Domperidone

In children with chronic vomiting or regurgitation, domperidone resulted in either resolution or marked improvement of symptoms. [Postgrad Med J 1979;55(Suppl 1):40-2]. It has also been used to prevent pediatric nausea and vomiting induced by cytotoxic drugs. Current evidence, however, does not support domperidone as a first-line antiemetic in children. Children with symptomatic reflux disease with upper GI motility abnormalities may benefit from domperidone [J Pediatr 1985;106(2):311-6].

Domperidone does not interact with renal or peripheral dopamine D₁ receptors and has no appreciable effect on plasma renin or aldosterone levels.

Domperidone is metabolized primarily by the liver (see Dosage and Administration, Hepatic Impairment).

See Contraindications.

Domperidone does not readily cross the blood-brain barrier, therefore, CNS effects occur rarely. Extrapyramidal symptoms are more likely to occur in infants and in patients given more than the maximum recommended dosage.

Patients may exhibit elevated serum prolactin levels. Elevations of serum AST, ALT and cholesterol have also been noted (<1%).

Caution is advised when administering domperidone to patients with a history of breast cancer, as certain breast cancers are thought to be prolactin-dependant. Serum prolactin levels increase during chronic administration of domperidone and return to baseline after discontinuation. Gynecomastia with long term domperidone use has been reported in men. Galactorrhea and breast tenderness have been reported in women. Galactorrhea usually occurs within the first 14 days of therapy but can take as long as 3 months to appear. Upon discontinuation, galactorrhea usually resolves within a week but may resolve gradually over a period of 2 months.

Although still rare, a higher incidence of CNS adverse effects has been noted in infants, possibly because of the incompletely developed blood-brain barrier of very young children. QT interval prolongation occurred in a 4-month-old infant treated with domperidone 0.6 mg/kg three times daily and resolved upon discontinuation of the drug. Hyperprolactinemia, galactorrhea, breast enlargement and neuroleptic syndrome occurred in a 3-month-old infant on maintenance hemodialysis who was treated with domperidone 0.25 mg/kg tid. The symptoms resolved and prolactin levels decreased after withdrawal of domperidone. Significant association between oral domperidone therapy (mean daily dose 1.3±0.7 mg/kg daily) and QT interval prolongation in neonates and infants has been demonstrated [J Pediatr 2008;153(5):663-6]. In this study, advanced gestational age and serum potassium at the upper limit of normal, were significantly and independently associated with significant QT interval prolongation.

Pregnancy Category C. Conclusive evidence is not available as to whether domperidone is safe to use in pregnancy. A small percentage of the maternal dose crosses the placenta in animals though this is not known for humans. Given the low molecular weight, availability of unbound drug and prolonged elimination half-life, theoretically, domperidone may cross the placenta. It is not known what risk, if any, this poses for the fetus.

Domperidone appears in the breast milk where the concentration is approximately 25% of the maternal serum concentration. The drug has been used to increase daily milk production in women who are nursing and have insufficient milk production. The American Academy of Pediatrics considers domperidone to be compatible with breastfeeding.

QT interval prolongation and ventricular tachyarrhythmias have occurred after administration of high doses of domperidone by the intravenous route. QT interval prolongation has also been documented in adults receiving the combination of orally administered domperidone and ketoconazole, therefore, avoid the combination.

In adults, hypokalemia has been associated as a risk factor for QT interval prolongation. A baseline electrocardiogram and serum potassium measurement may be useful prior to initiation of domperidone.

Domperidone is rapidly and extensively distributed into tissues with an apparent volume of distribution of 5.7 L/kg. Domperidone has a high affinity for GI tissue and a high concentration of the drug is found in the esophagus, stomach and small intestine. Plasma protein binding is approximately 92%. Domperidone does not readily cross the blood-brain barrier.

Domperidone is rapidly absorbed when administered orally under fasting conditions. The peak serum concentration occurs approximately 30 minutes after oral ingestion under fasting conditions. Oral bioavailability is low (13 to 17%) due to a high degree of both hepatic first-pass and gut wall metabolism. Bioavailability increases significantly when the drug is administered after a meal, although the time to achieve peak serum concentrations is increased. Patients taking the drug for dysmotility should take it 15 to 30 minutes before eating.

Domperidone is a peripheral dopamine antagonist that selectively blocks the effect of dopamine at D₂ receptors in myenteric motor neurons and the chemoreceptor trigger zone (CTZ). Through this action it stimulates peristalsis and helps coordinate antral and duodenal contractions, improving gastric motility. The antiemetic effects of domperidone are largely due to blockade of dopamine receptors in the CTZ, although there is indirect evidence to suggest that some of the antiemetic effect stems from its prokinetic properties. Domperidone does not readily cross the blood-brain barrier and has no appreciable effect on dopamine receptors in the brain. Domperidone does not have significant effects at renal or peripheral D₁ receptors.

In patients with symptoms of upper gastrointestinal tract dysmotility such as those resulting from gastroparesis, for example, domperidone has been shown to significantly improve gastric emptying rates. Domperidone normalizes gastric slow-wave activity that can contribute to symptoms of nausea in patients with upper gastrointestinal motility disorders. It helps synchronize peristaltic contractions, thus improving the movement of both solids and liquids through the stomach and duodenum. Domperidone has no effect on esophageal or colonic motility. Domperidone stimulates release of prolactin from the pituitary gland. In in vitro and ex vivo experiments conducted with clinically relevant concentrations of the drug, domperidone exhibited cardiac electrophysiologic effects similar to those of cisapride and class III antiarrhythmic drugs.

A small amount of domperidone (<1%) is excreted unchanged in urine and approximately 6% in the feces. The elimination half-life after oral administration is 7.5 hours in healthy subjects.

Domperidone is subject to extensive first-pass metabolism both in the gut wall and liver. Domperidone is metabolized to several inactive metabolites by CYP3A4-mediated hydroxylation and oxidative N-dealkylation.