Domperidone

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Domperidone
Domperidone 2D structure.svg
Domperidone ball-and-stick model.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, many others
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy
category
  • Not classified (US)
Routes of
administration
Oral, intramuscular, intravenous (d/c'd), rectal[1]
Legal status
Legal status
  • Not approved for use or sale: US; prescription medicine (POM): India, Australia, Canada, Israel, Belgium; over-the-counter: UK (Prescription Only Medicine as of 4th September 2014), Egypt, Ireland, Italy, Japan, Netherlands, South Africa, Switzerland, China, Russia, Slovakia, Ukraine,[2] Thailand, Malta, South Korea, and Romania[3]
Pharmacokinetic data
Bioavailability Oral: 13–17%[4][1]
Intramuscular: 90%[1]
Protein binding ~92%[1]
Metabolism Hepatic (CYP3A4/5) and intestinal (first-pass)[1][5]
Metabolites All inactive[1][5]
Biological half-life 7.5 hours[4][1]
Excretion Feces: 66%[1]
Urine: 32%[1]
Breast milk: small quantities[1]
Identifiers
CAS Number 57808-66-9 YesY
ATC code A03FA03 (WHO) QP51AX24 (WHO)
PubChem CID 3151
IUPHAR/BPS 965
DrugBank DB01184 YesY
ChemSpider 3039 YesY
UNII 5587267Z69 YesY
KEGG D01745 YesY
ChEBI CHEBI:31515 YesY
ChEMBL CHEMBL219916 YesY
Chemical data
Formula C22H24ClN5O2
Molar mass 425.911 g/mol
Physical data
Melting point 242.5 °C (468.5 °F)
  (verify)
Not to be confused with Dom Pérignon or droperidol.

Domperidone (INN, USAN, BAN, JAN) (brand name Motilium, many others) is a peripherally selective dopamine D2 receptor antagonist developed by Janssen Pharmaceutica that is used as an antiemetic, gastroprokinetic agent, and galactogogue.[6][1][7] It may be administered orally or rectally, and is available in the form of tablets, orally disintegrating tablets (based on Zydis technology),[8] suspension, and suppositories.[9] 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.[1][7]

Medical 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.[10] 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.[11] 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.

It was reported in 2007 that domperidone is available in 58 countries, including Canada.[12]

Nausea and vomiting[edit]

There is some evidence that domperidone has antiemetic activity.[13] It is recommended in the Canadian Headache Society's guidelines for treatment of nausea associated with acute migraine.[14]

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.[15][16]

However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate (equate) well with relief of symptoms.[17]

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 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).[18] In addition to this, domperidone may enhance the bioavailability (effect) of levodopa (one of the main treatments in Parkinson's disease).[19]

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).[20] 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).[21]

Functional dyspepsia[edit]

Domperidone may be used in functional dyspepsia in both adults and children.[22][23]

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.[24][25] In the United States, domperidone is not approved for this or any other use.[26][27] 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.[28]

To induce lactation, domperidone is used at a dosage of 10 to 20 mg 3 or 4 times per day by mouth.[29] Effects may be seen within 24 hours or may not been seen for 3 or 4 days.[29] The maximum effect occurs after 2 or 3 weeks of treatment, and the treatment period generally lasts for 3 to 8 weeks.[29]

Pediatric reflux[edit]

Domperidone has been found effective in the treatment of pediatric reflux.[30] However some specialists consider it to be an excessively powerful drug for treating babies with reflux.[31]

Side effects[edit]

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).[29] 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.[1][7] 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.[1][7]

Excess prolactin levels[edit]

Due to D2 receptor blockade, domperidone causes hyperprolactinemia.[32] 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).[33] As such, male patients may experience low libido, erectile dysfunction, and impaired spermatogenesis.[33] 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.[32] Gynecomastia has been reported in males treated with domperidone,[34] and galactorrhea could occur in males as well.[33]

Rare reactions[edit]

Cardiac reactions[edit]

Domperidone use is associated with an increased risk of sudden cardiac death (by 70%)[35] most likely through its prolonging effect of the cardiac QT interval and ventricular arrhythmias.[36][37] The cause is thought to be blockade of hERG voltage-gated potassium channels.[38][39] 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).[40][41] Conflicting reports exist, however.[42] In neonates and infants, QT prolongation is controversial and uncertain.[43][44]

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:[41]

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[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 neuroleptic malignant syndrome as a side effect of domperidone due to the drug crossing the child's immature blood-brain-barrier.[45]

Interactions[edit]

Domperidone is almost exclusively metabolized by CYP3A4, and for this reason, inhibitors and inducers of this enzyme may alter the metabolism and concentrations of domperidone. Moreover, domperidone has been identified as a modest mechanism-based (irreversible) inhibitor of CYP3A4 (Ki = 12 μM), and it has been estimated that it may increase the serum concentrations of CYP3A4 substrates by approximately 50%.[46]

Itraconazole and ketoconazole, both used to treat fungal infections, are potent CYP3A4 inhibitors and increase the plasma concentration of domperidone.[47][48] In healthy volunteers, ketoconazole increased the Cmax and AUC concentrations of domperidone by 3- to 10-fold.[49] 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.[49] As such, domperidone with ketoconazole or other CYP3A4 inhibitors is a potentially dangerous combination.[49]

Erythromycin and certain other macrolide antibiotics are CYP3A4 inhibitors and 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.[50]

There is evidence that domperidone should not be taken with grapefruit juice, which is a known CYP3A4 inhibitor.[51]

Contraindications[edit]

Pharmacology[edit]

Pharmacodynamics[edit]

Domperidone is a peripherally selective dopamine D2 and D3 receptor antagonist.[7] It has no clinically significant interaction with the D1 receptor, unlike metoclopramide.[7] The drug provides relief from nausea by blocking receptors at the chemoreceptor trigger zone (a location in the nervous system that mediates 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[53] 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.[54][55] 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.[56]

Effects on prolactin levels[edit]

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).[57][7][58][59] 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).[58][59] 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).[7][59] 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.[58][59] The mechanism of the difference is unknown.[59] The increase in prolactin levels observed with the two drugs was, as expected, much greater in women than in men.[58][59] This appears to be due to the higher estrogen levels in women, as estrogen stimulates prolactin secretion.[60]

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.[61][62]

Effects on TSH levels[edit]

Along with prolactin, domperidone has, to a lesser extent, been found to increase the secretion of thyroid-stimulating hormone (TSH), even in patients with hypothyroidism.[58] A single 4 mg intravenous dose of domperidone produced peak TSH levels of 1.9-fold above baseline and peak prolactin levels of 23-fold above baseline (which occurred at 30 minutes post-administration) in women with hypothyroidism.[58] Levels of TSH and prolactin decreased to 1.6-fold and 17-fold above baseline, respectively, at 120 minutes post-administration.[58]

Pharmacokinetics[edit]

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)[63] and in the intestines.[5] Due to the marked first-pass effect via this route, the oral bioavailability of domperidone is low (13–17%);[1] conversely, its bioavailability is high via intramuscular injection (90%).[1] 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.[1] All of the metabolites of domperidone are inactive as D2 receptor ligands.[1][5] 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.[64]

Chemistry[edit]

Domperidone is a benzimidazole derivative and is structurally related to butyrophenone neuroleptics like haloperidol.[65][66]

History[edit]

  • 1974 – Domperidone synthesized at Janssen Pharmaceutica[67] following the research on antipsychotic drugs.[68] 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.[68] This led to the discovery of domperidone as a strong anti-emetic with minimal central effects.[68][69]
  • 1978 – On January 3, 1978 Domperidone was patented in the United States 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.[70]
  • 1999 – Domperidone was introduced in the forms of orally disintegrating tablets (based on Zydis technology).[71]
  • 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.[9]

Society and culture[edit]

Availability[edit]

Domperidone is available over-the-counter to treat gastroesophageal reflux and functional dyspepsia in many countries, such as Ireland, the Netherlands, Italy, South Africa, Mexico, Chile, and China.[72] Domperidone is not approved for use in the United States, but is prescribable and limitedly available in this country for use in people with treatment-refractory gastrointestinal symptoms under an FDA Investigational New Drug application.[1] In 2007, it was reported that domperidone was available in 58 countries.[1]

Formulations[edit]

Nation Manufacturer Brand Formulations
Australia Janssen–Cilag Motilium 10 mg scored tablets[52]
Belgium and the Netherlands - Motilium From 2013 only by prescription in Belgium.[73]
Bangladesh Square Motigut 10 mg scored tablets
Bangladesh Astra Pharma Domperon 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.[74]
India Torrent pharmaceuticals Domstal - [75]
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
India Draavin Pharma Draaci-XD Pantaprazole 40 mg and Domperione 30 mg
Iran Abidi Pharmaceutical Co. MOTiDON 10 mg tablet
Ireland McNeil Healthcare Motilium 10 mg orally disintegrating tablet (ODT)
Italy - Peridon domperidone 10 mg tablets; 30 ml suspension
Lithuania Johnson & Johnson Motilium -
Pakistan Johnson & Johnson Pakistan Motilium-v domperidone 10 mg tablets; 30 ml suspension
Pakistan ATCO Laboratories Limited Vomilux domperidone 10 mg tablets
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)
Saudi Arabia JamJoom Pharmaceuticals Dompy Domperidone 10 mg tablets
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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