General Description
White crystals with a slight sulfur-mercaptan odor.
Air & Water Reactions
Slightly water soluble.
Fire Hazard
Flash point data for this compound are not available. CIMETIDINE is probably combustible.
Chemical Properties
White Solid
Originator
Tagamet,SKF,UK,1977
Uses
Cimetidine is used for treating ulcer problems of the stomach and duodenum and for
other conditions accompanied by an elevation of acidity and excess secretion of gastric
juice. It is used for preventing injuries and the blood flow of the upper regions of the gastrointestinal tract.
Uses
Competitive histamine H2-receptor antagonist which inhibits gastric acid secretion and reduces pepsin output
Definition
ChEBI: A member of the class of guanidines that consists of guanidine carrying a methyl substituent at position 1, a cyano group at position 2 and a 2-{[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl}ethyl group at position 3. It is a H
-receptor antagonist that inhibits the production of acid in stomach.
Indications
Cimetidine, the first released H2-blocker, like histamine,
contains an imidazole ring structure. It is well absorbed
following oral administration, with peak blood
levels 45 to 90 minutes after drug ingestion. Blood levels
remain within therapeutic concentrations for approximately
4 hours after a 300-mg dose. Following oral
administration, 50 to 75% of the parent compound is
excreted unchanged in the urine; the rest appears primarily
as the sulfoxide metabolite.
Manufacturing Process
In an initial step, 2-chloroacetic acid ethyl ester is reacted with formamide to
give 5-methylimidazole-4-carboxylic acid ethyl ester. Then sodium in ammonia
is used to convert that to 4-hydroxymethyl-5-methylimidazole-hydrochloride.
Cysteamine HCl (HSCH2CH2NH2·HCl) is then reacted to give 4-(2-
aminomethyl)-thiomethyl-5-methyl-imidazole dihydrochloride. Then Ncyanamido-5,5-dimethyl-dithio-carbonate (from cyanamid, KOH, CS2 and
((CH3)2SO4) is reacted to give a further intermediate which is finally reacted
with methylamine to give cimetidine
The preparation of the pyridyl analogs of the imidazolyl compounds of the
type of cimetidine are discussed in the patent cited below.
Further references are given by Kleeman and Engel in the reference below.
Brand name
Tagamet
(GlaxoSmithKline).
Therapeutic Function
Antiulcer
Biological Activity
Widely used H 2 histamine antagonist which has more recently been described as an inverse agonist. Also a potent I 1 imidazoline binding site ligand.
Biochem/physiol Actions
H2 histamine receptor antagonist; I1 imidazoline receptor agonist; anti-ulcer agent. Blocks cancer metastasis by inhibiting the expression of E-selectin on the surface of endothelial cells, thus blocking tumor cell adhesion.
Pharmacology
The main pharmacological effect of cimetidine is the suppression of gastric juice
secretion associated with H2 receptors of the stomach walls. It suppresses both basal and
stimulated hydrochloric acid produced by food as well as histamine and gastrine, which
simultaneously lower pepsin activity.
Clinical Use
H2
antagonist:
Conditions associated with hyperacidity
Refractory uraemic pruritus (unlicensed use)
Synthesis
Cimetidine, 1-cyano-2-methyl-3-[2-[[5-[[methylimidazol-4-yl)methyl]thio]
ethyl] guanidine (16.2.5), is synthesized in the following manner. Reacting 2-chloroacetoacetic
ether with two moles of formamide gives 4-carbethoxy-5-methylimidazol (16.2.1).
Reduction of the carbethoxy group of this produced with sodium in liquid ammonia gives 4-
hydroxymethyl-5-methylimidazol (16.2.2). The hydrochloride of the resulting alcohol is
reacted with 2-mercaptoethylamine hydrochloride to produce 4-(2-aminomethyl)-thiomethyl-
5-methylimidazol dihydrochloride (16.2.3). This is reacted with N-cyanimido-S,Sdimethyldithiocarbonate
to give a thiourea derivative (16.2.4), which upon reaction with
methylamine turns into cimetidine (16.2.5).
Veterinary Drugs and Treatments
In veterinary medicine, cimetidine has been used for the treatment
and/or prophylaxis
of gastric, abomasal and duodenal ulcers, uremic
gastritis, stress-related or drug-induced erosive
gastritis, esophagitis,
duodenal gastric reflux, and esophageal reflux. It has also been
employed to treat hypersecretory conditions associated with gastrinomas
and systemic mastocytosis. Cimetidine
has also been used
investigationally as a immunomodulating agent (see doses) in dogs.
Cimetidine has been used for the treatment of melanomas in horses,
but the drug’s poor bioavailability and subsequent high doses (48
mg/kg/day) in adult horses makes it a very expensive, unproven
treatment.
Drug interactions
Potentially hazardous interactions with other drugs
Alpha-blockers: effects of tolazoline antagonised.
Aminophylline and theophylline: metabolism of
aminophylline and theophylline inhibited.
Anti-arrhythmics: increased concentration of
amiodarone, flecainide, lidocaine, procainamide and
propafenone.
Anticoagulants: enhanced effect of coumarins.
Antiepileptics: metabolism of carbamazepine,
fosphenytoin, phenytoin and valproate inhibited.
Antifungals: absorption of itraconazole and
ketoconazole reduced; posaconazole concentration
reduced - avoid; terbinafine concentration increased.
Antimalarials: avoid with artemether/lumefantrine;
metabolism of chloroquine, hydroxychloroquine and
quinine inhibited.
Antipsychotics: possibly enhanced effect of
antipsychotics, chlorpromazine and clozapine.
Antivirals: concentration of atazanavir reduced;
concentration of raltegravir and saquinavir possibly
increased - avoid; avoid for 12 hours before and 4
hours after rilpivirine.
Ciclosporin: possibly increased ciclosporin levels.
Clopidogrel: possibly reduces antiplatelet effect.
Cytotoxics: possibly enhances myelosuppressive
effects of carmustine and lomustine; concentration
of epirubicin and fluorouracil increased; avoid with
dasatinib and erlotinib; possibly reduced absorption
of lapatinib; possibly reduced absorption of
pazopanib - give at least 2 hours before or 10 hours
after cimetidine.
Ergot alkaloids: increased risk of ergotism - avoid.
Fampridine: avoid concomitant use.
Ulipristal: contraceptive effect possibly reduced -
avoid with high dose ulipristal.
Metabolism
The bioavailability of cimetidine after oral doses is about
60-70%, due to hepatic first-pass metabolism. Cimetidine
is partially metabolised in the liver to the sulfoxide and to
hydroxymethylcimetidine. About 50% of an oral dose, and
75% of an intravenous dose, is excreted unchanged in the
urine in 24 hours. After an oral or parenteral dose of 300
mg, blood concentrations remain above that required to
provide 80% inhibition of basal gastric acid secretion for
4-5 hours.
Dosage forms
300 mg PO q.i.d. or 800 mg at bedtime.
