Metoclopramide

Metoclopramide
Systematic (IUPAC) name
4-Amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide
Clinical data
Pronunciation /ˌmɛtəˈklɒprəmaɪd/
Trade names Many names worldwide[1]
AHFS/Drugs.com monograph
MedlinePlus a684035
License data
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
Routes of
administration		 Oral, intravenous, intramuscular
Legal status
Legal status
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 YesY
ATC code A03FA01 (WHO)
PubChem CID 4168
IUPHAR/BPS 241
DrugBank DB01233 YesY
ChemSpider 4024 YesY
UNII L4YEB44I46 YesY
KEGG D00726 YesY
ChEBI CHEBI:107736 YesY
ChEMBL CHEMBL86 YesY
Chemical data
Formula C14H22ClN3O2
Molar mass 299.80 g/mol
Physical data
Melting point 147.3 °C (297.1 °F)
  (verify)

Metoclopramide is a medication used mostly for stomach and esophageal problems.[2] 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.[3] It is also used to treat migraine headaches.[4]

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.[3] It is thus rarely recommended that people take the medication for longer than twelve weeks.[3] 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.[3][5] It belongs to the group of medications known as dopamine-receptor antagonists.[3]

In 2012, metoclopramide was one of the top 100 most prescribed medications in the United States.[6] 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.[7]

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.[3][8][9][10] 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.[11]

Evidence also supports its use for gastroparesis, a condition that causes the stomach to empty poorly, and gastroesophageal reflux disease.[3] It is also used in pregnancy as a second choice for treatment of hyperemesis gravidarum (severe nausea and vomiting of pregnancy).[3] 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.[12]

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.[9]

Metoclopramide may be the most common cause of drug-induced movement disorders.[13] The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy.[8][9] 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.[13] 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.[13]

Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with diphenhydramine injected intramuscularly.[14] 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.[15]

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.[16]

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.[9] It is contraindicated in patients with a suspected bowel obstruction[3] 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.[10]

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.

Pregnancy

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or unborn baby.[17] In the USA, it has been assigned to pregnancy category B by the US FDA.[18] 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. [19] A large cohort study in Denmark found, in addition, no association between metoclopramide exposure and miscarriage.[20] Metoclopramide is excreted into milk.[17]

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.[21]

Mechanism of action

Metoclopramide was first described by Dr. Louis Justin-Besançon and C. Laville in 1964.[22]

It appears to bind to dopamine D2 receptors with nanomolar affinity (Ki 28.8 nM),[23] 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.[24] 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.[25][26] The gastroprokinetic effect itself may also contribute to the antiemetic effect. Metoclopramide also increases the tone of the lower esophageal sphincter.[27]

Brand names

Metoclopramide is available world-wide under various trade names.[1]

Veterinary use

Metoclopramide is also commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits.[28]

See also

References

  1. 1 2 Drugs.com International names for metoclopramide Page accessed March 28, 2016
  2. ↑ "Metoclopramide". nlm.nih.gov. Retrieved 28 September 2014.
  3. 1 2 3 4 5 6 7 8 9 "Metoclopramide hydrochloride". Monograph. The American Society of Health-System Pharmacists. Retrieved 2014-09-27.
  4. ↑ Derry, S; Moore, RA; McQuay, HJ (Nov 10, 2010). "Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults.". The Cochrane database of systematic reviews (11): CD008040. doi:10.1002/14651858.CD008040.pub2. PMID 21069700.
  5. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Retrieved 22 April 2014.
  6. ↑ Bartholow, Michael. "Top 200 Drugs of 2012". Pharmacy Times. Retrieved 22 April 2014.
  7. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  8. 1 2 "Maxolon (Australian Approved Product Information)". Valeant Pharmaceuticals. 2000.
  9. 1 2 3 4 Rossi S., ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3.
  10. 1 2 http://xpil.medicines.org.uk/ViewPil.aspx?DocID=8068
  11. ↑ "Ambulance Victoria Clinical Guideline A0701"http://www.ambulance.vic.gov.au/media/docs/Adult%20CPG%20wm-a01f0e1e-4fc0-405c-bc83-3136adf4a723-0.pdf
  12. ↑ "METOCLOPRAMIDE (metoclopramide hydrochloride) injection, solution [Hospira, Inc.]" http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=373ba08b-33ad-49fc-28a7-928e89a65314#nlm34089-3
  13. 1 2 3 "FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs" (Press release). U.S. Food and Drug Administration. 2009-02-26. Retrieved 2009-06-11. "Lay Summary – WebMD".
  14. ↑ "Metoclopramide (metoclopramide hydrochloride) injection, solution [Hospira, Inc.]" http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=373ba08b-33ad-49fc-28a7-928e89a65314#nlm34089-3
  15. ↑ Olanow C, Schapira AV. Chapter 372. Parkinson's Disease and Other Movement Disorders. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
  16. ↑ Parlak, I; Atilla, R; Cicek, M; Parlak, M; Erdur, B; Guryay, M; Sever, M; Karaduman, S (Sep 2005). "Rate of metoclopramide infusion affects the severity and incidence of akathisia.". Emergency medicine journal : EMJ 22 (9): 621–4. doi:10.1136/emj.2004.014712. PMC 1726928. PMID 16113179.
  17. 1 2 Briggs, G. G.; Freeman, R. K.; Yaffe, S. J. (2008). Drugs in Pregnancy and Lactation (8th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 1197–1200. ISBN 0-7817-7876-X. Retrieved 2009-06-11.
  18. ↑ http://www.drugs.com/metoclopramide.html
  19. ↑ Matok, I.; Gorodischer, R.; Koren, G.; Sheiner, E.; Wiznitzer, A.; Levy, A. (2009). "The Safety of Metoclopramide Use in the First Trimester of Pregnancy" (pdf). New England Journal of Medicine 360 (24): 2528–2535. doi:10.1056/NEJMoa0807154. PMID 19516033.
  20. ↑ Pasternak, B. R.; Svanström, H.; Mølgaard-Nielsen, D.; Melbye, M.; Hviid, A. (2013). "Metoclopramide in Pregnancy and Risk of Major Congenital Malformations and Fetal Death". JAMA 310 (15): 1601–1611. doi:10.1001/jama.2013.278343. PMID 24129464.
  21. ↑ Hibbs, AM; Lorch, SA (Aug 2006). "Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic review.". Pediatrics 118 (2): 746–52. doi:10.1542/peds.2005-2664. PMID 16882832.
  22. ↑ Justin-Besancon, L.; Laville, C. (1964). "Antiemetic Action of Metoclopramide with Respect to Apomorphine and Hydergine". Comptes Rendus des Séances de la Société de Biologie et de ses Filiales (in French) 158: 723–727. PMID 14186927.
  23. ↑ Prediction of Catalepsies Induced by Amiodarone, Aprindine and Procaine: Similarity in Conformation of Diethylaminoethyl Side Chain http://jpet.aspetjournals.org/content/287/2/725.full.pdf
  24. ↑ Rang, H. P.; Dale, M. M.; Ritter, J. M.; Moore, P. K. (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
  25. ↑ Sweetman S., ed. (2004). Martindale: The Complete Drug Reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4.
  26. ↑ Tonini, M.; Candura, S. M.; Messori, E.; Rizzi, C. A. (1995). "Therapeutic Potential of Drugs with Mixed 5-HT4 Agonist/5-HT3 Antagonist Action in the Control of Emesis". Pharmacological Research 31 (5): 257–260. doi:10.1016/1043-6618(95)80029-8. ISSN 1043-6618. PMID 7479521.
  27. ↑ Feldman, M.; Friedman, L. S.; Brandt, L. J., eds. (2010). "Ch. 43: Gastroesophageal Reflux Disease". Sleisenger and Fordtran's Gastrointestinal and Liver Disease (9th ed.). Philadelphia: Saunders. ISBN 978-1-4160-6189-2.
  28. ↑ Mikota, S. K.; Plumb, D. C. (June 2003). "Metoclopramide HCl". The Elephant Formulary. Elephant Care International.

Further reading

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