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Domperidone

Domperidone

Introduction

Domperidone is a peripheral dopamine D2-receptor antagonist that is widely used in the treatment of gastrointestinal disorders, particularly those associated with delayed gastric emptying and nausea. It is also used to manage symptoms of gastroesophageal reflux disease (GERD), functional dyspepsia, and vomiting. While domperidone is not approved in all countries, its pharmacological profile makes it a compelling option in cases where prokinetic and antiemetic therapies are required.

Chemical and Pharmacological Profile

  • IUPAC Name: 5-chloro-1-[1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

  • Molecular Formula: C22H24ClN5O2

  • Molecular Weight: 425.91 g/mol

  • Drug Class: Dopamine D2 receptor antagonist, antiemetic, prokinetic agent

Mechanism of Action

Domperidone works primarily by blocking dopamine receptors in the chemoreceptor trigger zone (CTZ) and the gastrointestinal tract. By antagonizing peripheral D2 receptors, domperidone enhances the motility of the upper gastrointestinal tract and accelerates gastric emptying without affecting gastric secretions.

Unlike metoclopramide, domperidone does not readily cross the blood-brain barrier, which significantly reduces the risk of central nervous system (CNS) side effects such as extrapyramidal symptoms (EPS).

Pharmacokinetics

  • Absorption: Rapidly absorbed from the gastrointestinal tract but undergoes significant first-pass metabolism.

  • Bioavailability: Approximately 15% orally due to first-pass hepatic metabolism.

  • Protein Binding: Around 91-93%

  • Metabolism: Liver (CYP3A4 enzymes)

  • Half-life: 7-9 hours

  • Excretion: Mainly feces (66%), urine (33%)

Indications and Uses

  1. Gastroesophageal Reflux Disease (GERD):

    • Domperidone helps improve esophageal motility and prevent reflux symptoms in non-erosive reflux disease.

  2. Functional Dyspepsia:

    • Used to relieve symptoms such as bloating, early satiety, and upper abdominal discomfort by enhancing gastric emptying.

  3. Nausea and Vomiting:

    • Effective in controlling nausea and vomiting from various causes including gastrointestinal infections, chemotherapy, and migraine-related emesis.

  4. Gastroparesis:

    • Especially beneficial in diabetic patients where delayed gastric emptying is a common complication.

  5. Lactation Promotion (Off-label Use):

    • Occasionally used off-label to stimulate prolactin secretion and enhance lactation in postpartum women.

Formulations and Dosage

  • Oral Tablets: 10 mg, 20 mg

  • Suspension: 1 mg/mL

  • Suppositories: Used in pediatric patients in some regions

Adult Dosage:

  • Typical dose: 10 mg taken 15-30 minutes before meals and, if necessary, before bedtime.

  • Maximum recommended dose: 30 mg/day

Pediatric Dosage:

  • Calculated based on weight (0.25 to 0.5 mg/kg/dose), usually not exceeding 30 mg/day

Administration Guidelines

  • Should be taken 15-30 minutes before meals for maximum prokinetic effect

  • Duration of use should generally not exceed 7-10 days unless supervised by a physician

Efficacy in Clinical Practice

Numerous studies have demonstrated domperidone’s effectiveness in relieving nausea, vomiting, and symptoms of dyspepsia. It is often favored for its peripheral action, reducing the risk of CNS side effects. It is also especially useful in pediatric gastroenterology and for elderly patients who may be more susceptible to adverse effects from centrally acting drugs.

Safety Profile and Side Effects

Domperidone is generally well tolerated. However, certain adverse effects and safety warnings should be noted:

  • Common Side Effects:

    • Dry mouth

    • Abdominal cramps

    • Headache

  • Rare but Serious Side Effects:

    • QT interval prolongation

    • Ventricular arrhythmias

    • Sudden cardiac death (particularly in elderly or high-dose users)

Because of these cardiac risks, domperidone use is contraindicated in patients with pre-existing heart conditions and in those taking medications that prolong QT interval or inhibit CYP3A4.

Drug Interactions

  • CYP3A4 Inhibitors (e.g., ketoconazole, erythromycin): Increase serum levels of domperidone, heightening the risk of QT prolongation

  • Antacids/Antisecretory drugs: May reduce domperidone absorption

  • Dopaminergic agents (e.g., levodopa): Domperidone can antagonize the gastrointestinal side effects of levodopa without reducing its central effects

Contraindications and Cautions

  • Known hypersensitivity to domperidone

  • Gastrointestinal hemorrhage or mechanical obstruction

  • Prolactin-releasing pituitary tumor (prolactinoma)

  • Known QT prolongation or concurrent use with QT-prolonging drugs

Use in Special Populations

  • Pregnancy: Category C; use only if the potential benefit justifies the potential risk

  • Lactation: Domperidone is excreted in small amounts in breast milk; use under medical advice

  • Geriatric Patients: Use with caution due to increased risk of cardiac events

Regulatory Status and Controversies

Domperidone has a complex regulatory status:

  • Europe: Approved with restricted indications and maximum daily dose limits

  • Canada: Approved for motility disorders and nausea/vomiting with cautionary use

  • United States: Not FDA-approved; available only through investigational new drug (IND) programs

The concerns primarily stem from the potential for cardiac side effects. Regulatory bodies have recommended that it be used at the lowest effective dose for the shortest duration necessary.

Comparative Analysis

  • Versus Metoclopramide:

    • Domperidone is less likely to cause extrapyramidal symptoms and CNS-related side effects

    • Metoclopramide crosses the blood-brain barrier and is often associated with sedation and Parkinsonian symptoms

  • Versus Erythromycin:

    • Erythromycin is another prokinetic agent, but its use is limited by antibiotic resistance and gastrointestinal side effects

Patient Counseling Points

  • Take domperidone 15–30 minutes before meals

  • Do not exceed the recommended dose

  • Avoid grapefruit juice and CYP3A4 inhibitors

  • Report symptoms like palpitations, fainting, or irregular heartbeat

Myths and Misconceptions

  • "Domperidone is totally safe because it's used for babies": While it has pediatric uses, safety concerns still exist and dosage must be carefully calculated

  • "It has no side effects because it acts peripherally": Peripheral actions do not negate the risk of cardiac toxicity

  • "It helps with all GI problems": Domperidone is specifically useful for motility issues, not inflammatory or structural disorders

Future Directions and Research

  • Cardiac Risk Mitigation: Studies are being conducted to develop safer analogues and establish definitive risk profiles

  • Novel Delivery Systems: Efforts to create slow-release or localized formulations that reduce systemic exposure

  • Combination Therapies: Research on pairing domperidone with other agents to improve safety and effectiveness

Conclusion

Domperidone remains an important tool in the management of nausea, vomiting, and motility-related gastrointestinal conditions. While it offers significant advantages over other prokinetics—particularly in terms of CNS side effect reduction—its use must be tempered by careful consideration of cardiac risks, dosage, and drug interactions. As research continues and regulatory frameworks evolve, the role of domperidone in clinical practice will become increasingly refined. Clinicians and patients alike must remain informed to balance the drug's benefits with its potential risks, ensuring optimal therapeutic outcomes.

References

  1. EMA. Domperidone: Summary of Product Characteristics.

  2. Canadian Pharmacists Association. e-CPS: Domperidone Monograph.

  3. NIH. Domperidone Lactation Safety Data.

  4. American Gastroenterological Association. Prokinetic Use Guidelines.

  5. Medsafe New Zealand: Domperidone Regulatory Update.