Metoclopramide
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Metoclopramide is a
medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
used to treat nausea, vomiting,
gastroparesis Gastroparesis (gastro- from Ancient Greek  – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis") is a medical disorder of ineffective neuromuscular contractions (peristalsis) of the stomach, resulting in food and l ...
, and
gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...
. It is also used to treat
migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...
headaches. Common side effects include feeling tired,
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
, akathisia, and tardive dyskinesia. More serious side effects include
neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...
and depression. It is thus rarely recommended that people take the medication for longer than twelve weeks. No evidence of harm has been found after being taken by many pregnant women. It belongs to the group of medications known as dopamine-receptor antagonists and works as a prokinetic. In 2012, metoclopramide was one of the top 100 most prescribed medications in the United States. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. In 2022, it was the 245th most commonly prescribed medication in the United States, with more than 1million prescriptions.


Medical uses


Nausea

Metoclopramide is commonly used to treat nausea and vomiting associated with conditions such as
uremia Uremia is the condition of having high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess in the blood of amino acid and protein metabolism end products, such as urea and creatinine, which ...
,
radiation sickness Acute radiation syndrome (ARS), also known as radiation sickness or radiation poisoning, is a collection of health effects that are caused by being exposed to high amounts of ionizing radiation in a short period of time. Symptoms can start wit ...
,
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
and the effects of
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
,
labor Labour or labor may refer to: * Childbirth, the delivery of a baby * Labour (human activity), or work ** Manual labour, physical work ** Wage labour, a socioeconomic relationship between a worker and an employer ** Organized labour and the labour ...
,
infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
, 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 Hyperemesis gravidarum (HG) is a pregnancy complication that is characterized by severe nausea, vomiting, weight loss, and possibly dehydration. Feeling faint may also occur. It is considered a more severe form of morning sickness. Symptoms ...
(severe nausea and vomiting of pregnancy). It is also used preventatively by some EMS providers when transporting people who are conscious and spinally immobilized.


Migraine

In migraine headaches, metoclopramide may be used in combination with paracetamol (acetaminophen) or in combination with
aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...
.


Gastroparesis

Evidence also supports its use for
gastroparesis Gastroparesis (gastro- from Ancient Greek  – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis") is a medical disorder of ineffective neuromuscular contractions (peristalsis) of the stomach, resulting in food and l ...
, 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. It is also used in
gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...
.


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

Metoclopramide is contraindicated in
pheochromocytoma Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they relea ...
. It should be used with caution in
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
since, as a dopamine antagonist, it may worsen symptoms. Long-term use should be avoided in people with
clinical depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
, as it may worsen one's mental state. It is contraindicated for people with a suspected bowel obstruction, 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. The
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
reviewed the drug's safety 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.


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 A cohort study is a particular form of longitudinal study that samples a Cohort (statistics), cohort (a group of people who share a defining characteristic, typically those who experienced a common event in a selected period, such as birth or gra ...
of babies born to Israeli women exposed to metoclopramide during pregnancy found no evidence that the drug increases the risk of
congenital malformation A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
s, low birth weight,
preterm birth Preterm birth, also known as premature birth, is the Childbirth, birth of a baby at fewer than 37 weeks Gestational age (obstetrics), gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 ...
, or
perinatal mortality Perinatal mortality (PNM) is the death of a fetus or neonate and is the basis to calculate the perinatal mortality rate. ''Perinatal'' means "relating to the period starting a few weeks before birth and including the birth and a few weeks after bi ...
. A large cohort study in Denmark found, in addition, no association between metoclopramide exposure and
miscarriage Miscarriage, also known in medical terms as a spontaneous abortion, is an end to pregnancy resulting in the loss and expulsion of an embryo or fetus from the womb before it can fetal viability, survive independently. Miscarriage before 6 weeks ...
. Metoclopramide is excreted into milk.


Infants

A systematic review found a wide range of reported outcomes for the treatment of
gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...
(GERD) in infants rating the evidence as "poor" and "inconclusive" for safety and efficacy for the treatment of GERD in infants.


Side effects

Common
adverse drug reaction An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or may result from the combination of two or more drugs. The meaning of this ...
s (ADRs) associated with metoclopramide therapy include restlessness (
akathisia Akathisia (IPA: /æ.kə.ˈθɪ.si.ə/) is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those a ...
), and focal dystonia. Infrequent ADRs include
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
,
hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
,
hyperprolactinaemia Hyperprolactinaemia (also spelled hyperprolactinemia) is a condition characterized by abnormally high levels of prolactin in the blood. In women, normal prolactin levels average to about 13 ng/mL, while in men, they average 5 ng/mL. ...
leading to
galactorrhea Galactorrhea ( also spelled galactorrhoea) ( galacto- + -rrhea) or lactorrhea ( lacto- + -rrhea) is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing. Galactorrhea is reported to occur in 5–32% of females. ...
, headache, and extrapyramidal effects such as
oculogyric crisis Oculogyric crisis (OGC) is a rare sudden, paroxysmal, dystonic reaction that may manifest in response to specific drugs, particularly neuroleptics, or medical conditions, such as movement disorders. This neurological phenomenon is characterized ...
. Metoclopramide may be the most common cause of drug-induced
movement disorder Movement disorders are clinical syndromes with either an excess of movement or a paucity of voluntary and involuntary movements, unrelated to weakness or spasticity. Movement disorders present with extrapyramidal symptoms and are caused by basa ...
s. The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy. 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. 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 In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...
regarding the risk of tardive dyskinesia with chronic or high-dose use of the drug. Dystonic reactions may be treated with benzatropine,
diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...
, trihexyphenidyl, or
procyclidine Procyclidine is an anticholinergic medication, drug principally used for the treatment of drug-induced parkinsonism, akathisia and acute dystonia, Parkinson's disease, and idiopathic or secondary dystonia. Medical uses It is used in patients ...
. Symptoms usually subside with intramuscularly injected
diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...
. Agents in the
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
class of drugs may be helpful, but benefits are usually modest, and the side effects of sedation and weakness can be problematic. In some cases, the
akathisia Akathisia (IPA: /æ.kə.ˈθɪ.si.ə/) is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those a ...
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. * Panic disorder * Major depressive disorder * Agoraphobia *
Agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing neutropenia in the circulating blood. I ...
,
supraventricular tachycardia Supraventricular tachycardia (SVT) is an umbrella term for fast heart rhythms arising from the upper part of the heart. This is in contrast to the other group of fast heart rhythms – ventricular tachycardia, which start within the lower cham ...
, hyperaldosteronism,
neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...
,
akathisia Akathisia (IPA: /æ.kə.ˈθɪ.si.ə/) is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those a ...
and
tardive dyskinesia Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...
. * Methaemoglobinaemia*


Pharmacology

Metoclopramide appears to bind to dopamine D2 receptors with nanomolar affinity (Ki = 28.8 nM), where it is a
receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
, 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 activity of metoclopramide is mediated by
muscarinic A muscarinic acetylcholine receptor agonist, also simply known as a muscarinic agonist or as a muscarinic agent, is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, lab ...
activity, D2 receptor antagonist activity, and 5-HT4 receptor agonist activity. 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. While muscarinic receptors affect gastrointestinal motility, metoclopramide’s prokinetic effects are not primarily due to direct muscarinic receptor activity. Instead, they result from its actions on 5-HT4 and D2 receptors.


Pharmacokinetics

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...
metabolizes metoclopramide, a reversible inhibitor, but not inactivator, of CYP2D6. The major metabolites of metoclopramide are N-hydroxylation and N-deethylation by all common CYP enzymes.


Chemistry

Metoclopramide is a substituted
benzamide Benzamide is an organic compound with the chemical formula of C7H7NO. It is the simplest amide derivative of benzoic acid. In powdered form, it appears as a white solid, while in crystalline form, it appears as colourless crystals. It is slightly ...
; cisapride and mosapride are structurally related.


History

Metoclopramide was first described by Louis Justin-Besançon and Charles Laville in 1964, while working to improve the anti-dysrhythmic properties of
procainamide Procainamide (PCA) is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is a sodium channel blocker of cardiomyocytes; thus it is classified by the Vaughan Williams classification system as class Ia. ...
. That research project also produced the product
sulpiride Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic (although some texts have referred to it as a typical antipsychotic) medication of the benzamide class which is used mainly in the treatment of psychosi ...
. The first clinical trials were published by Tourneu et al. in 1964 and by Boisson and Albot in 1966. Justin-Besançon and Laville worked for Laboratoires Delagrange and that company introduced the drug Primperan in 1964. Laboratoires Delagrange was acquired by Synthelabo in 1991 which eventually became part of
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
. 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 Wyeth Pharmaceuticals Inc. was a pharmaceutical company until it was purchased by Pfizer in 2009. The company was founded in Philadelphia, Pennsylvania, in 1860 as John Wyeth and Brother. Its headquarters moved to Collegeville, Pennsylvania, a ...
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. In the US the injectable form was labelled for chemotherapy-induced nausea and the oral form was eventually labelled for
gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...
. It became widely used in the 1980s, becoming the most commonly used drug to treat anesthesia-induced nausea and for treating
gastritis Gastritis is the inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Othe ...
in emergency rooms. 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 Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...
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.com In 2009 the FDA required that a
black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...
be added to the label. The emergence of this severe side effect led to a wave of product liability litigation against generic manufacturers as well as Wyeth. 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. The precedent was not widely followed in California nor in other states. Litigation over the same issues related to metoclopramide also reached the US Supreme Court in Pliva, Inc. v. Mensing, 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


Brand names


Veterinary use

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


References


External links

* {{Portal bar, Medicine 4-Amino-N-(3-(diethylamino)propyl)-2-methoxybenzamides 5-HT3 antagonists 5-HT4 agonists Antiemetics Chloroarenes CYP2D6 inhibitors D2 antagonists Diethylamino compounds Galactagogues Motility stimulants Prolactin releasers World Health Organization essential medicines Wikipedia medicine articles ready to translate