Domperidone


Domperidone, sold under the brand name Motilium among others, is a medication used as an antiemetic, gastric prokinetic agent, and galactagogue. It may be taken by mouth or rectally, and is available as a tablet, orally disintegrating tablets, suspension, and suppositories. The drug is used to relieve nausea and vomiting; to increase the transit of food through the stomach ; and to promote lactation by release of prolactin.
It is a peripherally selective dopamine D2 receptor antagonist and was developed by Janssen Pharmaceutica.

Medical uses

Nausea and vomiting

There is some evidence that domperidone has antiemetic activity. It is recommended by the Canadian Headache Society for treatment of nausea associated with acute migraine.

Gastroparesis

is a medical condition characterised by delayed emptying of the stomach when there is no mechanical gastric outlet obstruction. Its cause is most commonly idiopathic, a diabetic complication or a result of abdominal surgery. The condition causes nausea, vomiting, fullness after eating, early satiety, abdominal pain and bloating.
Domperidone may be useful in diabetic and idiopathic gastroparesis.
However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate well with relief of symptoms.

Parkinson's disease

is a chronic neurological condition where a decrease in dopamine in the brain leads to rigidity, tremor and other symptoms and signs. Poor gastrointestinal function, nausea and vomiting is a major problem for people with Parkinson's disease because most medications used to treat Parkinson's disease are given by mouth. These medications, such as levodopa, can cause nausea as a side effect. Furthermore, anti-nausea drugs, such as metoclopramide, which do cross the blood–brain barrier may worsen the extra-pyramidal symptoms of Parkinson's disease.
Domperidone can be used to relieve gastrointestinal symptoms in Parkinson's disease; it blocks peripheral D2 receptors but does not cross the blood–brain barrier in normal doses so has no effect on the extrapyramidal symptoms of the disease.

Functional dyspepsia

Domperidone may be used in functional dyspepsia in both adults and children.

Lactation

The hormone prolactin stimulates lactation. Dopamine, released by the hypothalamus stops the release of prolactin from the pituitary gland. Domperidone, by acting as an anti-dopaminergic agent, results in increased prolactin secretion, and thus promotes lactation. Domperidone moderately increases the volume of expressed breast milk in mothers of preterm babies where breast milk expression was inadequate, and appears to be safe for short-term use for this purpose. In the United States, domperidone is not approved for this or any other use.
A study called the EMPOWER trial was designed to assess the effectiveness and safety of domperidone in assisting mothers of preterm babies to supply breast milk for their infants. The study randomized 90 mothers of preterm babies to receive either domperidone 10 mg orally three times daily for 28 days or placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. Mean milk volumes at the beginning of the intervention were similar between the 2 groups. After the first 14 days, 78% of mothers receiving domperidone achieved a 50% increase in milk volume, while 58% of mothers receiving placebo achieved a 50% increase in milk volume.
To induce lactation, domperidone is used at a dosage of 10 to 20 mg 3 or 4 times per day by mouth. Effects may be seen within 24 hours or may not be seen for 3 or 4 days. The maximum effect occurs after 2 or 3 weeks of treatment, and the treatment period generally lasts for 3 to 8 weeks. A 2012 review shows that no studies support prophylactic use of a galactagogue medication at any gestation including domperidone.

Reflux in children

Domperidone has been found effective in the treatment of reflux in children. However some specialists consider its risks prohibitory of the treatment of infantile reflux.

Contraindications

Side effects associated with domperidone include dry mouth, abdominal cramps, diarrhea, nausea, rash, itching, hives, and hyperprolactinemia. Due to blockade of D2 receptors in the central nervous system, D2 receptor antagonists like metoclopramide can also produce a variety of additional side effects including drowsiness, akathisia, restlessness, insomnia, lassitude, fatigue, extrapyramidal symptoms, dystonia, Parkinsonian symptoms, tardive dyskinesia, and depression. However, this is not the case with domperidone, because, unlike other D2 receptor antagonists, it minimally crosses the blood-brain-barrier, and for this reason, is rarely associated with such side effects.

Excess prolactin levels

Due to D2 receptor blockade, domperidone causes hyperprolactinemia. Hyperprolactinemia can suppress the secretion of gonadotropin-releasing hormone from the hypothalamus, in turn suppressing the secretion of follicle-stimulating hormone and luteinizing hormone and resulting in hypogonadism. As such, male patients may experience low libido, erectile dysfunction, and impaired spermatogenesis. Also in accordance with hyperprolactinemia, 10–15% of female patients have been reported to experience mammoplasia, mastodynia, galactorrhea, and amenorrhea with domperidone treatment. Gynecomastia has been reported in males treated with domperidone, and galactorrhea could occur in males as well.

Rare reactions

Cardiac reactions

Domperidone use is associated with an increased risk of sudden cardiac death most likely through its prolonging effect of the cardiac QT interval and ventricular arrhythmias. The cause is thought to be blockade of hERG voltage-gated potassium channels. The risks are dose-dependent, and appear to be greatest with high/very high doses via intravenous administration and in the elderly, as well as with drugs that interact with domperidone and increase its circulating concentrations. Conflicting reports exist, however. In neonates and infants, QT prolongation is controversial and uncertain.
UK drug regulatory authorities the following restriction on domperidone in 2014 due to increased risk of adverse cardiac effects:
However, a 2015 Australian review concluded the following:

Possible central toxicity in infants

In Britain a legal case involved the death of two children of a mother whose three children had all had hypernatraemia. She was charged with poisoning the children with salt. One of the children, who was born at 28 weeks gestation with respiratory complications and had a fundoplication for gastroesophageal reflux and failure to thrive was prescribed domperidone. An advocate for the mother suggested the child may have suffered neuroleptic malignant syndrome as a side effect of domperidone due to the drug crossing the child's immature blood-brain-barrier.

Interactions

In healthy volunteers, ketoconazole increased the Cmax and AUC concentrations of domperidone by 3- to 10-fold. This was accompanied by a QT interval prolongation of about 10–20 milliseconds when domperidone 10 mg four times daily and ketoconazole 200 mg twice daily were administered, whereas domperidone by itself at the dosage assessed produced no such effect. As such, domperidone with ketoconazole or other CYP3A4 inhibitors is a potentially dangerous combination.

Pharmacology

Pharmacodynamics

Domperidone is a peripherally selective dopamine D2 and D3 receptor antagonist. It has no clinically significant interaction with the D1 receptor, unlike metoclopramide. The medication provides relief from nausea by blocking D receptors. It blocks dopamine receptors in the anterior pituitary gland increasing release of prolactin which in turn increases lactation. Domperidone may be more useful in some patients and cause harm in others by way of the genetics of the person, such as polymorphisms in the drug transporter gene ABCB1, the voltage-gated potassium channel KCNH2 gene, and the α1D—adrenoceptor ADRA1D gene.

Effects on prolactin levels

A single 20 mg oral dose of domperidone has been found to increase mean serum prolactin levels in non-lactating women from 8.1 ng/mL to 110.9 ng/mL. This was similar to the increase in prolactin levels produced by a single 20 mg oral dose of metoclopramide. After two weeks of chronic administration, the increase in prolactin levels produced by domperidone was reduced, but the increase in prolactin levels produced by metoclopramide, conversely, was heightened. This indicates that acute and chronic administration of both domperidone and metoclopramide is effective in increasing prolactin levels, but that there are differential effects on the secretion of prolactin with chronic treatment. The mechanism of the difference is unknown. The increase in prolactin levels observed with the two drugs was, as expected, much greater in women than in men. This appears to be due to the higher estrogen levels in women, as estrogen stimulates prolactin secretion.
For comparison, normal prolactin levels in women are less than 20 ng/mL, prolactin levels peak at 100 to 300 ng/mL at parturition in pregnant women, and in lactating women, prolactin levels have been found to be 90 ng/mL at 10 days postpartum and 44 ng/mL at 180 days postpartum.

Pharmacokinetics

With oral administration, domperidone is extensively metabolized in the liver and in the intestines. Due to the marked first-pass effect via this route, the oral bioavailability of domperidone is low ; conversely, its bioavailability is high via intramuscular injection. The terminal half-life of domperidone is 7.5 hours in healthy individuals, but can be prolonged to 20 hours in people with severe renal dysfunction. All of the metabolites of domperidone are inactive as D2 receptor ligands. The drug is a substrate for the P-glycoprotein transporter, and animal studies suggest that this is the reason for the low central nervous system penetration of domperidone.

Chemistry

Domperidone is a benzimidazole derivative and is structurally related to butyrophenone neuroleptics like haloperidol.

History

Generic names

Domperidone is the generic name of the drug and its,,, and.

Regulatory approval

It was reported in 2007 that domperidone is available in 58 countries, including Canada, but the uses or indications of domperidone vary between nations. In Italy it is used in the treatment of gastroesophageal reflux disease and in Canada, the drug is indicated in upper gastrointestinal motility disorders and to prevent gastrointestinal symptoms associated with the use of dopamine agonist antiparkinsonian agents. In the United Kingdom, domperidone is only indicated for the treatment of nausea and vomiting and the treatment duration is usually limited to 1 week.
In the United States, domperidone is not currently a legally marketed human drug and it is not approved for sale in the U.S. On 7 June 2004, FDA issued a public warning that distributing any domperidone-containing products is illegal.
It is available over-the-counter to treat gastroesophageal reflux and functional dyspepsia in many countries, such as Ireland, the Netherlands, Italy, South Africa, Mexico, Chile, and China.
Domperidone is not generally approved for use in the United States. There is an exception for use in people with treatment-refractory gastrointestinal symptoms under an FDA Investigational New Drug application.

Formulations

Research

Domperidone has been studied as a potential hormonal contraceptive to prevent pregnancy in women.