Originator
Motilium,Cilag,Switz.,1979
Definition
ChEBI: 1-[3-(Piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-2-one in which the 4-position of the piperidine ring is substituted by a 5-chloro-1,3-dihydro-2H-benzimidazol-2-on-1-yl group. A dopamine antagonist, it is used
s an antiemetic for the short-term treatment of nausea and vomiting, and to control gastrointestinal effects of dopaminergic drugs given in the management of parkinsonism. The free base is used in oral suspensions, while the maleate salt is used in tablet
reparations.
Manufacturing Process
A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-
one, 2.5 parts of 5-chloro-1,3-dihydro-l-(4-piperidinyl)-2H-benzimidazol-2-
one, 3.2 parts of sodium carbonate, 0.1 part of potassium iodide and 80 parts
of 4-methyl-2-pentanone is stirred and refluxed for 24 hours. The reaction
mixture is cooled to room temperature and water is added. The undissolved
product is filtered off and purified by column chromatography over silica gel
using a mixture of trichloromethane and 10% methanol as eluent. The pure
fractions are collected and the eluent is evaporated. The residue is crystallized
from 4-methyl-2-pentanone. The product is filtered off and recrystallized from
a mixture of N,N-dimethylformamide and water, yielding 1.3 parts (30%) of 5-
chloro-1-[1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-
piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one; MP 242.5°C.
Brand name
Motilium (Janssen);Evixub;Kw 5338;Moperidona;Neta662;R 33812;Tametil;Touristic.
Therapeutic Function
Antiemetic
World Health Organization (WHO)
Domperidone, a peripheral dopaminergic antagonist, was
introduced in 1979 for the symptomatic relief of acute nausea and vomiting. The
major manufacturer became aware that the injectable formulation was being used
in some countries in much higher doses than those recommended to combat
nausea and vomiting in cancer patients treated with cytostatic agents. Such use -
which was not in conformity with the approved indications - was associated with
cardiotoxicity, which in some cases was fatal, and the manufacturer decided to
withdraw the injectable dosage form from the market worldwide in January 1985.
Suppositories, tablets and a suspension remain available and the manufacturer
continues to supply the injection for the treatment of a named patient at the written
request of a doctor on the understanding that the appropriate dosage
recommendations will be followed.
Biological Activity
Peripheral dopamine D 2 -like receptor antagonist that does not readily cross the blood brain barrier. Displays gastroprokinetic and antiemetic properties; increases the frequency and duration of antral and duodenal contractions and protects from apomorphine-induced emesis (ED 50 values are 0.003 and 0.03 mg/kg for i.v. and oral administration respectively).
Clinical Use
Acute nausea and vomiting (including that caused by
levodopa and bromocriptine)
Gastro-oesophageal reflux
Dyspepsia
Veterinary Drugs and Treatments
Domperidone may be useful for treatment of fescue toxicosis in
pregnant mares or as a prokinetic or antiemetic agent in small animals.
It has more effect on conditions with delayed gastric emptying
than other GI hypomotility conditions.
Via its effects on prolactin, domperidone may also be used to
stimulate milk production in horses and small animals.
Domperidone has been shown to increase plasma ACTH in
horses with equine pituitary pars intermedia dysfunction (Equine
Cushing’s) and may be useful in helping diagnose this condition.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: possible increased risk of ventricular
arrhythmias with clarithromycin, delamanid and
erythromycin - avoid with clarithromycin and
erythromycin.
Antifungals: possibly increased risk of ventricular
arrhythmias with itraconazole, ketoconazole and
voriconazole - avoid.
Antimalarials: possible increased risk of ventricular
arrhythmias with piperaquine with artenimol -
avoid.
Antivirals: possible increased risk of ventricular
arrhythmias with boceprevir; possible increased risk
of ventricular arrhythmias with ritonavir, saquinavir
and telaprevir - avoid
Apomorphine: possible increased risk of ventricular
arrhythmias.
Cobicistat: possible increased risk of ventricular
arrhythmias - avoid.
Cytotoxics: increased risk of ventricular arrhythmias
with bosutinib and ceritinib - avoid with bosutinib.
Metabolism
Domperidone undergoes extensive first-pass hepatic and
intestinal metabolism. It undergoes rapid and extensive
hepatic metabolism. The main metabolic pathways
are N-dealkylation by cytochrome P450 isoenzyme
CYP3A4, and aromatic hydroxylation by CYP3A4,
CYP1A2, and CYP2E1.
About 30% of an oral dose is excreted in urine within 24
hours, almost entirely as metabolites; the remainder of a
dose is excreted in faeces over several days, about 10% as
unchanged drug.
References
[1] Patent: CN105541800, 2016, A. Location in patent: Paragraph 0014; 0015
