Metoclopramide

Metoclopramide is a medication used mostly for stomach

and esophageal problems.[2] It is commonly used to treat and
prevent nausea and vomiting, to help with emptying of the
stomach in people with delayed stomach emptying, 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 and works as a prokinetic.[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
Metoclopramide
Essential Medicines, the most effective
and safe medicines needed in a health
system.[7] It is available as a generic
medication.[3] The wholesale cost in
the developing world as of 2014 is
Clinical data
US$0.003 to US$0.08 per pill.[8] In the
Pronunciation /ˌmɛtəˈklɒ
United States a month worth of
Trade Primperan,
medication is generally less than names
Reglan,
US$25.[9] In 2016 it was the 250th most others[1]
prescribed medication in the United AHFS/Drugs.com Mono
States with more than 1 million MedlinePlus a684035
prescriptions.[10]
License US FDA: Metocl
data
Pregnancy AU: A
Medical uses category
US: B (No
risk in non-
human
studies)

Metoclopramide 5-mg tablets

Routes of By mouth
administration
intraveno
Nausea
intramus

Metoclopramide is commonly used to

Drug class D2
treat nausea and vomiting associated
receptor
with conditions such as uremia, antagonist;
5-HT3
radiation sickness, cancer and the
receptor
effects of chemotherapy, labor,
antagonist;
infection, and emetogenic 5-HT4
drugs.[3][11][12][13] As a perioperative receptor
anti-emetic, the effective dose is agonist;
Prolactin
usually 25 to 50 mg (compared to the
releaser
usual 10 mg dose).
ATC code A03FA01
It is also used in pregnancy as a (WHO )
second choice for treatment of Legal status
hyperemesis gravidarum (severe Legal AU: S3
status
nausea and vomiting of pregnancy).[3] (combination
with
It is also used preventatively by some paracetamol),
EMS providers when transporting S4 (alone)

people who are conscious and spinally CA: ℞-only

immobilized.[14] UK: POM

(Prescription
only)
Migraine US: ℞-only

In migraine headaches, Pharmacokinetic data

metoclopramide may be used in Bioavailability 80 ±

15% (by
combination with paracetamol
mouth)
(acetaminophen) or in combination
Metabolism Liver
with aspirin.[15]
 Elimination 5–6 hours
Gastroparesis half-life
Excretion Urine: 70–
Evidence also supports its use for 85%
gastroparesis, a condition that causes Feces: 2%

the stomach to empty poorly, and as of Identifiers

2010 it was the only drug approved by IUPAC name

the FDA for that condition.[3][16] 4-Amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenza

mide

It is also used in gastroesophageal CAS 364-62-5  

reflux disease.[3][17] Number

PubChem 4168
CID
IUPHAR/BPS 241
Lactation
DrugBank DB01233  

While metoclopramide is used to try to

ChemSpider 4024  
increase breast milk production,
UNII L4YEB44I46
evidence that it is effective for this is
KEGG D00726  
poor.[18] Its safety for this use is also
ChEBI CHEBI:107736  
unclear.[19]

ChEMBL ChEMBL86  

Aspiration
CompTox DTXSID6045
While metoclopramide reduces gastric Dashboard
(EPA)
volume and acidity, there is not enough
ECHA 100.006.058
evidence to say that it reduces the InfoCard
incidence of pulmonary aspiration.
Chemical and
Contraindications physical data
Formula C H ClN O
14 22 3 2
Metoclopramide is contraindicated in Molar 299.80 g·mol−1
mass
pheochromocytoma. It should be used
3D model Interactive
with caution in Parkinson's disease (JSmol)
image
since, as a dopamine antagonist, it may
Melting 147.3 °C
worsen symptoms. Long-term use point
(297.1 °F)
should be avoided in people with
SMILES
clinical depression, as it may worsen Clc1cc(c(OC)cc1N)C(=O)NCCN(CC)CC

one's mental state.[12] It is InChI

InChI=1S/C14H22ClN3O2/c1-4-18(5-2)7-6-17-14(19)1
0-8-11(15)12(16)9-13(10)20-3/h8-9H,4-7,16H2,1-3H

contraindicated for people with a 3,(H,17,19) 

Key:TTWJBBZEZQICBI-UHFFFAOYSA-N 

suspected bowel obstruction[3] and in   (verify)

epilepsy, if a stomach operation has

been performed in the previous three or four days, if the
person has ever had bleeding, perforation or blockage of the
stomach, and in newborn babies.[13]

People 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. People who take antipsychotics are
recommended not to take metoclopramide.

The safety of the drug was reviewed by the European

Medicines Agency in 2011, which determined that it should
not be prescribed in high doses, for periods of more than five
days, or given to children below 1 year of age. They suggested
its use in older children should be restricted to treating post-
chemotherapy or post-surgery nausea and vomiting, and even
then only for patients where other treatments have failed. For
adults, they recommended its use be restricted to treating
migraines and post-chemotherapy or post-surgery patients.[20]

Pregnancy

Metoclopramide has long been used in all stages of

pregnancy with no evidence of harm to the mother or unborn
baby.[21] In the US, it has been assigned to pregnancy
category B by the US FDA.[22] 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.[23] A large cohort study in Denmark
found, in addition, no association between metoclopramide
exposure and miscarriage.[24] Metoclopramide is excreted
into milk.[21]

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.[25]

Side 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,
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.[12][26]

Metoclopramide may be the most common cause of drug-

induced movement disorders.[27] The risk of extrapyramidal
effects is increased in people under 20 years of age, and with
high-dose or prolonged therapy.[11][12] Tardive dyskinesia may
be persistent and irreversible in some people. The majority of
reports of tardive dyskinesia occur in people who have used
metoclopramide for more than three months.[27]
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.[27]

Dystonic reactions may be treated with benzatropine,

diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms
usually subside with diphenhydramine injected
intramuscularly.[17] 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.[28]

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.[29]

Pharmacology
Pharmacodynamics
Metoclopramide appears to bind to dopamine D2 receptors
with nanomolar affinity (Ki = 28.8 nM),[30] where it is a
receptor antagonist, and is also a mixed 5-HT3 receptor
antagonist/5-HT4 receptor agonist.

Mechanism of action

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.[31] At
higher doses, 5-HT3 antagonist activity may also contribute to
the antiemetic effect.[32]

The gastroprokinetic activity of metoclopramide is mediated

by muscarinic activity, D2 receptor antagonist activity, and 5-
HT4 receptor agonist activity.[33][34] The gastroprokinetic
effect itself may also contribute to the antiemetic effect.
Metoclopramide also increases the tone of the lower
esophageal sphincter.[35]

Metoclopramide 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.

Chemistry
Metoclopramide is a substituted benzamide; cisapride and
mosapride are structurally related.[32]

History
Metoclopramide was first described by Louis Justin-
Besançon and Charles Laville in 1964, while working to
improve the anti-dysrhythmic properties of
procainamide.[36][37][38][39] That research project also
produced the product sulpiride.[36] The first clinical trials were
published by Tourneu et al. in 1964 and by Boisson and Albot
in 1966.[39] Justin-Besançon and Laville worked for
Laboratoires Delagrange[36] and that company introduced the
drug as Primperan in 1964.[40][41] Laboratoires Delagrange
was acquired by Synthelabo in 1991[42][43] which eventually
became part of Sanofi.[44]
A.H. Robins introduced the drug in the US under the
tradename Reglan in 1979[45] as an injectable[46] and an oral
form was approved in 1980.[47] in 1989 A.H. Robins was
acquired by American Home Products,[48] which changed its
name to Wyeth in 2002.[49]

The drugs were initially used to control nausea for people with
severe headaches or migraines, and later uses for nausea
caused by radiation therapy and chemotherapy, and later yet
for treating nausea caused by anesthesia.[39] In the US the
injectable form was labelled for chemotherapy-induced
nausea and the oral form was eventually labelled for
gastroesophageal reflux disease.[50]

It became widely used in the 1980s, becoming the most

commonly used drug to treat anesthesia-induced nausea[39]
and for treating gastritis in emergency rooms.[51]

The first generics were introduced in 1985.[50][52]

In the early 1980s signs began to emerge in

pharmacovigilance studies from Sweden that the drug was
causing tardive dyskinesia in some patients.[53] The FDA
required a warning about tardive dyskinesia to be added to
the drug label in 1985 stating that: "tardive dyskinesia . . . may
develop in patients treated with metoclopramide,” and warned
against use longer than 12 weeks, as that was how long the
drug has been tested.[54][55] In 2009 the FDA required that a
black box warning be added to the label.[16][27]

The emergence of this severe side effect led to a wave of

product liability litigation against generic manufacturers as
well as Wyeth.[56] The litigation was complicated since there
was a lack of clarity in jurisdiction between state laws, where
product liability is determined, and federal law, which
determines how drugs are labelled, as well as between
generics companies, which had no control over labelling, and
the originator company, which did.[56][57] The litigation yielded
at least two important cases. In Conte v. Wyeth in the
California state courts, the claims of the plaintiff against the
generic companies Pliva, Teva, and Purepac that had sold the
drugs that the plaintiff actually took, and the claims against
Wyeth, whose product the plaintiff never took, were all
dismissed by the trial court, but the case was appealed, and in
2008 the appellate court upheld the dismissal of the cases
against the generic companies, but reversed on Wyeth,
allowing the case against Wyeth to proceed.[56][57][58] This
established an "innovator liability" or "pioneer liability" for
pharmaceutical companies.[56] The precedent was not widely
followed in California nor in other states.[57] Litigation over the
same issues related to metoclopramide also reached the US
Supreme Court in PLIVA, Inc. v. Mensing,[59][60] in which the
court held in 2011 that generic companies cannot be held
liable for information, or the lack of information, on the
originator's label.[55][57][61] As of August 2015 there were about
5000 suits pending across the US and efforts to consolidate
them into a class action had failed.

Shortly following the Pliva decision, the FDA proposed a rule

change that would allow generics manufacturers to update
the label if the originating drug had been withdrawn from the
market for reasons other than safety.[62] As of May 2016 the
rule, which turned out to be controversial since it would open
generic companies to product liability suits, was still not
finalized, and the FDA had stated the final rule would be
issued in April 2017.[63] The FDA issued a draft guidance for
generic companies to update labels in July 2016.[64]

Society and culture

Brand names
List of trade names for metoclopramide[1][65]
Adco-Contromet, Aeroflat (Metoclopramide and Dimeticone), Afipran, Anaflat Compuesto (Metoclopramide and Simeticone;
A
Pancreatin), Anausin Métoclopramide, Anolexinon, Antiementin, Antigram (Metoclopramide and Acetylsalicylic Acid), Aswell

B Balon, Betaclopramide, Bio-Metaclopramide, Bitecain AA

Carnotprim, Carnotprim, Cephalgan (Metoclopramide and Carbasalate Calcium), Cerucal, Chiaowelgen, Chitou, Clifar (Metoclopramide
C and Simeticone), Clodaset (Metoclopramide and Ondansetron), Clodoxin (Metoclopramide and Pyridoxine), Clomitene, Clopamon,
Clopan, Cloperan, Cloprame, Clopramel, Clozil

Damaben, Degan, Delipramil, Di-Aero OM (Metoclopramide and Simeticone), Dibertil, Digenor (Metoclopramide and Dimeticone),
D Digespar (Metoclopramide and Simeticone), Digestivo S. Pellegrino, Dikinex Repe (Metoclopramide and Pancreatin), Dirpasid, Doperan,
Dringen

Egityl (Metoclopramide and Acetylsalicylic Acid), Elieten, Eline, Elitan, Emenil, Emeprid (veterinary use), Emeran, Emetal, Emoject,
E
Emperal, Enakur, Enteran, Enzimar, Espaven M.D. (Metoclopramide and Dimeticone), Ethiferan, Eucil

F Factorine (Metoclopramide and Simeticone)

G Gastro-Timelets, Gastrocalm, Gastronerton, Gastrosil, Geneprami

H H-Peran, Hawkperan, Hemibe, Horompelin

I Imperan, Isaprandil, Itan

K K.B. Meta, Klometol, Klopra

L Lexapram, Linperan, Linwels

Malon, Manosil, Maril, Matolon, Maxeran, Maxolon, Maxolone, Meclam, Meclid, Meclomid, Meclopstad, Meniperan, Mepram, Met-Sil,
Metajex, Metalon, Metamide, Metilprednisolona Richet, Metoceolat, Metoclor, Metoco, Metocol, Metocontin, Metomide (veterinary use),
Metopar (Metoclopramide and Paracetamol), Metopar (Metoclopramide and Paracetamol), Metopelan, Metoperan, Metoperon,
Metopran, Metotag, Metozolv, Metpamid, Metsil, Mevaperan, Midatenk, Migaura (Metoclopramide and Paracetamol), Migpriv
M
(Metoclopramide and Acetylsalicylic Acid), Migracid (Metoclopramide and Paracetamol), Migraeflux MCP (Metoclopramide and
Paracetamol), Migrafin (Metoclopramide and Aspirin), Migralave + MCP (Metoclopramide and Paracetamol), MigraMax
(Metoclopramide and Acetylsalicylic Acid), Migräne-Neuridal (Metoclopramide and Paracetamol), Migränerton (Metoclopramide and
Paracetamol), Motilon

N N-Metoclopramid, Nastifran, Nausil, Nevomitan, Nilatika, Novomit

O Opram

Pacimol-M (Metoclopramide and Paracetamol), Pangastren (Metoclopramide and Simeticone), Paramax (Metoclopramide and
Paracetamol), Paspertin, Peraprin, Perinorm, Perinorm-MPS (Metoclopramide and Dimeticone), Perone, Piralen, Plamide, Plamine,
Plasil, PMS-Metoclopramide, Podokedon, Polun, Poriran, Pradis, Pramidin, Pramidyl, Pramin, Praux, Premig (Metoclopramide and
P
Acetylsalicylic Acid), Premosan, Prenderon, Prevomic, Primadol (Metoclopramide and Paracetamol), Primavera-N, Premier, Primlan,
Primperan, Primperil, Primperoxane (Metoclopramide and Dimeticone), Primram, Primran, Primsel, Pripram, Prokinyl, Promeran,
Prometin, Prowel, Pulin, Pulinpelin, Pulperan, Pusuan, Putelome, Pylomid

R R-J, Raclonid, Randum, Reglan, Reglomar, Reliveran, Remetin, Riamide, Rilaquin, Rowelcon

S Sabax Metoclopramide, Sinprim, Sinthato, Soho, Indonesia, Sotatic, Stomallin, Suweilan

T Talex (Metoclopramide and Pancreatin), Tivomit, Tomit, Torowilon

V Vertivom, Vilapon, Vitamet, Vomend (veterinary use), Vomesea, Vomiles, Vomipram, Vomitrol, Vosea

W Wei Lian, Winperan

Z Zudaw

Veterinary use
Metoclopramide is also commonly used to prevent vomiting
in cats and dogs. It is also used as a gut stimulant in
rabbits.[66]

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