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Domperidone Maleate

Domperidone Maleate

Introduction

Domperidone Maleate is a dopamine D2 receptor antagonist that plays a vital role in gastrointestinal pharmacotherapy. Often used as a prokinetic and antiemetic agent, it enhances gastric motility and alleviates nausea and vomiting associated with a variety of conditions. Though commonly referred to simply as "domperidone," the maleate salt form offers distinct pharmacokinetic properties that contribute to its therapeutic effectiveness.

Chemical and Pharmacological Profile

  • Chemical Name: 5-Chloro-1-[1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one maleate

  • Molecular Formula: C22H24ClN5O2.C4H4O4

  • Class: Dopamine D2 receptor antagonist

  • Salt Form: Maleate salt improves water solubility and stability

Mechanism of Action

Domperidone Maleate exerts its effects primarily by antagonizing peripheral dopamine D2 receptors:

  • Gastrointestinal Effects: Dopamine inhibits gastrointestinal motility. By blocking D2 receptors, Domperidone enhances the motility of the upper GI tract, promoting gastric emptying and transit.

  • Antiemetic Action: It acts on the chemoreceptor trigger zone (CTZ) located in the area postrema, outside the blood-brain barrier. Unlike metoclopramide, Domperidone does not readily cross the BBB, minimizing central nervous system side effects.

Pharmacokinetics

  • Absorption: Oral bioavailability is approximately 15% due to extensive first-pass metabolism

  • Peak Plasma Levels: Achieved within 30–60 minutes

  • Half-Life: 7–9 hours

  • Metabolism: Predominantly by the liver (CYP3A4 pathway)

  • Excretion: Primarily via feces (66%) and urine (33%)

Clinical Indications

  1. Gastroparesis: Delayed gastric emptying can cause nausea, vomiting, and bloating. Domperidone Maleate stimulates peristalsis and improves gastric motility.

  2. Functional Dyspepsia: Particularly in patients with bloating and early satiety, domperidone enhances GI motility.

  3. Gastroesophageal Reflux Disease (GERD): Used as adjunctive therapy, especially in patients unresponsive to PPIs alone.

  4. Nausea and Vomiting: Effective against nausea due to chemotherapy, migraine, radiotherapy, and gastrointestinal infections.

  5. Parkinson’s Disease-Related GI Symptoms: Useful for managing nausea associated with levodopa treatment.

  6. Lactation Support (Off-label): Sometimes prescribed to increase breast milk production due to its prolactin-releasing properties.

Formulations and Dosage

  • Available Forms: Tablets, orally disintegrating tablets, suspensions, suppositories

  • Adult Dosage: 10–20 mg orally 3–4 times daily before meals and at bedtime

  • Pediatric Use: 0.2–0.4 mg/kg per dose up to 4 times daily (under strict supervision)

Advantages of the Maleate Salt Form

  • Increased Solubility: Enhances oral absorption and uniform distribution

  • Better Stability: Prolongs shelf-life in pharmaceutical formulations

  • Consistent Plasma Levels: Facilitates more predictable pharmacokinetics

Adverse Effects

  • Common:

    • Dry mouth

    • Headache

    • Abdominal cramps

    • Diarrhea

  • Serious:

    • QT prolongation and risk of ventricular arrhythmias

    • Hyperprolactinemia leading to galactorrhea or gynecomastia

    • Rare extrapyramidal symptoms (especially in high doses or children)

Cardiac Safety Concerns

In 2014, the European Medicines Agency (EMA) and other regulatory authorities raised concerns about domperidone’s potential to cause QT interval prolongation and serious ventricular arrhythmias, especially in elderly patients and those with pre-existing heart conditions.

Precautionary Measures:

  • ECG monitoring in at-risk patients

  • Avoid use with other QT-prolonging drugs

  • Dose limitation: No more than 30 mg/day for adults in many jurisdictions

Drug Interactions

  • CYP3A4 Inhibitors (e.g., ketoconazole, erythromycin): Increase domperidone plasma concentration

  • Antacids and Proton Pump Inhibitors: May reduce absorption if taken simultaneously

  • Other QT-Prolonging Drugs: Increased risk of cardiac events

Contraindications

  • Known hypersensitivity to domperidone or any component of the formulation

  • Prolactin-releasing pituitary tumor (prolactinoma)

  • Cardiac arrhythmias or electrolyte imbalances

  • Gastrointestinal hemorrhage, mechanical obstruction, or perforation

Special Populations

  • Pregnancy: Use only if clearly needed (Category C)

  • Lactation: Domperidone is excreted in small amounts in breast milk; caution is advised

  • Geriatric: Increased susceptibility to cardiac side effects

  • Pediatric: Use with caution; avoid prolonged use

Regulatory Status

  • United States: Not FDA-approved for general use due to cardiac risk concerns

  • Europe: Available under prescription with restrictions on dose and duration

  • India and Asia: Widely available and frequently used

Clinical Evidence and Trials

  • Gastroparesis Trials: Showed statistically significant improvement in gastric emptying and symptom relief

  • Meta-Analysis (2015): Confirmed domperidone’s effectiveness in treating nausea and vomiting with fewer CNS effects compared to metoclopramide

  • Breast Milk Study: Indicated modest increases in milk volume but highlighted potential for prolactin-related side effects.

Patient Counseling Points

  • Take domperidone 15–30 minutes before meals

  • Avoid grapefruit juice and other CYP3A4 inhibitors

  • Do not exceed recommended dose or duration of treatment

  • Report symptoms like palpitations, dizziness, or fainting

  • Regular monitoring for long-term users

Alternatives and Comparisons

  • Metoclopramide: Effective but higher risk of EPS and sedation

  • Erythromycin: Prokinetic properties but limited by tachyphylaxis

  • Ondansetron: Powerful antiemetic without prokinetic activity

Innovations and Future Directions

  • Transdermal Patches: Under investigation to avoid first-pass metabolism

  • Nanoparticle Formulations: Aimed at improving bioavailability and targeting

  • Cardio-Safe Analogs: Research into D2 antagonists with reduced QT risk

Common Myths and Facts

  • "Domperidone is completely safe since it doesn't affect the brain": FALSE. While CNS side effects are fewer, cardiac risks are still significant.

  • "Can be used indefinitely for reflux": FALSE. Short-term use is advised; long-term requires monitoring

  • "Safe for breastfeeding women": PARTLY TRUE. It may increase milk supply, but safety should be assessed individually

Conclusion

Domperidone Maleate remains a cornerstone in the treatment of upper gastrointestinal motility disorders and nausea. Its favorable peripheral activity, minimal CNS penetration, and effective symptom control make it highly valuable in clinical practice. However, cardiac safety concerns and regulatory restrictions necessitate cautious use. With growing interest in novel delivery systems and safer analogs, the future of domperidone therapy is promising—provided it is used judiciously and with due medical supervision.

References

  1. EMA Safety Reviews on Domperidone (2014)

  2. American Journal of Gastroenterology – Prokinetics in Gastroparesis

  3. WHO Model List of Essential Medicines

  4. Martindale: The Complete Drug Reference

  5. ClinicalTrials.gov – Domperidone trials in functional GI disorders