Mechanism of Action of Domperidone

Introduction

Domperidone is a peripherally selective dopamine D₂ receptor antagonist used primarily as a prokinetic and antiemetic agent. It enhances gastrointestinal motility and suppresses nausea and vomiting without significant central nervous system effects because of its poor penetration across the blood–brain barrier. Domperidone is a high-yield drug in pharmacology, gastroenterology, and clinical examinations due to its dopamine antagonism–based mechanism and favorable CNS safety profile compared with metoclopramide.

Mechanism of Action (Step-wise)

Domperidone improves gastric motility and controls emesis by blocking dopamine D₂ receptors in the gastrointestinal tract and chemoreceptor trigger zone.

Step-wise mechanism:

1. Physiologic Role of Dopamine in the GI Tract
   Dopamine inhibits gastrointestinal motility by acting on dopamine D₂ receptors in the enteric nervous system.
2. Dopamine D₂ Receptor Antagonism
   Domperidone competitively blocks D₂ receptors located on presynaptic enteric neurons.
3. Disinhibition of Acetylcholine Release
   Blocking D₂ receptors removes dopamine-mediated inhibition, increasing acetylcholine release.
4. Enhanced GI Smooth Muscle Contraction
   Increased acetylcholine stimulates muscarinic receptors on GI smooth muscle.
5. Increased Gastric and Intestinal Motility
   This leads to:
   • Increased lower esophageal sphincter (LES) tone
   • Accelerated gastric emptying
   • Improved intestinal peristalsis
6. Antiemetic Action (Peripheral CTZ Blockade)
   Domperidone blocks D₂ receptors in the chemoreceptor trigger zone (outside the BBB), reducing nausea and vomiting.
7. Minimal Central Effects
   Poor CNS penetration results in negligible extrapyramidal side effects.

Pharmacokinetics

• Absorption: Moderate oral absorption
• Bioavailability: Low–moderate due to first-pass metabolism
• Distribution: Limited CNS penetration
• Metabolism: Hepatic metabolism (CYP3A4)
• Elimination: Fecal and renal excretion
• Half-life: Approximately 7–9 hours

Clinical Uses

Domperidone is used in disorders of gastric motility and nausea:

• Gastroesophageal reflux disease (GERD)
• Functional dyspepsia
• Diabetic gastroparesis
• Nausea and vomiting (drug-induced, postoperative)
• Parkinson disease–related nausea (adjunct)
• Lactation enhancement (off-label, due to prolactin increase)

Adverse Effects

Adverse effects are generally mild and predictable:

• Endocrine:
  • Hyperprolactinemia
  • Galactorrhea
  • Gynecomastia
• Cardiac:
  • QT interval prolongation
  • Ventricular arrhythmias (high dose or IV use)
• Gastrointestinal:
  • Dry mouth
  • Abdominal cramps

Domperidone should be used cautiously in patients with cardiac disease.

Comparative Analysis (must include a table + explanation)

Comparison of Prokinetic and Antiemetic Drugs

Explanation:
Domperidone provides effective prokinetic and antiemetic action with minimal extrapyramidal effects due to poor CNS penetration. Metoclopramide is more potent centrally but carries a higher EPS risk, while ondansetron lacks prokinetic activity.

MCQs (10–15)

1. Domperidone primarily blocks which receptor?
   a) Serotonin 5-HT₃
   b) Dopamine D₂
   c) Histamine H₁
   d) Muscarinic M₃

Answer: b) Dopamine D₂

2. Domperidone increases GI motility by increasing release of:
   a) Dopamine
   b) Serotonin
   c) Acetylcholine
   d) GABA

Answer: c) Acetylcholine

3. Domperidone differs from metoclopramide because it:
   a) Is centrally acting
   b) Has strong EPS risk
   c) Does not cross BBB significantly
   d) Has no antiemetic effect

Answer: c) Does not cross BBB significantly

4. Domperidone increases which GI parameter?
   a) Gastric acid secretion
   b) Lower esophageal sphincter tone
   c) Intestinal secretion
   d) Colonic water absorption

Answer: b) Lower esophageal sphincter tone

5. Domperidone is most useful in:
   a) Acute diarrhea
   b) Gastroparesis
   c) Intestinal obstruction
   d) Peptic ulcer bleeding

Answer: b) Gastroparesis

6. A major endocrine adverse effect of domperidone is:
   a) Hypothyroidism
   b) Hyperprolactinemia
   c) Hypercortisolism
   d) Diabetes mellitus

Answer: b) Hyperprolactinemia

7. Domperidone produces antiemetic action by blocking D₂ receptors in the:
   a) Vomiting center
   b) Vestibular nucleus
   c) Chemoreceptor trigger zone
   d) Cerebral cortex

Answer: c) Chemoreceptor trigger zone

8. Domperidone should be used cautiously due to risk of:
   a) Nephrotoxicity
   b) Hepatic failure
   c) QT prolongation
   d) Hypoglycemia

Answer: c) QT prolongation

9. Domperidone has minimal extrapyramidal effects because it:
   a) Is weak
   b) Is rapidly metabolized
   c) Poorly enters the CNS
   d) Blocks serotonin receptors

Answer: c) Poorly enters the CNS

10. Domperidone is metabolized mainly by:
    a) CYP2C9
    b) CYP2D6
    c) CYP3A4
    d) MAO

Answer: c) CYP3A4

FAQs (minimum 5)

1. What is the primary mechanism of domperidone?
   Peripheral dopamine D₂ receptor antagonism increasing GI motility.
2. Why does domperidone have fewer CNS side effects?
   Because it poorly crosses the blood–brain barrier.
3. Is domperidone a prokinetic drug?
   Yes, it enhances gastric emptying and intestinal peristalsis.
4. Why can domperidone increase prolactin levels?
   Due to dopamine blockade in the pituitary.
5. Is domperidone safer than metoclopramide?
   It has fewer extrapyramidal effects but carries a QT-prolongation risk.
6. Can domperidone be used for GERD?
   Yes, as an adjunct due to increased LES tone and gastric emptying.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  https://accessmedicine.mhmedical.com
• Katzung BG. Basic and Clinical Pharmacology
  https://accessmedicine.mhmedical.com
• Tripathi KD. Essentials of Medical Pharmacology
  https://www.jaypeebrothers.com
• Harrison’s Principles of Internal Medicine
  https://accessmedicine.mhmedical.com

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