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Domperidone And Cinnarizine

Domperidone and Cinnarizine Combination Therapy

Introduction

The combination of domperidone and cinnarizine is a widely used fixed-dose therapy in the management of gastrointestinal and vestibular disorders, particularly in patients presenting with nausea, vomiting, dizziness, and motion sickness. By combining the prokinetic and antiemetic effects of domperidone with the antihistaminic and calcium channel-blocking actions of cinnarizine, this dual-therapy offers synergistic benefits for a variety of indications.

Pharmacological Overview

Domperidone

  • Class: Dopamine D2 receptor antagonist

  • Mechanism: Acts peripherally to block dopamine receptors in the gastrointestinal tract and chemoreceptor trigger zone (CTZ), enhancing gastric motility and suppressing nausea/vomiting

  • Unique Feature: Minimal penetration of the blood-brain barrier, reducing the risk of central nervous system (CNS) side effects like extrapyramidal symptoms (EPS)

Cinnarizine

  • Class: Antihistamine (H1 receptor antagonist) and calcium channel blocker

  • Mechanism: Blocks histamine H1 receptors and inhibits calcium influx into vestibular sensory cells, thereby reducing motion-induced nausea and vertigo

  • Additional Effects: Mild sedative, vasodilatory properties, and efficacy in inner ear circulation improvement

Pharmacokinetics

Domperidone

  • Bioavailability: ~15% (due to first-pass metabolism)

  • Half-life: ~7-9 hours

  • Metabolism: Liver (CYP3A4)

  • Excretion: Feces and urine

Cinnarizine

  • Bioavailability: 70-85%

  • Half-life: ~4 hours

  • Metabolism: Hepatic

  • Excretion: Feces and urine

The relatively non-overlapping metabolic pathways reduce the likelihood of pharmacokinetic interference between the two drugs.

Clinical Indications

  1. Vertigo and Vestibular Disorders

    • The combination is particularly effective in treating vertigo associated with Meniere’s disease, vestibular neuritis, and labyrinthitis. Cinnarizine controls the vertigo while domperidone alleviates associated nausea and vomiting.

  2. Motion Sickness

    • The synergistic action makes the combination useful in preventing and treating motion sickness, with cinnarizine preventing the vestibular disturbance and domperidone acting as a potent antiemetic.

  3. Functional Dyspepsia and GERD

    • In patients with upper GI motility disorders, domperidone’s prokinetic properties relieve symptoms like bloating, early satiety, and nausea. Cinnarizine may help relieve accompanying dizziness or lightheadedness.

  4. Post-Operative and Chemotherapy-Induced Nausea

    • Although not first-line, the combination may be used off-label for managing post-operative or chemotherapy-induced nausea where both vestibular and gastrointestinal inputs are involved.

  5. Migraine-Associated Nausea

    • Cinnarizine’s role in migraine prophylaxis coupled with domperidone’s anti-nausea effect offers a dual-action advantage.

Fixed-Dose Formulation and Dosage

  • Common Fixed Dose: Domperidone 10 mg + Cinnarizine 20 mg

  • Route: Oral

  • Frequency: 1 tablet 2–3 times daily, preferably before meals

  • Duration: Short-term use unless under medical supervision

Benefits of the Combination

  • Complementary Mechanisms: Address both central and peripheral pathways in nausea and dizziness

  • Improved Compliance: One pill, dual relief

  • Lower Individual Doses: Reduced side effect risk compared to high-dose monotherapy

Adverse Effects

Domperidone

  • Dry mouth

  • Abdominal cramps

  • QT prolongation and arrhythmias in high-risk groups

Cinnarizine

  • Drowsiness and sedation

  • Weight gain (with prolonged use)

  • Extrapyramidal symptoms (at higher doses or prolonged use)

Combination Considerations

  • The sedative effect of cinnarizine may be potentiated when used with other CNS depressants.

  • Risk of cardiac side effects must be evaluated, especially in elderly or patients on QT-prolonging medications.

Contraindications

  • Known hypersensitivity to either component

  • Severe hepatic or renal impairment

  • Parkinson’s disease (due to dopamine antagonism)

  • Prolactinoma or existing extrapyramidal disorders

  • Cardiac arrhythmias or prolonged QT interval

Drug Interactions

  • Domperidone: Interacts with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) increasing cardiac risk

  • Cinnarizine: Additive sedation with alcohol or sedative drugs

Use in Special Populations

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

  • Lactation: Domperidone is excreted in small quantities; caution advised

  • Elderly: Increased susceptibility to cardiac and sedative side effects

  • Pediatrics: Use under strict medical supervision; not generally recommended for long-term use

Evidence from Clinical Studies

A range of clinical trials and observational studies have demonstrated the efficacy of the domperidone-cinnarizine combination:

  • A study involving patients with Meniere’s disease showed significantly better control of vertigo and nausea compared to monotherapy.

  • In motion sickness trials, the combination was more effective than cinnarizine alone, especially for individuals prone to vomiting.

  • Trials in functional dyspepsia showed improvements in symptom control and patient satisfaction scores.

Regulatory and Market Availability

  • India: Widely available over the counter or by prescription

  • Europe: Available in select countries with prescription due to concerns about domperidone’s cardiac effects

  • USA: Domperidone is not FDA-approved for general use; cinnarizine is also not available, limiting the use of this combination

Patient Counseling Points

  • Take the medication before meals for optimal effect

  • Avoid alcohol and other CNS depressants

  • Do not drive or operate machinery until the sedative effects are known

  • Report symptoms like palpitations, dizziness, or fainting

  • Use for the shortest duration necessary

Comparative Therapies

  • Domperidone + Metoclopramide: Dual prokinetics but higher risk of CNS side effects with metoclopramide

  • Cinnarizine + Dimenhydrinate: Common in motion sickness, but lacks the prokinetic benefit of domperidone

  • Ondansetron-based therapies: Powerful antiemetic but no prokinetic or vestibular benefits

Myths and Misconceptions

  • “Since it's available OTC, it's completely safe”: Misleading. Cardiac and CNS risks remain, especially with prolonged or unsupervised use

  • “Only useful for motion sickness”: False. Also indicated in vestibular disorders, GERD, dyspepsia

  • “Cannot be used in the elderly”: Can be used with caution and cardiac monitoring

Research and Future Outlook

  • New Formulations: Modified-release combinations for longer action with reduced dosing frequency

  • Pharmacogenomics: Studying individual variability in CYP3A4 and H1 receptor responses

  • Neuroprotective Effects: Investigating cinnarizine’s role in migraine prevention and vestibular rehabilitation

Conclusion

The domperidone-cinnarizine combination offers a well-balanced, dual-action approach for managing conditions where nausea, vomiting, and dizziness overlap. Its pharmacological synergy allows for effective symptom control while minimizing CNS side effects. However, like any combination therapy, its use should be carefully tailored to individual patient needs, with close attention to contraindications and potential interactions.

References

  1. EMA and WHO drug monographs on Domperidone and Cinnarizine

  2. Indian Journal of Pharmacology – Clinical studies on Domperidone + Cinnarizine

  3. Journal of Vestibular Research – Review of Antivertigo medications

  4. BNF and Martindale: The Complete Drug Reference