the blood-brain barrier, resulting in fewer central nervous system side effects than metoclopramide 3. Requires QTc interval monitoring, especially for long-term use due to cardiac risks 1.

2. Serotonergic Agents (5-HT4 Receptor Agonists)

• Cisapride: Enhances acetylcholine release in the myenteric plexus without anti-dopaminergic effects 3. Despite being effective, it has been largely withdrawn from markets due to risk of fatal cardiac arrhythmias related to QT prolongation 3.

• Prucalopride: A high-affinity selective 5-HT4 receptor agonist used primarily for chronic constipation. Unlike cisapride, it does not affect the QT interval, making it safer for cardiac patients 3.

• Tegaserod: A 5-HT4 receptor partial agonist that was used for irritable bowel syndrome but was withdrawn due to increased risk of heart attacks and strokes 3.

3. Motilin Receptor Agonists

• Erythromycin: A macrolide antibiotic that acts as a motilin receptor agonist at sub-antimicrobial doses. It stimulates gastric emptying but requires monitoring for QT prolongation and cardiac arrhythmias 1.

4. Cholinergic Agonists

• Bethanechol: A direct-acting cholinergic agonist that increases lower esophageal sphincter pressure and improves gastric emptying 3, 4.

5. GABA-B Receptor Agonists

• Baclofen: Works as a prokinetic by using a different mechanism than traditional agents, acting on GABA-B receptors 3.

Clinical Applications and Selection

For Gastroparesis:

• First-line: Metoclopramide (short-term) or itopride (long-term)
• Alternative: Domperidone (where available)
• For diabetic gastroparesis: Optimize glycemic control first, as hyperglycemia can further delay gastric emptying 1

For GERD:

• Start with PPI therapy
• Add prokinetic if symptoms persist
• Consider itopride as add-on therapy to PPI for refractory cases 1

For Functional Dyspepsia:

• Cisapride has shown significant responder rates in controlled studies, particularly in long-term treatment, but availability is limited 5
• Itopride is effective and well-tolerated 1

Safety Considerations

• Metoclopramide: Risk of tardive dyskinesia (0.1% per 1000 patient-years), extrapyramidal symptoms, QT prolongation, somnolence, and depression 1. FDA black box warning limits use to ≤12 weeks 3.

• Domperidone: Requires QTc monitoring; risk increases when co-administered with drugs like erythromycin and ketoconazole 6.

• Cisapride and Tegaserod: Largely withdrawn due to cardiac risks 3.

• Itopride: Generally well-tolerated with no significant effect on QT interval or extrapyramidal side effects 1.

Treatment Failure Approach

When initial prokinetic therapy fails:

1. Consider switching to an alternative agent
2. Try combination therapy (e.g., adding erythromycin or prucalopride)
3. Consider octreotide (50-100 μg once or twice daily) in severe cases 1

Important Caveats

• Withdraw medications that can worsen gastroparesis (opioids, anticholinergics, GLP-1 receptor agonists) before starting prokinetics 1
• Elderly patients are at higher risk of tardive dyskinesia with metoclopramide and should be monitored closely 1
• For systemic sclerosis-related GI motility disorders, experts recommend prokinetics despite limited RCT evidence 3
• Rotating antibiotics may be useful when malabsorption is caused by bacterial overgrowth in systemic sclerosis patients 3

Prokinetic selection should be based on the specific motility disorder being treated, anticipated duration of therapy, and patient-specific risk factors for adverse effects, with particular attention to cardiac and neurological safety profiles.