- Molecular FormulaC22H24ClN5O2
- Average mass425.911 Da
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 (by increasing gastrointestinal peristalsis); and to promote lactation (breast milk production) by release of prolactin.
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Prepn: J. Vandenberk et al., DE 2632870; eidem, US 4066772 (1977, 1978 both to Janssen).
Ruben Vardanyan, in Piperidine-Based Drug Discovery, 2017
Domperidone (7.1.6) (Motilium), a peripherally selective D2-like receptor antagonist, regulates the motility of the gastric and small intestinal smooth muscles and has been shown to have some effects on the motor function of the esophagus. It effectively prevents bile reflux but does not affect gastric secretion. As a result of the blockade of dopamine receptors in the chemoreceptor trigger zone it also has an antiemetic activity. Domperiodone provided relief of such symptoms as anorexia, nausea, vomiting, abdominal pain, early satiety, bloating, and distension in patients with symptoms of diabetic gastropathy. It also provided short-term relief of symptoms in patients with dyspepsia or gastroesophageal reflux, prevented nausea and vomiting associated with emetogenic chemotherapy, and prevented the gastrointestinal and emetic adverse effects of antiparkinsonian drugs. Because domperidone does not readily cross the blood brain barrier and does not inhibit dopamine receptors in the brain, reports of adverse effects on the CNS, such as dystonic reactions, are rare [52–61]. Domperidone is widely used in many countries and can now be officially prescribed to patients in the United States. There are very few treatment options currently available for patients with gastrointestinal motility disorders, especially for patients with gastroparesis. Domperidone has been successfully used in the United States and in many countries as a second-line treatment option for the treatment of gastroparesis.
Synthesis of domperidone (7.1.6) started with arylation of ethyl 4-aminopiperidine-1-carboxylate (7.1.28) with 1,4-dichloro-2-nitrobenzene (7.1.29) on heating at 150°C in cyclohexanol in the presence of sodium carbonate and potassium iodide (in a later disclosure in toluene in presence of sodium carbonate ) to give compound (7.1.30), which on reflux in 48% hydrobromic acid solution yielded N-(4-chloro-2-nitrophenyl)piperidin-4-amine (7.1.31). The obtained product was alkylated with 1-(3-chloropropyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (7.1.32) on reflux in MBIK in the presence of sodium carbonate and potassium iodide to give compound (7.1.33). The ring closure could be effected by heating o-phenylene diamine (7.1.33) with an appropriate cyclizing agent, such as phosgene, urea, potassium isocyanate , and the like. In this patent potassium isocyanate dissolved in water was carefully added to a solution of compound (7.1.34) in 10 N hydrochloric acid solution (exothermic reaction) to give desired domperidone (7.1.6) [64,65] (Scheme 7.4).
Nausea and vomiting
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.
However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate (equate) well with relief of symptoms.
Parkinson’s disease is a chronic 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 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 (the barrier between the blood circulation of the brain and the rest of the body) so has no effect on the extrapyramidal symptoms of the disease.
The hormone prolactin stimulates lactation (production of breast milk). 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 (that is, it is a galactogogue). 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 (Group A) or placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days (Group B). 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 (Group A) achieved a 50% increase in milk volume, while 58% of mothers receiving placebo (Group B) 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 stage of pregnancy, including domperidone.
Reflux in children
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). 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 (GnRH) from the hypothalamus, in turn suppressing the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and resulting in hypogonadism (low sex hormone (e.g., testosterone, estradiol) levels). 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 (breast enlargement), mastodynia (breast pain/tenderness), galactorrhea (inappropriate or excessive milk production/secretion), and amenorrhea (cessation of menstrual cycles) with domperidone treatment. Gynecomastia has been reported in males treated with domperidone, and galactorrhea could occur in males as well.
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:
Domperidone (Motilium) is associated with a small increased risk of serious cardiac side effects. Its use is now restricted to the relief of nausea and vomiting and the dosage and duration of use have been reduced. It should no longer be used for the treatment of bloating and heartburn. Domperidone is now contraindicated in those with underlying cardiac conditions and other risk factors. Patients with these conditions and patients receiving long-term treatment with domperidone should be reassessed at a routine appointment, in light of the new advice.
However, a 2015 Australian review concluded the following:
Based on the results of the two TQT (the regulatory agency gold standard for assessment of QT prolongation) domperidone does not appear to be strongly associated with QT prolongation at oral doses of 20 mg QID in healthy volunteers. Further, there are limited case reports supporting an association with cardiac dysfunction, and the frequently cited case-control studies have significant flaws. While there remains an ill-defined risk at higher systemic concentrations, especially in patients with a higher baseline risk of QT prolongation, our review does not support the view that domperidone presents intolerable risk.
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.
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.
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 (which encodes P-glycoprotein), the voltage-gated potassium channel KCNH2 gene (hERG/Kv11.1), 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 (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). After two weeks of chronic administration (30 mg/day in both cases), the increase in prolactin levels produced by domperidone was reduced (53.2 ng/mL; 6.6-fold above baseline), but the increase in prolactin levels produced by metoclopramide, conversely, was heightened (179.6 ng/mL; 24.3-fold above baseline). 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.
With oral administration, domperidone is extensively metabolized in the liver (almost exclusively by CYP3A4/5, though minor contributions by CYP1A2, CYP2D6, and CYP2C8 have also been reported) and in the intestines. Due to the marked first-pass effect via this route, the oral bioavailability of domperidone is low (13–17%); conversely, its bioavailability is high via intramuscular injection (90%). 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 (ABCB1) transporter, and animal studies suggest that this is the reason for the low central nervous system penetration of domperidone.
- 1974 – Domperidone synthesized at Janssen Pharmaceutica following the research on antipsychotic drugs. Janssen pharmacologists discovered that some of 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. This led to the discovery of domperidone as a strong anti-emetic with minimal central effects.
- 1978 – On 3 January 1978 Domperidone was patented in the United States under patent US4066772 A. The application has been filed on 17 May 1976. Jan Vandenberk, Ludo E. J. Kennis, Marcel J. M. C. Van der Aa and others has been cited as the inventors.
- 1979 – Domperidone marketed under trade name “Motilium” in Switzerland and (Western) Germany.
- 1999 – Domperidone was introduced in the forms of orally disintegrating tablets (based on Zydis technology).
- Janssen Pharmaceutical has brought domperidone before the United States Federal Drug Administration (FDA) several times, including in the 1990s.
- 2014 – In April 2014 Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) published official press-release suggesting to restrict the use of domperidone-containing medicines. It also approved earlier published suggestions by Pharmacovigilance Risk Assessment Committee (PRAC) to use domperidone only for curing nausea and vomiting and reduce maximum daily dosage to 10 mg.
Society and culture
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.
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.
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Domperidone, a benzimidazole derivative, is structurally related to the butyrophenone tranquilizers (eg, haloperidol (Haldol, Halperon]).
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|Trade names||Motilium, many others|
|AHFS/Drugs.com||Micromedex Detailed Consumer Information|
|By mouth, intramuscular, intravenous (d/c’d), rectal|
|Drug class||D2 receptor antagonist; Prolactin releaser|
|Metabolism||Hepatic (CYP3A4/5) and intestinal (first-pass)|
|Elimination half-life||7.5 hours|
Breast milk: small quantities
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||425.92 g·mol−1|
|3D model (JSmol)|
|Melting point||242.5 °C (468.5 °F)|
//////////////DOMPERIDONE, Antiemetic, Dopamine Receptor Antagonist, домперидон , دومبيريدون , 多潘立酮