MarketMetoclopramide
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Metoclopramide

Metoclopramide is a medication used to treat nausea, vomiting, gastroparesis, and gastroesophageal reflux disease. It is also used to treat migraine headaches.

Medical uses
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. 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). Migraine In migraine headaches, metoclopramide may be used in combination with paracetamol (acetaminophen) or in combination with aspirin. 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. Lactation While metoclopramide is used to increase breast milk production, evidence for its effectiveness for this indication is poor. Its safety for this use is also unclear. Procedures Intravenous metoclopramide is used in small-bowel follow-through, small-bowel enema, and radionuclide gastric-emptying studies to reduce the time taken for the barium to go through the intestines, thus reducing the total time needed for the procedures. Metoclopramide also prevents vomiting after oral ingestion of barium. ==Contraindications==
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. Pregnancy Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or foetus. 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. A large cohort study in Denmark found, in addition, no association between metoclopramide exposure and miscarriage. Metoclopramide is excreted into milk. ==Side effects==
Side effects
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. Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with intramuscularly injected diphenhydramine. 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 minutes after administering the dose of metoclopramide. Withdrawal effects were reported for a female taking metoclopramide for about six months. The adverse symptoms oscillated between akinesian and akathisian, including amenorrhea, and appeared like secondary parkinsonism. Adverse effects remained a year after the metoclopramide had been gradually withdrawn. Rare side effects Diabetes, age, and female gender are risk factors that increase the likelihood of experiencing a neuropsychiatric side effect of metoclopramide. • Major depressive disorder • Agoraphobia • Agranulocytosis, supraventricular tachycardia, hyperaldosteronism, neuroleptic malignant syndrome, akathisia and tardive dyskinesia. • Methaemoglobinaemia* ==Pharmacology==
Pharmacology
Metoclopramide appears to bind to dopamine D2 receptors with nanomolar affinity (Ki = 28.8 nM), where it is a receptor antagonist, and is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist. Mechanism of action The antiemetic action of metoclopramide is due to its antagonist activity at D2 receptors in the chemoreceptor trigger zone in the brain — this action prevents nausea and vomiting triggered by most stimuli. At higher doses, 5-HT3 antagonist activity may also contribute to the antiemetic effect. The gastroprokinetic effect itself may also contribute to the antiemetic effect. Metoclopramide also increases the tone of the lower esophageal sphincter. Metoclopramide might influence mood because of its antagonistic blockade on 5-HT3 and agonistic (activating) action on 5-HT4. ==Chemistry==
Chemistry
Metoclopramide is a substituted benzamide; cisapride and mosapride are structurally related. ==History==
History
Metoclopramide was first described by Louis Justin-Besançon and Charles Laville in 1964, while working to improve the anti-dysrhythmic properties of procainamide. That research project also produced the product sulpiride. Laboratoires Delagrange was acquired by Synthelabo in 1991 which eventually became part of Sanofi. A.H. Robins introduced the drug in the US under the brand name Reglan in 1979 as an injectable and an oral form was approved in 1980. in 1989 A.H. Robins was acquired by American Home Products, which changed its name to Wyeth in 2002. The drugs were initially used to control nausea for people with severe headaches or migraines, and later used for nausea caused by radiation therapy and chemotherapy, and later yet for treating nausea caused by anesthesia. The first generics were introduced in 1985. In the early 1980s signs began to emerge in pharmacovigilance studies from Sweden that the drug was causing tardive dyskinesia in some patients. 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. In 2009 the FDA required that a black box warning be added to the label. 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. 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. This established an "innovator liability" or "pioneer liability" for pharmaceutical companies. 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. As of August 2015 there were about 5000 suits pending across the US and efforts to consolidate them into a class action had failed. 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. 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. The FDA issued a draft guidance for generic companies to update labels in July 2016. ==Society and culture==
Society and culture
Brand names ==Veterinary use==
Veterinary use
Metoclopramide is commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits. == References ==
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