What is domperidone?

What is Domperidone?

Domperidone is a peripheral dopamine-2 (D2) receptor antagonist that functions as both a prokinetic agent and antiemetic, primarily used to accelerate gastric emptying and control nausea/vomiting in gastrointestinal motility disorders, though it carries significant cardiac safety concerns and is only available in the United States through FDA investigational drug protocols. 1

Mechanism of Action and Pharmacology

• Domperidone blocks dopamine receptors at the chemoreceptor trigger zone and enhances motor function of the stomach and small intestine 2
• Unlike other D2 antagonists (such as metoclopramide), domperidone does not readily cross the blood-brain barrier, which theoretically reduces the risk of central nervous system side effects like extrapyramidal symptoms 1, 2
• The drug increases gastric emptying of liquids and increases lower esophageal sphincter pressure 3
• It undergoes rapid and extensive hepatic metabolism with an average terminal plasma half-life of approximately 6 hours and very low systemic bioavailability 1

Clinical Applications

Approved and Off-Label Uses

• In the United States, domperidone is only available through an FDA investigational drug application, reflecting ongoing safety concerns 4
• It is used for treatment of gastroparesis and chronic nausea/vomiting 2
• The American Gastroenterological Association includes domperidone (10-20 mg three times daily) as a medication option to accelerate gastric emptying in medically refractory gastroparesis 5
• For systemic sclerosis-related gastrointestinal manifestations, prokinetic drugs including domperidone should be considered for symptomatic motility disturbances 5

Dosing Recommendations

• The recommended starting dose is 10 mg three times daily 4
• Doses can range from 10-20 mg three to four times daily, though doses above 10 mg three times daily are not recommended due to risk of QT prolongation 5, 4

Critical Safety Concerns and Contraindications

Cardiac Risks

• Domperidone is absolutely contraindicated in patients with pre-existing QT prolongation, electrolyte abnormalities (hypokalemia, hypomagnesemia), or concurrent use of QT-prolonging medications 4, 6
• QT prolongation can lead to life-threatening cardiac arrhythmias including torsades de pointes and sudden cardiac death 7
• Case-control studies have shown that patients who died suddenly or had severe ventricular arrhythmias were statistically significantly more likely to have been exposed to domperidone 7
• Regular QTc monitoring via ECG is particularly important for long-term therapy 4, 6

Duration Limitations

• Similar to the FDA's black box warning against metoclopramide use beyond 12 weeks, duration concerns apply to domperidone given its cardiac safety profile 4
• The European Medicines Agency recommends against long-term use of prokinetic agents like domperidone due to risk of serious adverse effects 4
• For patients requiring therapy beyond 12 weeks, alternative approaches should be strongly considered, including 5-HT3 receptor antagonists (ondansetron, granisetron), NK-1 receptor antagonists (aprepitant), or other prokinetic agents like prucalopride 4

Comparative Efficacy and Clinical Context

• Medical studies demonstrate superior efficacy of domperidone when compared with placebo and other pharmaceutical therapies available 8
• In a randomized controlled trial of 148 systemic sclerosis patients with partial response to high-dose proton pump inhibitors, both domperidone and alginic acid showed similar improvement in GERD symptom severity 5
• The major advantage over metoclopramide is the lower propensity to cause extrapyramidal side effects due to minimal blood-brain barrier penetration 3, 2

Common Pitfalls to Avoid

• Do not use domperidone without first screening for cardiac risk factors, particularly QT prolongation and electrolyte abnormalities 6
• Avoid escalation to 20 mg four times daily (80 mg/day total) for cardiovascular safety considerations 4
• Do not prescribe for long-term use without considering safer alternatives after 12 weeks 4
• Remember that in diabetic patients with gastroparesis, cardiac risks must be carefully weighed against benefits 6