Metoclopramide

Metoclopramide

Systematic (IUPAC) name
4-amino-5-chloro-N-(2-(diethylamino)ethyl)- 2-methoxybenzamide
Clinical data
Trade names	Reglan
AHFS/Drugs.com	monograph
MedlinePlus	a684035
Pregnancy cat.	A (Au), B (U.S.)
Legal status	S3/S4 (Au), POM (UK), ℞-only (U.S.)
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 Y
ATC code	A03FA01
PubChem	CID 4168
IUPHAR ligand	241
DrugBank	DB01233
ChemSpider	4024 Y
UNII	L4YEB44I46 Y
KEGG	D00726 Y
ChEBI	CHEBI:107736 N
ChEMBL	CHEMBL86 Y
Chemical data
Formula	C14H22ClN3O2
Mol. mass	299.80 g/mol
SMILES	eMolecules & PubChem
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
Melt. point	147.3 °C (297 °F)
N(what is this?)  (verify)

Metoclopramide (INN) ( /ˌmɛtəˈklɒprəmaɪd/) 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 which is due to chemotherapy and that occurring post operatively. Evidence also supports its use for gastroparesis (poor stomach emptying) and gastroesophageal reflux disease.^[1]

Antiemetic

Metoclopramide 5mg tablets (Pliva)

Metoclopramide commonly treats nausea and vomiting associated with conditions such as uremia, radiation sickness, malignancy, labor, infection, migraine headaches, and emetogenic drugs.^[2][3] 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.^[4]

Adverse effects

Plastic ampoule of metoclopramide

Common adverse drug reactions (ADRs) associated with metoclopramide therapy include restlessness, drowsiness, dizziness, fatigue, 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.^[3]

Recent research suggests that metoclopramide may be the most common cause of drug-induced movement disorders.^[5] The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy.^[2][3] 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.^[5] 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.^[5]

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.^[6]

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.^[7] 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.^[8][9] 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.^[3] Also contraindicated with a suspected bowel obstruction.^[1]

Use in pregnancy

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or unborn baby.^[10] 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. ^[11] Metoclopramide is excreted into milk.^[10]

Brand names

It is available under various trade names including Maxolon in the UK (Shire/Valeant), Reglan in the USA (Schwarz Pharma), Degan (Lek), Maxeran (Sanofi Aventis), Primperan (Sanofi Aventis), Pylomid (Bosnalijek), Cerucal (AWD Pharma), Pramin (Generic)).

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.

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

References

1. ^ ^{a b} "Metoclopramide hydrochloride". Monograph. The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/metoclopramide-hydrochloride.html. Retrieved 2011-04-03. 
2. ^ ^{a b} "Maxolon (Australian Approved Product Information)". Valeant Pharmaceuticals. http://www.mydr.com.au/medicines/cmis/maxolon-tablets. 
3. ^ ^{a b c d} Rossi S., ed (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3. 
4. ^ 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. PMID 12435222. http://www.annals.org/content/137/10/840.full.pdf.  edit
5. ^ ^{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. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149533.htm. Retrieved 2009-06-11.  "Lay summary–WebMD". http://www.webmd.com/digestive-disorders/news/20090227/metoclopramide-drugs-get-black-box-warning. 
6. ^ Justin-Besancon, L.; Laville, C. (1964). "Antiemetic Action of Metoclopramide with Respect to Apomorphine and Hydergine" (in french). Comptes rendus des seances de la Societe de biologie et de ses filiales 158: 723–727. PMID 14186927.  edit
7. ^ Rang, H.P.; Dale, M. M.; Ritter, J. M.; Moore, P. K. (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. 
8. ^ Sweetman S., ed (2004). Martindale: The complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. 
9. ^ 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
10. ^ ^{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. http://books.google.com/books?id=YOEV2w3XTxsC&pg=PA1197. Retrieved 2009-06-11. 
11. ^ 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. http://www.nejm.org/doi/pdf/10.1056/NEJMoa0807154.  edit

Further reading

• Brenner, G. M. (2000). Pharmacology. London: Saunders. ISBN 0-7216-7757-6. 

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

• Anderson, E. P.; Freeman, E. B. (May 2004). "Recognition of Movement Disorders and Extrapyramidal side effects - would you recognize them if you see them?" (pdf). Practical Gastroenterology: 14. http://www.reflux.org/reflux/webdoc01.nsf/487b3ba0c2f1a4ff85256ff30009f061/fdb3ea9e635ff41d8525702e001b6f6b/$FILE/Tardive%20PGMay04Article.pdf.