Domperidone

Nausea and vomiting There is some evidence that domperidone has antiemetic activity. Gastroparesis 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 (feeling full before the meal is finished), abdominal pain, and bloating. Domperidone can be used to increase the transit of food through the stomach by increasing gastrointestinal peristalsis and hence to treat gastroparesis. However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate well with relief of symptoms. Lactation Domperidone is used off-label in some countries to stimulate lactation or enhance breast milk production, but, as of December 2023, it is not approved for that purpose in any country, and is not approved for use in humans in the United States. Domperidone acts as a peripheral dopamine antagonist and is hypothesized to stimulate prolactin secretion, with a 2003 study supporting that hypothesis. A 2018 meta-analysis of five randomized controlled trials found that domperidone resulted in a moderate increase of in breast milk volume for mothers of preterm infants with insufficient milk supply. The analysis also indicated that domperidone was well tolerated with no significant difference in maternal adverse events compared to placebo. Domperidone has no officially established dosage for increasing milk supply, but most published studies have used 10 mg three times daily for 4 to 10 days (30 mg per day). The US Food and Drug Administration (FDA) has expressed concerns about serious adverse side effects and concerns about its effectiveness. A 2021 study found that postpartum usage of domperidone increased across five Canadian provinces from 2004 and 2017 with usage plateauing in 2011 and a drop in usage after a 2012 Health Canada advisory warning about domperidone. Other uses Parkinson's disease Parkinson's disease is a degenerative neurological condition where a decrease in dopamine in the brain leads to rigidity (stiffness of movement), tremor, and other symptoms and signs. Poor gastrointestinal function, nausea, and vomiting are major problems 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 also cause nausea as a side effect. Furthermore, anti-nausea drugs, such as metoclopramide, which do cross the blood–brain barrier, may worsen the extrapyramidal symptoms of Parkinson's disease. Domperidone can be used to relieve nausea and gastrointestinal symptoms in Parkinson's disease; it blocks peripheral D2 receptors but minimally crosses the blood-brain barrier in normal doses, so has no effect on the extrapyramidal symptoms of the disease. In addition, domperidone may be useful in the treatment of orthostatic hypotension caused by dopaminergic therapy in people with Parkinson's disease. Other gastrointestinal uses Domperidone may be used in functional dyspepsia in both adults and children. It has also been found effective in the treatment of reflux in children. However some specialists consider its risks prohibitory of the treatment of infantile reflux. Available forms Domperidone is available for use by oral administration in the form of tablets, orally disintegrating tablets (ODTs) and suspension, and by rectal administration in the form of suppositories. The oral tablets are available in the strength of 10mg. Domperidone has been studied for use by intramuscular injection and an intravenous formulation was previously available, but the medication is now only available in forms for oral and rectal administration. ==Veterinary uses==

Domperidone is used as immunotherapy to treat leishmania in dogs. Domperidone also has an FDA-approved formulation for the prevention of fescue toxicosis in periparturient mares. ==Contraindications==

Domperidone is contraindicated with QT-prolonging drugs like amiodarone. ==Side effects==

Side effects associated with domperidone include dry mouth, abdominal cramps, diarrhea, nausea, rash, itching, hives, and hyperprolactinemia (the symptoms of which may include breast enlargement, galactorrhea, breast pain/tenderness, gynecomastia, hypogonadism, and menstrual irregularities). Elevated prolactin levels Due to D2 receptor blockade, domperidone causes hyperprolactinemia. Hyperprolactinemia can suppress the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, in turn suppressing the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and resulting in hypogonadism and low levels of the sex hormones estradiol and testosterone. Accordingly, 10 to 15% of females have been reported to experience mammoplasia (breast enlargement), mastodynia (breast pain/tenderness), galactorrhea (inappropriate or excessive milk production/secretion), and amenorrhea (cessation of menstrual cycles) with domperidone therapy. D2 receptor antagonists like antipsychotics and domperidone may also increase the risk of prolactinomas, but more research is needed to confirm this. Rare reactions Cardiac complications Domperidone use is associated with an increased risk of sudden cardiac death (by 70%) 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 (namely CYP3A4 inhibitors). Conflicting reports exist, however. In neonates and infants, QT prolongation is controversial and uncertain. UK drug regulatory authorities (MHRA) have issued the following restriction on domperidone in 2014 due to increased risk of adverse cardiac effects: However, a 2015 Australian review concluded the following: == Interactions ==

In healthy volunteers, the CYP3A4 inhibitor 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. 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 (which encodes P-glycoprotein), the voltage-gated potassium channel KCNH2 gene (hERG/Kv11.1), and the α1D-adrenergic receptor ADRA1D gene. Effects on prolactin levels A single 20 mg oral dose of domperidone has been found to increase mean serum prolactin levels (measured 90 minutes post-administration) in non-lactating women from 8.1 ng/mL to 110.9 ng/mL (a 13.7-fold increase). This was similar to the increase in prolactin levels produced by a single 20 mg oral dose of metoclopramide (7.4 ng/mL to 124.1 ng/mL; 16.7-fold increase). 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 Absorption The absolute bioavailability of domperidone is low (13–17% or approximately 15%). Domperidone exposure increases proportionally with doses in the 10 to 20 mg dose range. Small amounts of domperidone cross the placenta in animals. CYP3A4 is the major enzyme involved in the N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 are involved in its aromatic hydroxylation. All of the metabolites of domperidone are inactive as D2 receptor ligands. Overall and peak levels of domperidone are increased by about 2.9- and 1.5-fold in moderate hepatic impairment, respectively. Elimination Domperidone is eliminated 31% in urine and 66% in feces. The proportion of domperidone excreted unchanged is small (10% in feces and 1% in urine). The elimination half-life of domperidone is about 7 to 9 hours in healthy individuals. However, the elimination half-life of domperidone can be prolonged to 20 hours in people with severe renal dysfunction. ==Chemistry==

Domperidone is a derivative of benzimidazolinone. It is structurally related to butyrophenone neuroleptics like haloperidol. ==History==

Domperidone was synthesized at Janssen Pharmaceutica in 1974 following their research on antipsychotic drugs. Janssen pharmacologists discovered that some antipsychotic drugs had a significant effect on dopamine receptors in the central chemoreceptor trigger zone that regulated vomiting, and started searching for a dopamine antagonist that would not pass the blood–brain barrier, thereby being free of the extrapyramidal side effects that were associated with drugs of this type. Domperidone was patented in the United States in 1978, with the patent filed in 1976. In 1979, domperidone was first marketed, under the brand name Motilium, in Switzerland and West Germany. Domperidone was subsequently introduced in the forms of orally disintegrating tablets (based on Zydis technology) in 1999. In April 2014, the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) published an official press release suggesting restricting the use of domperidone-containing medicines. It also approved earlier published suggestions by Pharmacovigilance Risk Assessment Committee (PRAC) to use domperidone only for treating nausea and vomiting and reduce maximum daily dosage to 10mg. ==Society and culture==

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, 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 a legally marketed human drug and it is not approved for sale there. Formulations ==Research==

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