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Metoclopramide



Metoclopramide
Systematic (IUPAC) name
4-amino-5-chloro-N-(2-(diethylamino)ethyl)- 2-methoxybenzamide
Identifiers
CAS number	364-62-5
ATC code	A03FA01
PubChem	4168
DrugBank	APRD00665
Chemical data
Formula	C₁₄H₂₂ClN₃O₂
Mol. mass	299.80 g/mol
Pharmacokinetic data
Bioavailability	80±15% (oral)
Metabolism	Hepatic
Half life	5–6 hours
Excretion	70–85% renal, 2% faecal
Therapeutic considerations
Pregnancy cat.	A (Au), B (U.S.)
Legal status	S3/S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Oral, IV, IM

Metoclopramide (INN) (pronounced /ˌmɛtəˈkloʊprəmaɪd/ or /ˌmɛtəˈklɒprəmaɪd) is a potent dopamine receptor antagonist used for its antiemetic and prokinetic properties. Thus it is primarily used to treat nausea and vomiting, and to facilitate gastric emptying in patients with gastric stasis.

It is available under various trade names including: Maxolon (Shire/Valeant), Reglan (Wyeth), Degan (Lek), Maxeran (Sanofi Aventis), Primperan (Sanofi Aventis), and Pylomid (Bosnalijek). It was protected under U.S. patent 3177252 until 6 April 1982.

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Mode of action

Metoclopramide was first described by Dr. Louis Justin-Besançon and C. Laville in 1964.^[1] 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.^[2] At higher doses, 5-HT₃ antagonist activity may also contribute to the anti-emetic effect.

The prokinetic activity of metoclopramide is mediated by muscarinic activity, D2 receptor antagonist activity and 5-HT₄ receptor agonist activity.^[3]^[4] The prokinetic itself may also contribute to the anti-emetic effect.

Clinical use

Antiemetic use

Metoclopramide is commonly used to treat nausea and vomiting (emesis) associated with conditions including: emetogenic drugs, uraemia, radiation sickness, malignancy, labor, and infection.^[5]^[6] It is also used by itself or in combination with paracetamol (acetaminophen) for the relief of migraine.

It is considered ineffective in postoperative nausea and vomiting (PONV) at standard doses, and ineffective for motion sickness.^[5]^[6] In nausea and vomiting associated with cancer chemotherapy, it has been superseded by the more effective 5-HT₃ antagonists (e.g. ondansetron).

Prokinetic use

Metoclopramide increases peristalsis of the jejunum and duodenum, increases tone and amplitude of gastric contractions, and relaxes the pyloric sphincter and duodenal bulb. These prokinetic effects make metoclopramide useful in the treatment of gastric stasis (e.g. after gastric surgery or diabetic gastroparesis), as an aid in gastrointestinal radiology by increasing transit in barium studies, and as an aid in difficult small intestinal intubation. It is also used in gastroesophageal reflux disease (GERD/GORD).

Other indications

By inhibiting the action of prolactin inhibiting hormone (i.e. dopamine), metoclopramide has sometimes been used to stimulate lactation.

Contraindications/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.^[6] Also contraindicated with a suspected bowel obstruction.

Adverse effects

Common adverse drug reactions (ADRs) associated with metoclopramide therapy include: restlessness, drowsiness, dizziness, lassitude, and/or dystonic reactions. Infrequent ADRs include: headache, extrapyramidal effects (EPSE) such as oculogyric crisis, hypertension, hypotension, hyperprolactinaemia leading to galactorrhoea, diarrhoea, constipation, and/or depression. Rare but serious ADRs associated with metoclopramide therapy include: agranulocytosis, supraventricular tachycardia, hyperaldosteronism, neuroleptic malignant syndrome and/or tardive dyskinesia.^[6]

The risk of EPSEs are increased in young adults (<20 years) and children.^[6] Such dystonic reactions are usually treated with benztropine or procyclidine. The risk of tardive dyskinesia and EPSE is increased with high dose therapy and with prolonged use. Tardive dyskinesias may be persistent and irreversible in some patients.^[5]

References

^ Justin-Besançon L, Laville C. Action antiémétique du métoclopramide vis-à-vis de l'apomorphine et de l'hydergine [Antiemetic action of metoclopramide with respect to apomorphine and hydergine]. C R Seances Soc Biol Fil 1964;158:723–7. PMID 14186927.
^ Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone; 2003. ISBN 0-443-07145-4
^ Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4
^ Tonini M, Candura SM, Messori E, Rizzi CA. Therapeutic potential of drugs with mixed 5-HT₄ agonist/5-HT₃ antagonist action in the control of emesis. Pharmacol Res 1995;31(5):257-60. PMID 7479521
^ ^a ^b ^c Valeant Pharmaceuticals. Maxolon (Australian Approved Product Information). Auburn (NSW): Valeant Pharmaceuticals Australasia; 2000.
^ ^a ^b ^c ^d ^e Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3