Metoclopramide

Metoclopramide (INN) is an antiemetic and gastroprokinetic agent. It is commonly used to treat nausea and vomiting, to facilitate gastric emptying in people with gastroparesis, and as a treatment for the gastric stasis often associated with migraine headaches.

Medical uses
Metoclopramide is commonly used to treat nausea including that due to chemotherapy and that occurring post operatively. Evidence also supports its use for gastroparesis (poor stomach emptying) and gastroesophageal reflux disease.

Antiemetic


Metoclopramide commonly treats nausea and vomiting associated with conditions such as uremia, radiation sickness, malignancy, labor, infection, migraine headaches, and emetogenic drugs such as morphine. In the setting of painful conditions such as migraine headaches, Metoclopramide may be used in combination with paracetamol (acetaminophen) (available in the UK as Paramax, and in Australia as Metomax) or in combination with aspirin (MigraMax).

Gastroprokinetic
Metoclopramide increases peristalsis of the jejunum and duodenum, increases tone and amplitude of gastric contractions, and relaxes the pyloric sphincter and duodenal bulb. These gastroprokinetic effects make metoclopramide useful in the treatment of gastric stasis (e.g. 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 (GERD).

Other indications
By inhibiting the action of dopamine, metoclopramide has sometimes been used to stimulate lactation. It can also be used in the treatment of migraines in the setting of allodynia, where it is more effective than triptans.

Adverse effects


Common adverse drug reactions (ADRs) associated with metoclopramide therapy include restlessness, drowsiness, dizziness, lassitude, 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.

Recent research suggests that 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 USFDA recommends that metoclopramide be used for short term treatment, preferably less than 12 weeks. In 2009, the USFDA 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 benztropine, diphenhydramine, trihexyphenidyl or procyclidine.

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 where it is a receptor antagonist, and is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist.

The anti-emetic action of metoclopramide is due to its antagonist activity at D2 receptors in the chemoreceptor trigger zone (CTZ) in the central nervous system (CNS)—this action prevents nausea and vomiting triggered by most stimuli. At higher doses, 5-HT3 antagonist activity may also contribute to the anti-emetic 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 anti-emetic effect.

Contraindications and precautions
Metoclopramide is contraindicated in phaeochromocytoma. 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 mental state. Also contraindicated with a suspected bowel obstruction.

Use in pregnancy
Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or unborn baby. 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. Metoclopramide is excreted into milk.

Brand names
It is available under various trade names including Maxolon (Shire/Valeant), Reglan (Schwarz Pharma), Degan (Lek), Maxeran (Sanofi Aventis), Primperan (Sanofi Aventis), Pylomid (Bosnalijek), Cerucal (AWD Pharma), Pramin (Generic), Macperan (in South Korea), and Perinom (in Nepal).

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