Metoclopramide

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Metoclopramide
Metoclopramide.svg
Systematic (IUPAC) name
4-amino-5-chloro-N-(2-(diethylamino)ethyl)-
2-methoxybenzamide
Clinical data
Trade names See list
AHFS/Drugs.com monograph
MedlinePlus a684035
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral, intravenous, intramuscular
Pharmacokinetic data
Bioavailability 80±15% (oral)
Metabolism Hepatic
Half-life 5–6 hours
Excretion 70–85% renal, 2% faecal
Identifiers
CAS number 364-62-5 YesY
ATC code A03FA01
PubChem CID 4168
IUPHAR ligand 241
DrugBank DB01233
ChemSpider 4024 YesY
UNII L4YEB44I46 YesY
KEGG D00726 YesY
ChEBI CHEBI:107736 YesY
ChEMBL CHEMBL86 YesY
Chemical data
Formula C14H22ClN3O2 
Mol. mass 299.80 g/mol
Physical data
Melt. point 147.3 °C (297 °F)
 YesY (what is this?)  (verify)

Metoclopramide (INN) /ˌmɛtəˈklɒprəmd/ is an antiemetic (useful in treating vomiting) and gastroprokinetic agent. It belongs to a group of medicines called dopaminergic blockers. 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.

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.[1]

Medical uses[edit]

Clinicians commonly use metoclopramide to treat nausea - including that due to chemotherapy and that occurring postoperatively. Evidence also supports its use for gastroparesis (poor stomach emptying) and gastroesophageal reflux disease.[2]

Antiemetic[edit]

Metoclopramide 5-mg tablets (Pliva)

Metoclopramide treats nausea and vomiting associated with conditions such as uremia, radiation sickness, malignancy, labor, infection, migraine headaches, and emetogenic drugs.[3][4] 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).

The Rosemont Patient Information Leaflet of their sugar-free metoclopramide hydrochloride (5 mg/5 ml) oral solution states, " Metoclopramide can be used to treat stomach upset including heartburn, wind, pain, indigestion, sickness and bile regurgitation, to stop nausea and vomiting, to relieve your symptoms of nausea and vomiting when you have a migraine, to help restore normal stomach emptying after an operation and during hospital tests such as a barium meal." and "In young adults and children, metoclopramide can be given for severe and long-lasting vomiting if the cause is known, to stop vomiting caused by cancer treatment such as radiotherapy and chemotherapy, to help in passing a tube into the stomach and intestine and to help stop feeling and being sick before having an operation." [5]

Gastroprokinetic[edit]

Metoclopramide increases peristalsis of the jejunum and duodenum, 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.[6]

Other indications[edit]

By inhibiting the action of dopamine, metoclopramide has sometimes been used to stimulate lactation.[7] It can also help treat migraines in the setting of allodynia, where it is more effective than triptans.[8]

Adverse effects[edit]

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.[4]

Metoclopramide may be the most common cause of drug-induced movement disorders.[9] The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy.[3][4] 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.[9] 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.[9]

Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with benadryl (diphenhydramine hydrochloride) or benzatropine injected intramuscularly.[10] 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.[11]

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 the dose of metoclopramide.[12]

Cautions[edit]

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.[4] Also, it is contraindicated in patients with a suspected bowel obstruction.[2]

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[edit]

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or unborn baby.[13] In the USA, it has been assigned to pregnancy category B by the US FDA.[14] 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. [15] A large cohort study in Denmark found, in addition, no association between metoclopramide exposure and miscarriage.[16] Metoclopramide is excreted into milk.[13]

Infants[edit]

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.[17]

Mechanism of action[edit]

Metoclopramide was first described by Dr. Louis Justin-Besançon and C. Laville in 1964.[18]

It appears to bind to dopamine D2 receptors with nanomolar affinity (Ki 28.8 nM),[19] 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.[20] 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.[21][22] The gastroprokinetic effect itself may also contribute to the antiemetic effect. Metoclopramide also increases the tone of the lower esophageal sphincter.[23]

Brand names[edit]

Metoclopramide is available world-wide under various trade names:

Veterinary use[edit]

Metoclopramide is also commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits.[26]

Use[edit]

Metoclopramide is contraindicated in case of 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.[5]

See also[edit]

References[edit]

  1. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  2. ^ a b "Metoclopramide hydrochloride". Monograph. The American Society of Health-System Pharmacists. Retrieved 2011-04-03. 
  3. ^ a b "Maxolon (Australian Approved Product Information)". Valeant Pharmaceuticals. 2000. 
  4. ^ a b c d Rossi S., ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3. 
  5. ^ a b http://xpil.medicines.org.uk/ViewPil.aspx?DocID=8068
  6. ^ "METOCLOPRAMIDE (metoclopramide hydrochloride) injection, solution [Hospira, Inc.]" http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=373ba08b-33ad-49fc-28a7-928e89a65314#nlm34089-3
  7. ^ "Metoclopramide". lowmilksupply.org. 
  8. ^ Snow, V.; Weiss, K.; Wall, E. M.; Mottur-Pilson, C.; American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine (2002). "Pharmacologic Management of Acute Attacks of Migraine and Prevention of Migraine Headache" (pdf). Annals of Internal Medicine 137 (10): 840–849. doi:10.7326/0003-4819-137-10-200211190-00014. PMID 12435222.  edit
  9. ^ a b c "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". 
  10. ^ "Metoclopramide (metoclopramide hydrochloride) injection, solution [Hospira, Inc.]" http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=373ba08b-33ad-49fc-28a7-928e89a65314#nlm34089-3
  11. ^ 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.
  12. ^ 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. 
  13. ^ a b 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. 
  14. ^ http://www.drugs.com/metoclopramide.html
  15. ^ 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.  edit
  16. ^ 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.  edit
  17. ^ Hibbs, AM; Lorch, SA (Aug 2006). "Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic review.". Pediatrics 118 (2): 746–52. PMID 16882832. 
  18. ^ 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.  edit
  19. ^ 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
  20. ^ Rang, H. P.; Dale, M. M.; Ritter, J. M.; Moore, P. K. (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. 
  21. ^ Sweetman S., ed. (2004). Martindale: The Complete Drug Reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. 
  22. ^ 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. ISSN 1043-6618. PMID 7479521.  edit
  23. ^ 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. 
  24. ^ felleskatalogen.no
  25. ^ Snyman, J.R., ed. (June 2010). MIMS (Monthly Index of Medical Specialities) (Vol. 50 no. 6 ed.). Johannesburg: Avusa Media Ltd. 
  26. ^ Mikota, S. K.; Plumb, D. C. (June 2003). "Metoclopramide HCl". The Elephant Formulary. Elephant Care International. 

Further reading[edit]

  • Compendium of Pharmaceuticals and Specialties 2011. Toronto: Canadian Pharmacists Association. 2011. ISBN 978-1-894402-54-5.