Cimetidine

Absorption

Two peak plasma concentrations are often observed after oral administration of cimetidine, likely as a result of discontinuous absorption in the gastrointestinal tract. In healthy patients, the absolute bioavailability of cimetidine is approximately 60%; however, the bioavailability can be as high as 70% in patients with peptic ulcer disease. Overall, rates of bioavailability are much more variable in patients with peptic ulcer disease.

Toxicity

In the rare event of cimetidine overdose, it is vital to maintain the airway and cardiovascular status. The patient should be closely monitored and provided with symptomatic and supportive treatment as needed. Interventions such as gastric lavage and administration of activated charcoal may be initiated if deemed appropriate and necessary.

Description

Cimetidine is a representative of first-generation antihistamine drugs that block H2 receptors.

Description

Cimetidine is a competitive histamine H2-receptor antagonist that inhibits gastric acid secretion and reduces pepsin output. It was one of the first drugs discovered using a rational design method. G. J. Durant and co-workers reported its synthesis was reported in 1974. Cimetidine is the active ingredient in Tagamet and other "heartburn" drugs and has been used off-label to treat other medical conditions.

Chemical properties

White Solid

Originator

Tagamet,SKF,UK,1977

The Uses of Cimetidine

Competitive histamine H2-receptor antagonist which inhibits gastric acid secretion and reduces pepsin output

The Uses of Cimetidine

antibacterial

The Uses of Cimetidine

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.

Background

A histamine congener, it competitively inhibits histamine binding to histamine H2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrins output. It also blocks the activity of cytochrome P-450 which might explain proposals for use in neoadjuvant therapy.

Indications

Cimetidine is indicated to reduce gastric acid secretion and to treat the following disease states: duodenal ulcers, non-malignant gastric ulcers, gastroesophageal reflux disease, and pathological hypersecretion associated with Zollinger-Ellison Syndrome, systemic mastocytosis, and multiple endocrine adenomas. It is indicated for prophylaxis of recurrent gastric or duodenal ulcers, as adjunctive therapy in the management of cystic fibrosis in children, and to treat NSAID induced lesions and gastrointestinal symptoms.

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.

What are the applications of Application

Cimetidine is an inhibitor of histamine binding to histamine H2 receptors

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

General Description

White crystals with a slight sulfur-mercaptan odor.

Air & Water Reactions

Slightly water soluble.

Fire Hazard

Flash point data for Cimetidine are not available. Cimetidine is probably combustible.

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.

Pharmacokinetics

Cimetidine is a histamine H2-receptor antagonist. It reduces basal and nocturnal gastric acid secretion and a reduction in gastric volume, acidity, and amount of gastric acid released in response to stimuli including food, caffeine, insulin, betazole, or pentagastrin. It is used to treat gastrointestinal disorders such as gastric or duodenal ulcer, gastroesophageal reflux disease, and pathological hypersecretory conditions. Cimetidine inhibits many of the isoenzymes of the hepatic CYP450 enzyme system. Other actions of Cimetidine include an increase in gastric bacterial flora such as nitrate-reducing organisms.

Clinical Use

H2 antagonist:
Conditions associated with hyperacidity

Refractory uraemic pruritus (unlicensed use)

Side Effects

Cimetidine may infrequently cause diarrhea, nausea, vomiting, or mental confusion. A rare association with granulocytopenia, thrombocytopenia, and pancytopenia has been reported. Gynecomastia has been demonstrated in patients receiving either high-dose or long-term therapy.

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.

Metabolism

After intravenous administration of cimetidine, the majority of the parent drug (58-77%) is eliminated unchanged in the urine. Cimetidine’s primary metabolite is cimetidine sulfoxide and represents an estimated 10-15% of total elimination. Researchers have also identified a minor cimetidine metabolite with a hydroxylated methyl group on the imidazole ring which represents only 4% of total elimination. Both cytochrome P450 enzymes and flavin-containing monooxygenases are implicated in the metabolism of cimetidine, although it is unclear which specific enzymes are involved. Cimetidine is a well known enzyme inhibitor and may impair the metabolism of certain co-administered medications.

storage

Store at RT

Dosage forms

300 mg PO q.i.d. or 800 mg at bedtime.