What are the uses, mechanism of action, and dosage of prokinetic agents, such as metoclopramide (Reglan), domperidone, and erythromycin, in patients with gastrointestinal motility disorders, including gastroparesis, constipation, and gastroesophageal reflux disease?

Prokinetic Agents: Uses, Mechanisms, and Dosing

Overview of Prokinetic Classes

Prokinetic agents enhance gastrointestinal motility by amplifying and coordinating muscular contractions to facilitate transit of luminal content, with specific agents targeting different receptors and segments of the GI tract. 1

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Metoclopramide (Reglan)

Mechanism of Action

• D2 dopamine receptor antagonist that blocks dopamine's inhibitory effect on GI motility and blocks the chemoreceptor trigger zone centrally 2, 3
• Enhances acetylcholine release from enteric nerves and sensitizes tissues to acetylcholine's effects 4, 3
• Increases gastric antral contractions, relaxes the pyloric sphincter, increases duodenal/jejunal peristalsis, and raises lower esophageal sphincter tone 3

Clinical Uses

• FDA-approved for diabetic gastroparesis (the only approved prokinetic in the United States) 4, 5
• Gastroesophageal reflux disease 1
• Nausea and vomiting (not primarily for abdominal pain) 4

Dosing

• 5-20 mg orally three to four times daily before meals 4
• Onset: 30-60 minutes orally, 10-15 minutes IM, 1-3 minutes IV 3
• Duration of effect: 1-2 hours 3

Critical Safety Warnings

• Maximum duration: 12 weeks only due to FDA black box warning for tardive dyskinesia risk 4
• The European Medicines Agency recommends against long-term use due to extrapyramidal side effects (especially in children) and potentially irreversible tardive dyskinesia in elderly patients 1, 2
• Avoid after bowel anastomosis 2

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Domperidone

Mechanism of Action

• Selective peripheral D2 dopamine receptor antagonist without the acetylcholine-like effects of metoclopramide 1
• Stimulates gastric emptying and small intestinal transit 1

Clinical Uses

• Gastroparesis 1
• Gastroesophageal reflux disease 6
• Available in the US only through FDA's Expanded Access to Investigational Drugs program 7

Safety Concerns

• QTc prolongation risk requiring ECG monitoring with long-term use per National Patient Safety Agency alerts 1
• Maximal prokinetic effect in proximal GI tract with minimal colonic effects 6

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Erythromycin

Mechanism of Action

• Motilin receptor agonist that stimulates gastrointestinal motility 8
• Most effective when absent or impaired antroduodenal migrating motor complexes are present 1, 2

Clinical Uses

• First-line prokinetic for critically ill patients with enteral feeding intolerance per ESPEN guidelines (Grade B recommendation) 8
• Diabetic gastroparesis 6, 9
• Small bowel dysmotility 2

Dosing

• Critically ill adults: 100-250 mg IV every 6-8 hours for maximum 2-4 days 8
• Chronic dysmotility: 900 mg/day orally (divided doses) 1
• Intravenous route preferred in severe feeding intolerance 8

Important Limitations

• Tachyphylaxis develops (effectiveness decreases to one-third after 72 hours of continuous use) 1, 8
• Limit to short courses (24-48 hours) to avoid antimicrobial resistance 8
• Can prolong QTc interval 8

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Prucalopride

Mechanism of Action

• High-affinity selective 5-HT4 receptor agonist without significant action on 5-HT1B/D receptors or cardiac potassium channels 1

Clinical Uses

• Chronic constipation 1, 2

Safety Advantage

• Does not affect QT interval, unlike cisapride or tegaserod (both withdrawn from market) 1
• Safer cardiac profile than older 5-HT4 agonists 2

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Azithromycin

Mechanism of Action

• Motilin agonist similar to erythromycin 1

Clinical Uses

• May be more effective than erythromycin for small bowel dysmotility 1, 2
• Preferred over erythromycin in neonates (<1 month) due to lower risk of infantile hypertrophic pyloric stenosis 8

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Octreotide

Mechanism of Action

• Somatostatin analogue that reduces perception of volume distension by inhibiting sensory afferent pathways 1
• May restore low-amplitude migrating motor complexes 1

Clinical Uses

• Severe refractory small bowel dysmotility, especially in systemic sclerosis when other treatments fail 1, 2

Dosing

• 50-100 μg subcutaneously once or twice daily 1
• Effect apparent within 48 hours and maintained for >2 years 1
• May be more effective when combined with erythromycin 1

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Combination Therapy Strategies

Metoclopramide + Erythromycin

• Consider combination when monotherapy insufficient for severe gastroparesis 8
• Both prolong QTc interval—use with caution and ECG monitoring 8

Octreotide + Erythromycin

• May be effective when erythromycin alone unsuccessful 1

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Withdrawn or Restricted Agents

Cisapride

• 5-HT4 agonist withdrawn due to fatal cardiac arrhythmias from QT prolongation 1

Tegaserod

• 5-HT4 partial agonist withdrawn due to increased risk of heart attacks and strokes 1

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Clinical Decision Algorithm

For gastroparesis:

1. Start metoclopramide 10 mg TID-QID before meals (maximum 12 weeks) 4
2. If inadequate response or contraindications, consider domperidone (if accessible) with QTc monitoring 1
3. For severe cases, add erythromycin 250 mg TID or combine with metoclopramide 8

For chronic constipation:

• Use prucalopride as safer 5-HT4 agonist option 1, 2

For critically ill patients with feeding intolerance:

• Erythromycin 100-250 mg IV TID is first-line (ESPEN Grade B) 8

For refractory small bowel dysmotility:

• Consider octreotide 50-100 μg SC daily/BID, especially in systemic sclerosis 1, 2

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Key Pitfalls to Avoid

• Never use metoclopramide beyond 12 weeks due to irreversible tardive dyskinesia risk 4
• Monitor QTc with domperidone, erythromycin, and combination therapy 1, 8
• Avoid prokinetics after bowel anastomosis 1, 2
• Recognize erythromycin tachyphylaxis—limit to short courses 1, 8
• Metoclopramide has minimal direct effect on abdominal pain—use tricyclic antidepressants or SNRIs for visceral pain instead 4