|Systematic (IUPAC) name|
|Routes||Oral, intravenous, rectal|
|Metabolism||Hepatic and intestinal (first-pass)|
|Excretion||Breast milk, renal|
|ATC code||A03 QP51|
|Molecular mass||425.911 g/mol|
|(what is this?)|
Domperidone (trade names Motilium, Motillium, Motinorm Costi, Nomit and Molax) is a medication developed by Janssen Pharmaceutica that is a peripheral, specific blocker of dopamine receptors. It is administered orally, rectally, or intravenously. Domperidone is given in order to relieve nausea and vomiting; to increase the transit of food through the stomach (as a prokinetic agent through increase in gastrointestinal peristalsis); and to increase lactation (breast milk production) by release of prolactin. It is also used in the scientific study of the way dopamine (an important neurotransmitter) acts in the body.
- 1 Mechanism of Action
- 2 Uses
- 3 Adverse effects
- 4 Interactions
- 5 Contraindications
- 6 History
- 7 Brand names and formulations by nation
- 8 See also
- 9 References
- 10 External links
Mechanism of Action
Domperidone is a peripheral dopamine (D2) and (D3) receptor antagonist. It provides relief from nausea by blocking receptors at the chemo-receptor trigger zone (a location in the nervous system that registers nausea) at the floor of the fourth ventricle (a location near the brain). It increases motility in the upper gastrointestinal tract to a moderate degree and increases lower esophageal sphincter pressure by blocking dopamine receptors in the gastric antrum and the duodenum. It blocks dopamine receptors in the posterior 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 genetic characteristic of the person, such as polymorphisms in the drug transporter gene ABCB1, the potassium channel KCNH2 gene, and α1D—adrenoceptor ADRA1D gene.
The uses or indications of domperidone vary between nations. For instance, 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 States domperidone's use is not approved, though patients with various gastrointestinal conditions may qualify for access through the Expanded Access to Investigational Drugs program.
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, because, even though it blocks dopamine receptors (which would be expected to worsen Parkinson's disease), it does not cross the blood brain barrier (the barrier between the blood circulation of the brain and the rest of the body). In addition to this, domperidone may enhance the bioavailability (effect) of levodopa (one of the main treatments in Parkinson's disease.)
Although these features make domperidone a useful drug in Parkinson's disease, caution is needed due to the cardiotoxic side effects of domperidone when given intravenously, in elderly people and in high doses (> 30 mg per day). A clinical sign of domperidone's potential toxicity to the heart is the prolongation (lengthening) of the QT interval (a segment of the heart's electrical pattern).
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). In some nations, including Australia, domperidone is used off label, based on uncertain and anecdotal evidence of its usefulness, as a therapy for mothers who are having difficulty breastfeeding. In the United States, domperidone is not approved for this or any other use. A study called the EMPOWER trial has been designed to assess the effectiveness and safety of domperidone in assisting mothers of preterm babies to supply breast milk for their infants.
Domperidone use (for premature infants and infants less than four weeks old.) is associated with an increased risk of sudden cardiac death most likely through its prolonging effect of the cardiac QT interval and ventricular arrhythmias.
Penetration of immature blood brain barrier
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.
UK drug regulatory authorities (MHRA) have issued the following restriction on Domperidone 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"
Erythromycin and other macrolide antibiotics inhibit the metabolism of domperidone (in-vitro) thus increasing the concentration of domperidone and potential side effects of the drug. This is of concern as both drugs may be used to treat gastroparesis.
- Prolactin secreting pituitary tumor.
- Triazole antifungal medications such as ketoconazole, itraconazole, fluconazole.
- Macrolide antibiotics such as erythromycin and clarithromycin.
- Potent CYP3A4 inhibitors.
- Mechanical bowel disorders such as bowel obstruction, gastrointestinal haemorrhage or bowel perforation
- Moderate hepatic impairment (liver disease).
Those taking QT-prolonging medicines or CYP3A4 inhibitors at the same time as 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 January 3, 1978 Domperidone was patented in the USA under patent US4066772 A. The application has been filed on May 17, 1976. Jan Vandenberk, Ludo E. J. Kennis, Marcel J. M. C. Van der Aa and others has been cited as the inventors.
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.
Brand names and formulations by nation
|Australia||Janssen–Cilag||Motilium||10 mg scored tablets|
|Belgium and the Netherlands||-||Motilium||From 2013 only by prescription in Belgium.|
|Canada||-||Motilium (1985–2002)||Generic brands available|
|India||Salius Pharma||Escacid DXR||pantoprazole 40 mg and domperidone SR 30 mg|
|India||Medley pharmaceuticals||Dompan||pantoprazole 40 mg and domperidone 10 mg|
|India||Rhubarb pharmaceuticals||-||domperidone 5, 10 and 20 mg tablets.|
|India||Ipca Laboratories, Mumbai||Domperi suspension||domperidone 1 mg/ml, 30 ml suspension.|
|India||Torrent pharmaceuticals||Domstal||- |
|India||Ozone pharmaceuticals and chemicals||Pantazone-D||10 mg domperidone and 40 mg pantoprazole|
|India||Chimak Health Care||Pancert D||10 mg Domperidone and 40 mg pantoprazole|
|Iran||Abidi Pharmaceutical Co.||MOTiDON||10 mg tablet|
|Ireland||McNeil Healthcare||Motilium||10 mg orally disintegrating tablet (ODT)|
|Pakistan||Johnson & Johnson Pakistan||Motilium-v||domperidone 10 mg tablets; 30 ml suspension|
|Philippines||Health Saver Pharma||Abdopen||-|
|Philippines||United Laboratories, Inc.||GI Norm||-|
|Portugal||Medinfar||Cinet||domperidone 1 mg/ml oral suspension (200 ml)|
|Russia||Janssen Pharmaceutica||Motilium||domperidone 10 mg film-coated tablets & ODT; 1 mg/ml suspension (100 ml)|
|-||OBL Pharm||Passagix||domperidone 10 mg film-coated tablets & chewable tablets|
|-||Dr. Reddy's Laboratories||Omez D||domperidone/omeprazole (10 mg/10 mg)|
|Sweden||Ebb medical||Domperidon Ebb (2013)||domperidone 10 mg ODT and peppermint|
- "Domperidone". Retrieved 2013-06-30.
- "MOTILIUM INSTANTS PL 13249/0028". Medicines and Healthcare Products Regulatory Agency. 2010-02-23. Archived from the original on 2014-10-31. Retrieved 2014-10-31.
- "CMDh confirms recommendations on restricting use of domperidone-containing medicines: European Commission to take final legal decision". European Medicines Agency. 2014-04-25. Archived from the original on 2014-10-31. Retrieved 2014-10-31.
- Bron B, Massih L (1980). "Domperidone: A drug with powerful action on the lower esophageal sphincter pressure". Digestion 20 (6): 375–8. PMID 7409348.
- Saeb-Parsy K. "Instant pharmacology." John Wiley & Sons, 1999 ISBN 0471976393, 9780471976394 p216.
- Sakamoto Y, Kato S, Sekino Y, Sakai E, Uchiyama T, Iida H et al. (2011). "Effects of domperidone on gastric emptying: a crossover study using a continuous real-time 13C breath test (BreathID system)". Hepato-gastroenterology 58 (106): 637–41. PMID 21661445.
- Parkman HP, Jacobs MR, Mishra A, Hurdle JA, Sachdeva P, Gaughan JP et al. (January 2011). "Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects". Digestive Diseases and Sciences 56 (1): 115–24. doi:10.1007/s10620-010-1472-2. PMID 21063774.
- "Domperidone - heart rate and rhythm disorders." Canadian adverse reactions newsletter. Government of Canada. January 2007 17(1)
- "Investigational New Drug Application > Domperidone" http://www.fda.gov. 2014-01-09. Retrieved 2014-06-08.
- Swann IL, Thompson EN, Qureshi K (November 1979). "Domperidone or metoclopramide in preventing chemotherapeutically induced nausea and vomiting". British Medical Journal 2 (6199): 1188. doi:10.1136/bmj.2.6199.1188 (inactive 2015-01-12). PMC 1597274. PMID 519355.
- Worthington I, Pringsheim T, Gawel MJ, Gladstone J, Cooper P, Dilli E et al. (September 2013). "Canadian Headache Society Guideline: acute drug therapy for migraine headache". The Canadian Journal of Neurological Sciences 40 (5 Suppl 3): S1–S80. PMID 23968886.
- Stevens JE, Jones KL, Rayner CK, Horowitz M (June 2013). "Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives". Expert Opinion on Pharmacotherapy 14 (9): 1171–86. doi:10.1517/14656566.2013.795948. PMID 23663133.
- Silvers D, Kipnes M, Broadstone V, Patterson D, Quigley EM, McCallum R et al. (1998). "Domperidone in the management of symptoms of diabetic gastroparesis: efficacy, tolerability, and quality-of-life outcomes in a multicenter controlled trial. DOM-USA-5 Study Group". Clinical Therapeutics 20 (3): 438–53. doi:10.1016/S0149-2918(98)80054-4. PMID 9663360.
- Janssen P, Harris MS, Jones M, Masaoka T, Farré R, Törnblom H et al. (September 2013). "The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis". The American Journal of Gastroenterology 108 (9): 1382–91. doi:10.1038/ajg.2013.118. PMID 24005344.
- Shindler JS, Finnerty GT, Towlson K, Dolan AL, Davies CL, Parkes JD (December 1984). "Domperidone and levodopa in Parkinson's disease". British Journal of Clinical Pharmacology 18 (6): 959–62. doi:10.1111/j.1365-2125.1984.tb02571.x. PMC 1463696. PMID 6529536.
- Nishikawa N, Nagai M, Tsujii T, Iwaki H, Yabe H, Nomoto M (2012). "Coadministration of domperidone increases plasma levodopa concentration in patients with Parkinson disease". Clinical Neuropharmacology 35 (4): 182–4. doi:10.1097/WNF.0b013e3182575cdb. PMID 22751085.
- Lertxundi U, Domingo-Echaburu S, Soraluce A, García M, Ruiz-Osante B, Aguirre C (February 2013). "Domperidone in Parkinson's disease: a perilous arrhythmogenic or the gold standard?". Current Drug Safety 8 (1): 63–8. doi:10.2174/1574886311308010009. PMID 23656449.
- Malek NM, Grosset KA, Stewart D, Macphee GJ, Grosset DG (June 2013). "Prescription of drugs with potential adverse effects on cardiac conduction in Parkinson's disease". Parkinsonism & Related Disorders 19 (6): 586–9. doi:10.1016/j.parkreldis.2013.02.004. PMID 23522959.
- Xiao M, Qiu X, Yue D, Cai Y, Mo Q (2013). "Influence of hippophae rhamnoides on two appetite factors, gastric emptying and metabolic parameters, in children with functional dyspepsia". Hellenic Journal of Nuclear Medicine 16 (1): 38–43. doi:10.1967/s002449910070 (inactive 2015-01-12). PMID 23529392.
- Huang X, Lv B, Zhang S, Fan YH, Meng LN (December 2012). "Itopride therapy for functional dyspepsia: a meta-analysis". World Journal of Gastroenterology 18 (48): 7371–7. doi:10.3748/wjg.v18.i48.7371. PMC 3544044. PMID 23326147.
- Grzeskowiak LE, Lim SW, Thomas AE, Ritchie U, Gordon AL (February 2013). "Audit of domperidone use as a galactogogue at an Australian tertiary teaching hospital". Journal of Human Lactation 29 (1): 32–7. doi:10.1177/0890334412459804. PMID 23015150.
- Donovan TJ, Buchanan K (2012). "Medications for increasing milk supply in mothers expressing breastmilk for their preterm hospitalised infants". The Cochrane Database of Systematic Reviews 3: CD005544. doi:10.1002/14651858.CD005544.pub2. PMID 22419310.
- da Silva OP, Knoppert DC (September 2004). "Domperidone for lactating women". CMAJ 171 (7): 725–6. doi:10.1503/cmaj.1041054. PMC 517853. PMID 15451832.
- "FDA warns against women using unapproved drug, domperidone to increase milk production." U.S. Food and Drug Administration 7 June 2004.
- Asztalos EV, Campbell-Yeo M, daSilva OP, Kiss A, Knoppert DC, Ito S (2012). "Enhancing breast milk production with Domperidone in mothers of preterm neonates (EMPOWER trial)". BMC Pregnancy and Childbirth 12: 87. doi:10.1186/1471-2393-12-87. PMC 3532128. PMID 22935052.
- Kapoor, A.K.; Raju, S.M. (2013). "7.2 Gastrointestinal Drugs". Illustrated Medical Pharmacology. JP Medical Ltd. p. 677. ISBN 9350906554. Retrieved 2014-10-31. (Google Books)
- Rebecca Smith (2014-08-01). "Fear that reflux treatment for babies will be denied under new Nice guidance". The Daily Telegraph. Archived from the original on 2014-10-31. Retrieved 2014-10-31.
- van Noord C, Dieleman JP, van Herpen G, Verhamme K, Sturkenboom MC (November 2010). "Domperidone and ventricular arrhythmia or sudden cardiac death: a population-based case-control study in the Netherlands". Drug Safety 33 (11): 1003–14. doi:10.2165/11536840-000000000-00000. PMID 20925438.
- Johannes CB, Varas-Lorenzo C, McQuay LJ, Midkiff KD, Fife D (September 2010). "Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: a nested case-control study". Pharmacoepidemiology and Drug Safety 19 (9): 881–8. doi:10.1002/pds.2016 (inactive 2015-01-12). PMID 20652862.
- Djeddi D, Kongolo G, Lefaix C, Mounard J, Léké A (November 2008). "Effect of domperidone on QT interval in neonates". The Journal of Pediatrics 153 (5): 663–6. doi:10.1016/j.jpeds.2008.05.013. PMID 18589449.
- Günlemez A, Babaoğlu A, Arisoy AE, Türker G, Gökalp AS (January 2010). "Effect of domperidone on the QTc interval in premature infants". Journal of Perinatology 30 (1): 50–3. doi:10.1038/jp.2009.96 (inactive 2015-01-12). PMC 2834362. PMID 19626027.
- Coulthard MG, Haycock GB (January 2003). "Distinguishing between salt poisoning and hypernatraemic dehydration in children". BMJ (Clinical Research Ed.) 326 (7381): 157–60. doi:10.1136/bmj.326.7381.157. PMC 1128889. PMID 12531853.
- Yoshizato T, Kotegawa T, Imai H, Tsutsumi K, Imanaga J, Ohyama T et al. (September 2012). "Itraconazole and domperidone: a placebo-controlled drug interaction study". European Journal of Clinical Pharmacology 68 (9): 1287–94. doi:10.1007/s00228-012-1258-x. PMID 22418831.
- Boyce MJ, Baisley KJ, Warrington SJ (March 2012). "Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study". British Journal of Clinical Pharmacology 73 (3): 411–21. doi:10.1111/j.1365-2125.2011.04093.x. PMC 3370345. PMID 21883386.
- Ung D, Parkman HP, Nagar S (October 2009). "Metabolic interactions between prokinetic agents domperidone and erythromycin: an in vitro analysis". Xenobiotica 39 (10): 749–56. doi:10.1080/00498250903096121. PMID 19575604.
- "Grapefruit, Medicine Interaction Warning Expanded". ABC News. 2012-11-26. Archived from the original on 2014-10-31. Retrieved 2014-10-31.
- Swannick G. (ed.) "MIMS Australia." December 2013
- Wan EW, Davey K, Page-Sharp M, Hartmann PE, Simmer K, Ilett KF (2008-05-27). "Dose-effect study of domperidone as a galactagogue in preterm mothers with insufficient milk supply, and its transfer into milk". British Journal of Clinical Pharmacology, Aguest 2008 66 (2): 283–289. doi:10.1111/j.1365-2125.2008.03207.x. PMC 2492930.
- Sneader, Walter (2005). "Plant Product Analogues and Compounds Derived from Them". Drug discovery : a history. Chichester: John Wiley & Sons Ltd. p. 125. ISBN 0-471-89979-8.
- Corsini, Giovanni Umberto (2010). "Apomorphine: from experimental tool to therpeutic aid". In Ban, Thomas A; Healy, David & Shorter, Edward. The Triumph of Psychopharacology and the Story of CINP. CINP. p. 54. ISBN 9634081819. Archived from the original on 2014-11-01.
- "Domperidone". Pharmaceutical Manufacturing Encyclopedia, 3rd Edition (Vol. 1-4). William Andrew Publishing. 2013. p. 138. ISBN 9780815518563. Retrieved 2014-12-12.
- Rathbone, Michael J.; Hadgraft, Jonathan; Roberts, Michael S. (2002). "The Zydis Oral Fast-Dissolving Dosage Form". Modified-Release Drug Delivery Technology. CRC Press. p. 200. ISBN 9780824708696. Retrieved 2014-10-31.
- "De Standaard: "Motilium from now on only with prescription"". standaard.be. 2013-05-07. Retrieved 2013-10-03.
- "ipcalabs.com". ipcalabs.com. Retrieved 2013-06-30.
- "torrentpharma.com". torrentpharma.com. Retrieved 2013-06-30.
- GPDA letter to the FDA about domperidone for gastroparesis.
- U.S. National Library of Medicine: Drug Information Portal - Domperidone