Metoclopramide

Systematic (IUPAC) name
4-Amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide
Clinical data
Pronunciation	/ˌmɛtəˈklɒprəmaɪd/
Trade names	Reglan, Metozolv, others
AHFS/Drugs.com	monograph
MedlinePlus	a684035
Licence data	US FDA:link
Pregnancy category	AU: A US: B (No risk in non-human studies)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral, intravenous, intramuscular
Pharmacokinetic data
Bioavailability	80±15% (oral)
Metabolism	Hepatic
Biological half-life	5 h to 6 h
Excretion	70–85% renal, 2% faecal
Identifiers
CAS Number	364-62-5 Y
ATC code	A03FA01 (WHO)
PubChem	CID: 4168
IUPHAR/BPS	241
DrugBank	DB01233 Y
ChemSpider	4024 Y
UNII	L4YEB44I46 Y
KEGG	D00726 Y
ChEBI	CHEBI:107736 Y
ChEMBL	CHEMBL86 Y
Chemical data
Formula	C14H22ClN3O2
Molecular mass	299.80 g/mol
SMILES Clc1cc(c(OC)cc1N)C(=O)NCCN(CC)CC
InChI 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) Y Key:TTWJBBZEZQICBI-UHFFFAOYSA-N Y
Physical data
Melting point	147.3 °C (297.1 °F)
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Metoclopramide is a medication used mostly for stomach and esophageal problems. It is commonly used to treat nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying due to either diabetes or following surgery, and to help with gastroesophageal reflux disease. It is also used to treat migraine headaches.

Common side effects include: feeling tired, diarrhea, and feeling restless. More serious side effects include: movement disorder like tardive dyskinesia, a condition called neuroleptic malignant syndrome, and depression. It is thus rarely recommended that people take the medication for longer than twelve weeks. It is pregnancy category B in the United States and category A in Australia, meaning 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.

In 2012, metoclopramide was one of the top 100 most prescribed medications in the United States. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.

Medical uses

Metoclopramide 5-mg tablets (Pliva)

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, migraine headaches, and emetogenic drugs. In the setting of painful conditions such as migraine headaches, metoclopramide may be used in combination with paracetamol (acetaminophen) or in combination with aspirin. It is also used preventatively by some EMS providers when transporting people who are conscious and spinally immobilized.

Evidence also supports its use for gastroparesis, a condition that causes the stomach to empty poorly, and gastroesophageal reflux disease. It is also used in pregnancy as a second choice for treatment of hyperemesis gravidarum (severe nausea and vomiting of pregnancy). It increases peristalsis of the duodenum and jejunum, increases tone and amplitude of gastric contractions, and relaxes the pyloric sphincter and duodenal bulb, while simultaneously increasing lower esophageal sphincter tone. These gastroprokinetic effects make metoclopramide useful in the treatment of gastric stasis (for example: after gastric surgery or diabetic gastroparesis), as an aid in gastrointestinal radiographic studies by accelerating transit through the gastrointestinal system in barium studies, and as an aid in difficult intubation of the small intestine. It is also used in gastroesophageal reflux disease.

Adverse effects

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, constipation, depression, headache, and extrapyramidal effects such as oculogyric crisis. Rare but serious ADRs associated with metoclopramide therapy include agranulocytosis, supraventricular tachycardia, hyperaldosteronism, neuroleptic malignant syndrome, akathisia and tardive dyskinesia.

Metoclopramide may be the most common cause of drug-induced movement disorders. 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 patients. 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 regarding the risk of tardive dyskinesia with chronic or high-dose use of the drug.

Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with diphenhydramine injected intramuscularly. 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.

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.

Cautions and 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 patients with clinical depression, as it may worsen one's mental state. It is contraindicated in patients with a suspected bowel obstruction and in epilepsy, if a stomach operation has been performed in the previous three or four days, if the patient has ever had bleeding, perforation or blockage of the stomach, in cases of pheochromocytoma, and in newborn babies.

Patients with a history of ADHD, restless legs syndrome, hyperprolactinaemia, and Parkinson's disease should be closely monitored when using dopamine antagonists for treatment of emesis. Patients who take antipsychotics are recommended not to take metoclopramide.

In 2011, the country of France restricted use of the drug in children and adolescents, and issued concerns about usage in certain populations.

Pregnancy

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or unborn baby. In the USA, it has been assigned to pregnancy category B by the US FDA. 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.

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.

Mechanism of action

Metoclopramide was first described by Dr. Louis Justin-Besançon and C. Laville in 1964.

It 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.

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. At higher doses, 5-HT₃ antagonist activity may also contribute to the antiemetic effect.

The gastroprokinetic activity of metoclopramide is mediated by muscarinic 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.

Brand names

Metoclopramide is available world-wide under various trade names.

Veterinary use

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

See also

• Benzamide, the chemical class to which metoclopramide belongs
  • Bromopride, the bromo- analogue of metoclopramide
  • Cisapride, a benzamide with a different mechanism of action
  • Itopride, a newer benzamide with effects similar to those of metoclopramide
  • Domperidone, another drug with antiemetic and prokinetic properties