Domperidone

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Domperidone
Domperidone structure.png
Domperidone 3D.png
Systematic (IUPAC) name
5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
Clinical data
Trade names Motilium
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy cat.
  • Not classified (US)
Legal status
  • Not approved for use or sale: US; prescription medicine (POM): India, Australia, Canada, Israel, Belgium; Over the Counter (OTC): UK (Prescription Only Medicine as of 4th September 2014)), Egypt, Ireland, Italy, Japan, Netherlands, South Africa, Switzerland, China, Russia, Slovakia, Thailand, Malta, South Korea, and Romania[1]
Routes Oral, intravenous, rectal
Pharmacokinetic data
Bioavailability High
Protein binding 91–93%
Metabolism Hepatic and intestinal (first-pass)
Half-life 7 hours
Excretion Breast milk, renal
Identifiers
CAS number 57808-66-9 YesY
ATC code A03FA03 QP51AX24
PubChem CID 3151
IUPHAR ligand 965
DrugBank DB01184
ChemSpider 3039 YesY
UNII 5587267Z69 YesY
KEGG D01745 YesY
ChEBI CHEBI:31515 YesY
ChEMBL CHEMBL219916 YesY
Chemical data
Formula C22H24ClN5O2 
Mol. mass 425.911 g/mol
 YesY (what is this?)  (verify)

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.

Mechanism of Action[edit]

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 lowers 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.[2][3] 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.[4]

Uses[edit]

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.[5] 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.[6]

Nausea and vomiting[edit]

There is some evidence that domperidone has antiemetic activity.[7] It is recommended in the Canadian Headache Society's guidelines for treatment of nausea associated with acute migraine.[8]

Gastroparesis[edit]

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 may be useful in diabetic and idiopathic gastroparesis.[9][10]

However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate (equate) well with relief of symptoms.[11]

Parkinson's disease[edit]

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 worse 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).[12] In addition to this, domperidone may enhance the bioavailability (effect) of levodopa (one of the main treatments in Parkinson's disease.)[13]

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 (> 30mg per day).[14] 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).[15]

Functional dyspepsia[edit]

Domperidone may be used in functional dyspepsia in both adults and children.[16][17]

Lactation[edit]

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.[18][19] In the United States, domperidone is not approved for this or any other use.[20][21] 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.[22]

Adverse effects[edit]

QT prolongation[edit]

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.[23][24]

QT prolongation in neonates and infants is controversial and uncertain.[25][26]

Penetration of immature blood brain barrier[edit]

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 neurolept malignant syndrome as a side effect of domperidone due to the drug crossing the child's immature blood brain barrier.[27]

Interactions[edit]

Itraconazole and ketoconazole, both used to treat fungal infections increase the plasma concentration of domperidone.[28][29]

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.[30]

Contraindications[edit]

[31]

History[edit]

Janssen Pharmaceutical has brought domperidone before the United States Federal Drug Administration (FDA) several times, including in the 1990s.

Brand names and formulations by nation[edit]

Brand names and formulations by nation
Nation Manufacturer Brand Formulations
Australia Janssen–Cilag Motilium 10 mg scored tablets[31]
Belgium and the Netherlands - Motilium From 2013 only by prescription in Belgium.[32]
Bangladesh - Ridon -
Canada - Motilium (1985–2002) Generic brands available
India Salius Pharma Escacid DXR pantoprazole 40 mg and domperidone SR 30mg
India Medley pharmaceuticals Dompan pantoprazole 40 mg and domperidone 10mg
India Rhubarb pharmaceuticals - domperidone 5, 10 and 20 mg tablets.
India Ipca Laboratories, Mumbai Domperi suspension domperidone 1 mg/ml, 30 ml suspension.[33]
India Torrent pharmaceuticals Domstal - [34]
India Ozone pharmaceuticals and chemicals Pantazone-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)
Italy - Peridon -
Pakistan Johnson & Johnson Pakistan Motilium-v domperidone 10 mg tablets; 30 ml suspension
Philippines Health Saver Pharma Abdopen -
Philippines United Laboratories, Inc. GI Norm -
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
Taiwan - Dotitone -
Thailand - Motilium M -
Turkey Saba Motinorm -
- GlaxoSmithKline Motinorm -

See also[edit]

References[edit]

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  4. ^ Parkman HP, Jacobs MR, Mishra A, 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. 
  5. ^ "Domperidone - heart rate and rhythm disorders." Canadian adverse reactions newsletter. Government of Canada. January 2007 17(1)
  6. ^ "Investigational New Drug Application > Domperidone" http://www.fda.gov. 2014-01-09. Retrieved 2014-06-08.
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  8. ^ Worthington I, Pringsheim T, Gawel MJ, 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. 
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  16. ^ 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 2014-03-31). PMID 23529392. 
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  18. ^ 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. 
  19. ^ 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. 
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  21. ^ "FDA warns against women using unapproved drug, domperidone to increase milk production." U.S. Food and Drug Administration 7 June 2004.
  22. ^ 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. 
  23. ^ 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. 
  24. ^ 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. PMID 20652862. 
  25. ^ 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. 
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  27. ^ 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. 
  28. ^ Yoshizato T, Kotegawa T, Imai H, 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. 
  29. ^ 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. 
  30. ^ 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. 
  31. ^ a b Swannick G. (ed.) "MIMS Australia." December 2013
  32. ^ "De Standaard: "Motilium from now on only with prescription"". standaard.be. 2013-05-07. Retrieved 2013-10-03. 
  33. ^ "ipcalabs.com". ipcalabs.com. Retrieved 2013-06-30. 
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External links[edit]