Prokinetic Agents

Prokinetics: Introduction - Gut Go-Getters

• Drugs enhancing coordinated GI motility & accelerating gut transit.
• "Gut Go-Getters": Promote forward movement, relieving stasis symptoms (e.g., bloating, nausea).
• Uses: Gastroparesis, severe GERD, functional dyspepsia, chronic constipation.
• Key Mechanisms:
  • D2 dopamine receptor antagonism (prokinetic, anti-emetic).
  • 5-HT4 serotonin receptor agonism (↑ ACh release).
  • Motilin receptor activation (initiates MMC).

⭐ Many prokinetics work by modulating neurotransmitter activity (e.g., ACh, dopamine, serotonin) in the enteric nervous system.

D2 Antagonists - Dopamine Blockers

• MOA: Block D2 receptors (CTZ → anti-emetic; GI → prokinetic). ↑ GI ACh release → ↑ LES tone, ↑ gastric emptying, ↑ motility.
• 📌 Mnemonic: Dopey Don & Meta Move Guts (Domperidone, Metoclopramide, Motility).
• Drugs & Features:
  • Metoclopramide:
    • Crosses BBB: EPS (dystonia, akathisia, parkinsonism), tardive dyskinesia (⚠️ chronic use >12 wks).
    • Hyperprolactinemia.
    • Also: 5-HT4 agonist (prokinetic), 5-HT3 antagonist (anti-emetic).
    • Uses: Gastroparesis, GERD, anti-emetic.
  • Domperidone:
    • Peripherally acting: ↓ EPS.
    • Hyperprolactinemia.
    • ⚠️ QT prolongation, ventricular arrhythmias.
    • Uses: Gastroparesis, anti-emetic.
• Contraindications: GI obstruction/perforation, pheochromocytoma (metoclopramide).

⭐ Metoclopramide-induced acute dystonia: treat IV anticholinergics (diphenhydramine) or benzodiazepines.

5-HT4 Agonists - Serotonin Surfers

• Mechanism: Activate 5-HT4 receptors on enteric neurons → ↑Acetylcholine (ACh) release → ↑GI motility & secretion.
• Key Agents & Uses:
  • Cisapride:
    • Broad prokinetic.
    • ⚠️ Withdrawn/restricted: Significant risk of cardiac arrhythmias (QT prolongation, Torsades de Pointes).
  • Mosapride:
    • Used for dyspepsia, GERD.
    • Generally considered to have a safer cardiac profile than cisapride.
  • Prucalopride:
    • Highly selective 5-HT4 agonist.
    • Primarily for chronic idiopathic constipation (CIC) in adults. Minimal cardiac effects.
  • Tegaserod:
    • Partial 5-HT4 agonist.
    • For IBS with constipation (IBS-C) in women < 65 years; emergency use for CIC.
    • Restricted use due to potential cardiovascular ischemic events.
• Common Adverse Effects: Headache, abdominal pain, diarrhea, nausea.
• 📌 Mnemonic: "Serotonin Surfers RIDE the wave of motility" (CisapRIDE, MosapRIDE, PrucalopRIDE).

⭐ Cisapride was largely withdrawn from markets due to its significant risk of causing life-threatening cardiac arrhythmias, specifically QT prolongation and Torsades de Pointes, by blocking hERG K+ channels.

Motilin Agonists & Others - Motility Movers

• Erythromycin (Macrolide)
  • Mechanism: Agonist at motilin receptors on GI smooth muscle & enteric neurons → ↑ upper GI motility (stomach, duodenum).
  • Action: Stimulates Phase III of Migrating Motor Complex (MMC).
  • Uses: Gastroparesis (e.g., diabetic, post-operative), pre-endoscopy gastric clearance.
  • Dose: Low, e.g., 3 mg/kg or 200-250 mg PO/IV.
  • Adverse Effects: Tachyphylaxis (limits chronic use), QTc prolongation (risk of Torsades), GI upset, antibiotic resistance concerns.
  • 📌 Elephant Moves Massively (Erythromycin, Motilin, MMC).

⭐ Erythromycin, a macrolide antibiotic, acts as a prokinetic at low doses by stimulating motilin receptors, particularly useful for diabetic gastroparesis; tachyphylaxis is a key limitation.

• Other Prokinetic Approaches:
  • Ghrelin receptor agonists and cholecystokinin (CCK1) receptor antagonists are newer areas of investigation for prokinetic effects.

High‑Yield Points - ⚡ Biggest Takeaways

• Metoclopramide: D2 antagonist & 5-HT4 agonist; causes EPS, tardive dyskinesia, ↑prolactin.
• Domperidone: Peripheral D2 antagonist; fewer CNS effects, risk of QT prolongation.
• Cisapride: 5-HT4 agonist; withdrawn due to severe cardiac arrhythmias.
• Prucalopride: Selective 5-HT4 agonist for chronic constipation; better safety profile.
• Erythromycin: Motilin agonist (low dose); for acute gastroparesis, tachyphylaxis.
• Mechanism: Most enhance ACh release, promoting GI motility.
• Key uses: Gastroparesis, GERD, antiemesis, constipation.