Domperidone

For the brand of champagne or the inventor of champagne, see Dom Pérignon (disambiguation).

Not to be confused with Dronabinol or Droperidol.

Domperidone

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 category	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, Ukraine, Thailand, Malta, South Korea, and Romania
Routes of administration	Oral, intravenous, rectal
Pharmacokinetic data
Bioavailability	Low (13–17%)
Protein binding	91–93%
Metabolism	Hepatic and intestinal (first-pass)
Biological half-life	7.5 hours
Excretion	Breast milk, renal
Identifiers
CAS Number	57808-66-9 Y
ATC code	A03FA03 (WHO) QP51AX24 (WHO)
PubChem	CID: 3151
IUPHAR/BPS	965
DrugBank	DB01184 Y
ChemSpider	3039 Y
UNII	5587267Z69 Y
KEGG	D01745 Y
ChEBI	CHEBI:31515 Y
ChEMBL	CHEMBL219916 Y
Chemical data
Formula	C22H24ClN5O2
Molecular mass	425.911 g/mol
SMILES Clc1cc2c(cc1)N(C(=O)N2)C5CCN(CCCN4c3ccccc3NC4=O)CC5
InChI InChI=1S/C22H24ClN5O2/c23-15-6-7-20-18(14-15)25-22(30)28(20)16-8-12-26(13-9-16)10-3-11-27-19-5-2-1-4-17(19)24-21(27)29/h1-2,4-7,14,16H,3,8-13H2,(H,24,29)(H,25,30) Y Key:FGXWKSZFVQUSTL-UHFFFAOYSA-N Y
(verify)

Domperidone (INN, USAN, BAN, JAN) (trade names Motilium, Motillium, Motinorm Costi, Nomit, Brulium Molax) is a medication developed by Janssen Pharmaceutica that acts as a peripherally selective antagonist of the dopamine D₂ and D₃ 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 and hormone) acts in the body.

Domperidone is available in the form of tablets, orally disintegrating tablets (based on Zydis technology), suspension and suppositories.

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 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 genetic characteristic of the person, such as polymorphisms in the drug transporter gene ABCB1, the potassium channel KCNH2 gene, and α1D—adrenoceptor ADRA1D gene.

Uses

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 is not currently a legally marketed human drug and it is not approved for sale in the U.S. On June 7, 2004, FDA issued a public warning that distributing any domperidone-containing products is illegal. "How to Obtain" http://www.fda.gov. Page Last Updated: 02/10/2015 Retrieved 2015-08-04. 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.

Nausea and vomiting

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

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 may be useful in diabetic and idiopathic gastroparesis.

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

Parkinson's disease

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 especially 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).

Functional dyspepsia

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

Lactation

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.

Pediatric reflux

Domperidone has been found effective in the treatment of pediatric reflux. However some specialists consider it to be an excessively powerful drug for treating babies with reflux.

Adverse effects

QT prolongation

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.

QT prolongation in neonates and infants is controversial and uncertain.

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.

Cardiac side-effects

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"

Other side effects

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.

Interactions

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

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.

There is evidence that domperidone shouldn't be taken with grapefruit juice.

Contraindications

• Prolactin secreting pituitary tumor.
• Triazole antifungal medications such as ketoconazole, itraconazole, fluconazole.
• Macrolide antibiotics such as erythromycin and clarithromycin.
• Potent CYP3A4 inhibitors.
• Amiodarone
• Mechanical bowel disorders such as bowel obstruction, gastrointestinal haemorrhage or bowel perforation
• Moderate hepatic impairment (liver disease)
• Cardiac disease

Those taking QT-prolonging medicines or CYP3A4 inhibitors at the same time as domperidone.

History

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.

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.

Brand names and formulations by nation

Brand names and formulations by nation

Nation	Manufacturer	Brand	Formulations
Australia	Janssen–Cilag	Motilium	10 mg scored tablets
Belgium and the Netherlands	-	Motilium	From 2013 only by prescription in Belgium.
Bangladesh	Square	Motigut	10 mg scored tablets
Bangladesh	-	Ridon	-
Canada	-	Motilium (1985–2002)	Generic brands available
France	Mylan	Dompéridone	10 mg tablets
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)
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	-
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
Taiwan	-	Dotitone	-
Thailand	-	Motilium M	-
Turkey	Saba	Motinorm	-
-	GlaxoSmithKline	Motinorm	-

Synthesis

Domperidone synthesis:

See also

• Benzamide
• Cisapride
• Halopemide
• Itopride
• Metoclopramide

External links

• GPDA letter to the FDA about domperidone for gastroparesis.
• U.S. National Library of Medicine: Drug Information Portal - Domperidone