Metoclopramide

Last updated

Metoclopramide
Metoclopramide.svg
Metoclofinal.png
Clinical data
Pronunciation /ˌmɛtəˈklɒprəmaɪd/
Trade names Primperan, Reglan, others [1]
AHFS/Drugs.com Monograph
MedlinePlus a684035
License data
Pregnancy
category
Routes of
administration 		By mouth, intravenous, intramuscular, nasal spray
Drug class D2 receptor antagonist; 5-HT3 receptor antagonist; 5-HT4 receptor agonist; Prolactin releaser
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 80 ± 15% (by mouth)
Metabolism Liver
Elimination half-life 5–6 hours
Excretion Urine: 70–85%
Feces: 2%
Identifiers
  • 4-Amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.006.058 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H22ClN3O2
Molar mass 299.80 g·mol−1
3D model (JSmol)
Melting point 147.3 °C (297.1 °F)
  • Clc1cc(c(OC)cc1N)C(=O)NCCN(CC)CC
  • InChI=1S/C14H22ClN3O2/c1-4-18(5-2)7-6-17-14(19)10-8-11(15)12(16)9-13(10)20-3/h8-9H,4-7,16H2,1-3H3,(H,17,19) Yes check.svgY
  • Key:TTWJBBZEZQICBI-UHFFFAOYSA-N Yes check.svgY
   (verify)

Metoclopramide is a medication used for stomach and esophageal problems. [5] It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease. [6] It is also used to treat migraine headaches. [7]

Contents

Common side effects include: feeling tired, diarrhea, and feeling restless. More serious side effects include neuroleptic malignant syndrome and depression. [6] It is thus rarely recommended that people take the medication for longer than twelve weeks. [6] No evidence of harm has been found after being taken by many pregnant women. [6] [8] It belongs to the group of medications known as dopamine-receptor antagonists and works as a prokinetic. [6]

In 2012, metoclopramide was one of the top 100 most prescribed medications in the United States. [9] It is available as a generic medication. [6] It is on the World Health Organization's List of Essential Medicines. [10] In 2020, it was the 352nd most commonly prescribed medication in the United States, with more than 600,000 prescriptions. [11]

Medical uses

Metoclopramide 5 mg tablets Metoclopramide-5mg.jpg
Metoclopramide 5 mg tablets

Nausea

Metoclopramide is commonly used to treat nausea and vomiting associated with conditions such as uremia, radiation sickness, cancer and the effects of chemotherapy, labor, infection, and emetogenic drugs. [6] [12] [13] [14] As a perioperative anti-emetic, the effective dose is usually 25 to 50 mg (compared to the usual 10 mg dose).

It is also used in pregnancy as a second choice for treatment of hyperemesis gravidarum (severe nausea and vomiting of pregnancy). [6]

It is also used preventatively by some EMS providers when transporting people who are conscious and spinally immobilized. [15]

Migraine

In migraine headaches, metoclopramide may be used in combination with paracetamol (acetaminophen) or in combination with aspirin. [16]

Gastroparesis

Evidence also supports its use for gastroparesis, a condition that causes the stomach to empty poorly, and as of 2010 it was the only drug approved by the FDA for that condition. [6] [17]

It is also used in gastroesophageal reflux disease. [6] [4]

Lactation

While metoclopramide is used to try to increase breast milk production, evidence for its effectiveness for this is poor. [18] Its safety for this use is also unclear. [19]

Procedures

Intravenous metoclopramide is used in small-bowel follow-through, small-bowel enema, and radionuclide gastric-emptying studies to reduce the time taken for barium to go through the intestines, thus reducing the total time needed for the procedures. Metoclopramide also prevents vomiting after oral ingestion of barium. [20]

Contraindications

Metoclopramide is contraindicated in pheochromocytoma. It should be used with caution in Parkinson's disease since, as a dopamine antagonist, it may worsen symptoms. Long-term use should be avoided in people with clinical depression, as it may worsen one's mental state. [13] It is contraindicated for people with a suspected bowel obstruction, [6] in epilepsy, if a stomach operation has been performed in the previous three or four days, perforation or blockage of the stomach, and in newborn babies. [14]

The safety of the drug was reviewed by the European Medicines Agency in 2011, which determined that it should not be prescribed in high doses, for periods of more than five days, or given to children below 1 year of age. They suggested its use in older children should be restricted to treating post-chemotherapy or post-surgery nausea and vomiting, and even then only for patients where other treatments have failed. For adults, they recommended its use be restricted to treating migraines and post-chemotherapy or post-surgery patients. [21] [22]

Pregnancy

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or foetus. [23] A large cohort study of babies born to Israeli women exposed to metoclopramide during pregnancy found no evidence that the drug increases the risk of congenital malformations, low birth weight, preterm birth, or perinatal mortality. [24] A large cohort study in Denmark found, in addition, no association between metoclopramide exposure and miscarriage. [25] Metoclopramide is excreted into milk. [23]

Infants

A systematic review found a wide range of reported outcomes for treatment of gastroesophageal reflux disease (GERD) in infants and concluded a "poor" rating of evidence and "inconclusive" rating of safety and efficacy for the treatment of GERD in infants. [26]

Side effects

Plastic ampoule of metoclopramide Metoclopramide ampule.jpg
Plastic ampoule of metoclopramide

Common adverse drug reactions (ADRs) associated with metoclopramide therapy include restlessness (akathisia), and focal dystonia. Infrequent ADRs include hypertension, hypotension, hyperprolactinaemia leading to galactorrhea, headache, and extrapyramidal effects such as oculogyric crisis. [13] [4]

Metoclopramide may be the most common cause of drug-induced movement disorders. [27] The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy. [12] [13] Tardive dyskinesia may be persistent and irreversible in some people. The majority of reports of tardive dyskinesia occur in people who have used metoclopramide for more than three months. [27] Consequently, the US Food and Drug Administration (FDA) recommends that metoclopramide be used for short-term treatment, preferably less than 12 weeks. In 2009, the FDA required all manufacturers of metoclopramide to issue a black box warning regarding the risk of tardive dyskinesia with chronic or high-dose use of the drug. [27]

Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with diphenhydramine injected intramuscularly. [4] Agents in the benzodiazepine class of drugs may be helpful, but benefits are usually modest and side effects of sedation and weakness can be problematic. [28]

In some cases, the akathisia effects of metoclopramide are directly related to the infusion rate when the drug is administered intravenously. Side effects were usually seen in the first 15 min after the dose of metoclopramide. [29]

Rare side effects

Diabetes, age, and female gender are risk factors that increase the likelihood of experiencing a neuropsychiatric side effect of metoclopramide. [30]

Pharmacology

Metoclopramide appears to bind to dopamine D2 receptors with nanomolar affinity (Ki = 28.8 nM), [32] where it is a receptor antagonist, and is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist. [30]

Mechanism of action

The antiemetic action of metoclopramide is due to its antagonist activity at D2 receptors in the chemoreceptor trigger zone in the central nervous system— this action prevents nausea and vomiting triggered by most stimuli. [33] At higher doses, 5-HT3 antagonist activity may also contribute to the antiemetic effect. [34] [ failed verification ]

The gastroprokinetic activity of metoclopramide is mediated by muscarinic activity, D2 receptor antagonist activity, and 5-HT4 receptor agonist activity. [35] [36] The gastroprokinetic effect itself may also contribute to the antiemetic effect.[ citation needed ] Metoclopramide also increases the tone of the lower esophageal sphincter. [37]

Metoclopramide might influence mood because of its antagonistic blockade on 5-HT3 and agonistic (activating) action on 5-HT4. [30]

Pharmacokinetics

Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6. The major metabolites of metoclopramide are N-hydroxylation and N-deethylation by all common CYP enzymes. [38]

Chemistry

Metoclopramide is a substituted benzamide; cisapride and mosapride are structurally related. [34]

History

Metoclopramide was first described by Louis Justin-Besançon and Charles Laville in 1964, while working to improve the anti-dysrhythmic properties of procainamide. [39] [40] [41] [42] That research project also produced the product sulpiride. [39] The first clinical trials were published by Tourneu et al. in 1964 and by Boisson and Albot in 1966. [42] Justin-Besançon and Laville worked for Laboratoires Delagrange [39] and that company introduced the drug as Primperan in 1964. [43] [44] Laboratoires Delagrange was acquired by Synthelabo in 1991 [45] [46] which eventually became part of Sanofi. [47]

A.H. Robins introduced the drug in the US under the brand name Reglan in 1979 [48] as an injectable [49] and an oral form was approved in 1980. [50] in 1989 A.H. Robins was acquired by American Home Products, [51] which changed its name to Wyeth in 2002. [52]

The drugs were initially used to control nausea for people with severe headaches or migraines, and later uses for nausea caused by radiation therapy and chemotherapy, and later yet for treating nausea caused by anesthesia. [42] In the US the injectable form was labelled for chemotherapy-induced nausea and the oral form was eventually labelled for gastroesophageal reflux disease. [53]

It became widely used in the 1980s, becoming the most commonly used drug to treat anesthesia-induced nausea [42] and for treating gastritis in emergency rooms. [54]

The first generics were introduced in 1985. [53] [55]

In the early 1980s signs began to emerge in pharmacovigilance studies from Sweden that the drug was causing tardive dyskinesia in some patients. [56] The FDA required a warning about tardive dyskinesia to be added to the drug label in 1985 stating that: "tardive dyskinesia . . . may develop in patients treated with metoclopramide,” and warned against use longer than 12 weeks, as that was how long the drug has been tested. [57] [58] In 2009 the FDA required that a black box warning be added to the label. [17] [27]

The emergence of this severe side effect led to a wave of product liability litigation against generic manufacturers as well as Wyeth. [59] The litigation was complicated since there was a lack of clarity in jurisdiction between state laws, where product liability is determined, and federal law, which determines how drugs are labelled, as well as between generics companies, which had no control over labelling, and the originator company, which did. [59] [60] The litigation yielded at least two important cases. In Conte v. Wyeth in the California state courts, the claims of the plaintiff against the generic companies Pliva, Teva, and Purepac that had sold the drugs that the plaintiff actually took, and the claims against Wyeth, whose product the plaintiff never took, were all dismissed by the trial court, but the case was appealed, and in 2008 the appellate court upheld the dismissal of the cases against the generic companies, but reversed on Wyeth, allowing the case against Wyeth to proceed. [59] [60] [61] This established an "innovator liability" or "pioneer liability" for pharmaceutical companies. [59] The precedent was not widely followed in California nor in other states. [60] Litigation over the same issues related to metoclopramide also reached the US Supreme Court in Pliva, Inc. v. Mensing, [62] in which the court held in 2011 that generic companies cannot be held liable for information, or the lack of information, on the originator's label. [58] [60] [63] As of August 2015 there were about 5000 suits pending across the US and efforts to consolidate them into a class action had failed.[ citation needed ]

Shortly following the Pliva decision, the FDA proposed a rule change that would allow generics manufacturers to update the label if the originating drug had been withdrawn from the market for reasons other than safety. [64] As of May 2016 the rule, which turned out to be controversial since it would open generic companies to product liability suits, was still not finalized, and the FDA had stated the final rule would be issued in April 2017. [65] The FDA issued a draft guidance for generic companies to update labels in July 2016. [66]

Society and culture

Brand names

List of brand names for metoclopramide [1] [67]
AAdco-Contromet, Aeroflat (metoclopramide and dimeticone), Afipran, Anaflat Compuesto (metoclopramide and simeticone; pancreatin), Anagraine (metoclopramide and paracetamol), [68] Anausin Métoclopramide, Anolexinon, Antiementin, Antigram (Metoclopramide and Acetylsalicylic Acid), Aswell
BBalon, Betaclopramide, Bio-Metaclopramide, Bitecain AA
CCarnotprim, Carnotprim, Cephalgan (metoclopramide and carbasalate calcium), Cerucal, Chiaowelgen, Chitou, Clifar (Metoclopramide and Simeticone), Clodaset (metoclopramide and ondansetron), Clodoxin (metoclopramide and pyridoxine), Clomitene, Clopamon, Clopan, Cloperan, Cloprame, Clopramel, Clozil
DDamaben, Degan, Delipramil, Di-Aero OM (metoclopramide and simeticone), Dibertil, Digenor (Metoclopramide and Dimeticone), Digespar (Metoclopramide and Simeticone), Digestivo S. Pellegrino, Dikinex Repe (Metoclopramide and Pancreatin), Dirpasid, Doperan, Dringen
EEgityl (metoclopramide and acetylsalicylic Acid), Elieten, Eline, Elitan, Emenil, Emeprid (veterinary use), Emeran, Emetal, Emoject, Emperal, Enakur, Enteran, Enzimar, Espaven M.D. (Metoclopramide and Dimethicone), Ethiferan, Eucil
FFactorine (Metoclopramide and Simeticone)
GGastro-Timelets, Gastrocalm, Gastronerton, Gastrosil, Geneprami
HH-Peran, Hawkperan, Hemibe, Horompelin
IImperan, Isaprandil, Itan
J
KK.B. Meta, Klometol, Klopra
LLexapram, Linperan, Linwels
MMalon, Manosil, Maril, Matolon, Maxeran, Maxolon, Maxolone, Meclam, Meclid, Meclizine, Meclomid, Meclopstad, Meniperan, Mepram, Met-Sil, Metajex, Metalon, Metamide, Metilprednisolona Richet, Metoceolat, Metoclor, Metoco, Metocol, Metocontin, Metomide (veterinary use), Metonia, Metopar (Metoclopramide and Paracetamol), Metopar (Metoclopramide and Paracetamol), Metopelan, Metoperan, Metoperon, Metopran, Metotag, Metozolv, Metpamid, Metsil, Mevaperan, Midatenk, Migaura (Metoclopramide and Paracetamol), Migpriv (Metoclopramide and Acetylsalicylic Acid), Migracid (Metoclopramide and Paracetamol), Migraeflux MCP (Metoclopramide and Paracetamol), Migrafin (Metoclopramide and Aspirin), Migralave + MCP (Metoclopramide and Paracetamol), MigraMax (Metoclopramide and Acetylsalicylic Acid), Migräne-Neuridal (Metoclopramide and Paracetamol), Migränerton (Metoclopramide and Paracetamol), Motilon
NN-Metoclopramid, Nastifran, Nausil, Nevomitan, Nilatika, Novomit
OOpram
PPacimol-M (Metoclopramide and Paracetamol), Pangastren (Metoclopramide and Simeticone), Paramax (Metoclopramide and Paracetamol), Paspertin, Peraprin, Perinorm, Perinorm-MPS (Metoclopramide and Dimeticone), Perone, Piralen, Plamide, Plamine, Plasil, PMS-Metoclopramide, Podokedon, Polun, Poriran, Pradis, Pramidin, Pramidyl, Pramin, Praux, Premig (Metoclopramide and Acetylsalicylic Acid), Premosan, Prenderon, Prevomic, Primadol (Metoclopramide and Paracetamol), Primavera-N, Premier, Primlan, Primperan, Primperil, Primperoxane (Metoclopramide and Dimeticone), Primram, Primran, Primsel, Pripram, Prokinyl, Promeran, Prometin, Prowel, Pulin, Pulinpelin, Pulperan, Pusuan, Putelome, Pylomid
Q
RR-J, Raclonid, Randum, Reglan, Reglomar, Reliveran, Remetin, Riamide, Rilaquin, Rowelcon
SSabax Metoclopramide, Sinprim, Sinthato, Soho, Indonesia, Sotatic, Stomallin, Suweilan
TTalex (Metoclopramide and Pancreatin), Tivomit, Tomit, Torowilon
U
VVertivom, Vilapon, Vitamet, Vomend (veterinary use), Vomesea, Vomiles, Vomipram, Vomitrol, Vosea
WWei Lian, Winperan
X
Y
ZZudaw

Veterinary use

Metoclopramide is commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits. [69]

Related Research Articles

An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be used for severe cases of gastroenteritis, especially if the patient is dehydrated.

<span class="mw-page-title-main">Tardive dyskinesia</span> Neurological disorder featuring involuntary, repetitive body movements

Tardive dyskinesia (TD) is a disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips. Additionally, there may be chorea or slow writhing movements. In about 20% of people with TD, the disorder interferes with daily functioning. If TD is present in the setting of a long-term drug therapy, reversibility can be determined primarily by severity of symptoms and how long symptoms have been present before the long-term drug has been stopped.

<span class="mw-page-title-main">Granisetron</span> Serotonin 5-HT3 antiemetic

Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

<span class="mw-page-title-main">Cisapride</span> Chemical compound

Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system. It has been sold under the trade names Prepulsid (Janssen-Ortho) and Propulsid (in the United States). It was discovered by Janssen Pharmaceuticals in 1980. In many countries, it has been either withdrawn from the market or had its indications limited due to incidence of serious cardiac side-effects. Propulsid was linked to children's deaths.

<span class="mw-page-title-main">Domperidone</span> Peripheral D2 receptor antagonist

Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis. It raises the level of prolactin in the human body and is used to induce and promote breast milk production off label. It may be taken by mouth or rectally.

<span class="mw-page-title-main">Promethazine</span> Pharmaceutical drug

Promethazine, sold under the brand name Phenergan among others, is a first-generation antihistamine, antipsychotic, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold and may also be used for sedating people who are agitated or anxious, an effect that has led to some recreational use. Promethazine is taken by mouth (oral), as a rectal suppository, or by injection into a muscle (IM).

<span class="mw-page-title-main">Ondansetron</span> Medication to prevent nausea and vomiting

Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery. It is also effective for treating gastroenteritis. It can be given orally, intramuscularly, or intravenously.

<span class="mw-page-title-main">Prochlorperazine</span> Medication for nausea, psychosis, and anxiety

Prochlorperazine, formerly sold under the brand name Compazine among others, is a medication used to treat nausea, migraines, schizophrenia, psychosis and anxiety. It is a less preferred medication for anxiety. It may be taken by mouth, rectally, injection into a vein, or injection into a muscle.

<span class="mw-page-title-main">Dolasetron</span> Pharmaceutical drug

Dolasetron (trade name Anzemet) is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when symptoms are due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

<span class="mw-page-title-main">Amisulpride</span> Atypical antipsychotic and antiemetic medication

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold under the brand names Barhemsys and Solian, Socian, Deniban and others. At very low doses it is also used to treat dysthymia.

<span class="mw-page-title-main">Droperidol</span> Antidopaminergic drug

Droperidol is an antidopaminergic drug used as an antiemetic and as an antipsychotic. Droperidol is also often used as a rapid sedative in intensive-care treatment, and where "agitation aggression or violent behavior" are present.

<span class="mw-page-title-main">Cyclizine</span> Medication for motion sickness or vertigo

Cyclizine, sold under a number of brand names, is a medication used to treat and prevent nausea, vomiting and dizziness due to motion sickness or vertigo. It may also be used for nausea after general anaesthesia or that which developed from opioid use. It is taken by mouth, in the rectum, or injected into a vein.

<span class="mw-page-title-main">Biperiden</span> Group of stereoisomers

Biperiden, sold under the brand name Akineton among others, is a medication used to treat Parkinson disease, certain drug-induced movement disorders and Touret Syndrome. It is not recommended for tardive dyskinesias. It is taken by mouth, injection into a vein, or muscle.

<span class="mw-page-title-main">Trimethobenzamide</span> Antiemetic medication

Trimethobenzamide is an antiemetic used to prevent nausea and vomiting.

5-HT<sub>3</sub> antagonist Anti-nausea group of medications

The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

<span class="mw-page-title-main">Metopimazine</span> Chemical compound

Metopimazine, sold under the brand names Vogalen and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting. It is marketed in Europe, Canada, and South America. As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.

<span class="mw-page-title-main">Bromopride</span> Chemical compound

Bromopride (INN) is a dopamine antagonist with prokinetic properties widely used as an antiemetic, closely related to metoclopramide. It is not available in the United States.

Paracetamol/metoclopramide hydrochloride is an oral fixed dose combination prescription medication containing the analgesic paracetamol (500 mg) and the anti-emetic metoclopramide hydrochloride (5 mg). Formulated as a tablet and as sachets of a water-soluble powder, it is sold under the trade name Paramax by Sanofi-Synthelabo, and in Switzerland as Migraeflux MCP, in Australia it is sold as Meteclomax and Anagraine.

<span class="mw-page-title-main">Nausea</span> Medical symptom or condition

Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.

<span class="mw-page-title-main">Cinitapride</span> Chemical compound

Cinitapride (trade names Cintapro, Pemix) is a gastroprokinetic agent and antiemetic agent of the benzamide class which is marketed in India, Mexico, Pakistan and Spain. It acts as an agonist of the 5-HT1 and 5-HT4 receptors and as an antagonist of the 5-HT2 receptors.

References

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