Cimetidine Chemical Properties

Melting point:

139-144°C

Boiling point:

476.2±55.0 °C(Predicted)

Density 

1.2583 (rough estimate)

refractive index 

1.5700 (estimate)

storage temp. 

2-8°C

solubility 

Slightly soluble in water, soluble in ethanol (96 per cent), practically insoluble in methylene chloride. It dissolves in dilute mineral acids.

pka

pKa 6.80 (Uncertain)

color 

White to Off-White

Water Solubility 

0.5 g/100 mL at 20 ºC

Merck 

14,2279

InChIKey

AQIXAKUUQRKLND-UHFFFAOYSA-N

CAS DataBase Reference

51481-61-9(CAS DataBase Reference)

NIST Chemistry Reference

Cimetidine(51481-61-9)

IARC

3 (Vol. 50) 1990

EPA Substance Registry System

Guanidine, N-cyano-N'-methyl-N''-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]- (51481-61-9)

Safety Information

Hazard Codes 

T,Xn

Risk Statements 

60-42/43-36/37/38-20/22

Safety Statements 

53-26-36/37/39-45-36-22

WGK Germany 

3

RTECS 

MF0035500

HS Code 

29339900

Hazardous Substances Data

51481-61-9(Hazardous Substances Data)

Toxicity

LD50 in mice, rats (mg/kg): 2600, 5000 orally; 150, 106 i.v.; 470, 650 i.p. (Brimblecombe)

MSDS

• Language:English Provider:2-Cyano-1-methyl-3-(2-(((5-methylimidazol-4-yl)methyl)thio)ethyl)guanidine
• Language:English Provider:SigmaAldrich

Cimetidine Usage And Synthesis

Description

Cimetidine (brand name: Tagamet) is a kind of histamine H2 receptor antagonist being capable of inhibiting the production of stomach acid, which reduces the gastric volume and acidity. It is mainly used for the treatment of heartburn and peptic ulcers. There are also evidences that it can be used for the treatment of common warts, chronic calcific tendinitis of the shoulder, and even colorectal cancer. It is capable of not only inhibiting the gastric acid secretion, as well as pepsin and gastrins output, but also inhibiting the activity of cytochrome P450. It reduces the gastric acid secretion through binding to the H2 receptor locating on the basolateral membrane of the gastric parietal cell, and further blocking histamine effect.

Medical Uses

Cimetidine is a medical drug that inhibits acid production by specific cells in the human stomach and can be dispensed orally or intravenously. Cimetidine is an effective remedy for heartburn that is resultant of a sour stomach or acid indigestion. The drug also reliefs heart burn that is associated with the consumption of certain beverages and foods.
Cimetidine is used in the treatment of ulcers and the prevention of certain conditions that may influence the stomach to produce excess amounts of acid. The drug is also used for the treatment of gastrointestinal reflux disease (GERD), a condition when stomach acid accumulates and oozes into the esophagus resulting in heartburn.
Some of the conditions associated with overproduction of acid by the stomach may include systemic mastocytosis, Zollinger-Ellison syndrome, and multiple endocrine adenomas. Cimetidine is an effective remedy for these conditions as it decreases the amount of acid produced by the stomach.

Information on Dosing

Cimetidine is available as Tagamet HB. In children and adults, the recommended injectable dosage is 150mg/ml whereas the oral solution is 300mg/5ml. The drug also comes in 300 mg, 200 mg, 800 mg (Rx), 600 mg (Rx), and 400mg (Rx) tablets.
For duodenal ulcers, Cimetidine should be used if the potential advantages surpass the risks involved for children below 16 years. The recommended dosage consideration for this group is 20-40mg/kg administered orally or intravenously every day in 6-hour intervals.
Cimetidine is not the most appropriate choice of drug for use amongst the elderly, especially due to potential drug interactions and confusion. However, for benign gastric and duodenal ulcers, administer 800 mg of Cimetidine once per day, or 400 mg taken orally every 12 hours or 300 mg taken orally every 6 hours orally. For erosive GERD, administer 800mg of cimetidine in a single daily dose or 400 mg taken orally every 12 hours.
In the event of an overdose, one should seek emergency medical attention. Symptoms associated with an overdose may include extreme weakness, fainting confusion, diarrhea, vomiting or nausea.

Mechanism of Action

Cimetidine inhibits the secretion of acid in the stomach, and it is taken orally or intravenously. It belongs to histamine-2 (H2) drug class suppressors which also include famotidine, nizatidine, and ranitidine. Histamine is a naturally occurring substance that influences acid production in parietal cells located in the stomach. H2-blockers suppress histamine activity on the cells, which decreases acid production by the stomach. When acid production in the stomach is relatively high, the stomach lining, the duodenum and the esophagus can be affected negatively, which may also result in ulceration and inflammation. Therefore, minimizing the rate of acid production by the stomach allows for ulcers and acid-induced inflammation to heal. The drug is also approved by the FDA.

Interactions

Severe drug interactions associated with cimetidine include terfenadine, pimozide, lomitapide, eliglustat, dofetilide, cisapride and astemizole. However, if a patient is advised by their pharmacist or doctor to use this medication, then there could be a possibility that they are aware of potential drug interactions. Therefore, one should not discontinue or adjust the dosage of any drugs without consulting their healthcare practitioner.
Cimetidine has mild, moderate and adverse drug interactions with 69, 193 and 143 medical drugs respectively. Medications other than the ones highlighted above may have negative interactions with cimetidine.

Side Effects

Minor side effects associated with cimetidine include fatigue, nausea, headache, vomiting, muscle pain, insomnia, diarrhea and constipation. Adverse side effects in may consist of hallucinations and confusion in critically ill or geriatric patients, breast enlargement, impotence especially after prolonged use of high doses, and a reduction in white blood cell count.
Other side effects may include hepatitis, allergic reactions, visual changes, skin rash and irregular heartbeat.
One should consult their doctor if they experience an irregular heartbeat, dizziness, abdominal pain, crusting or bleeding sores on the lips, mental or mood changes, signs of infection such as swollen glands, sore throat or chills, liver problems such as yellowing of the skin and dark urine, and swelling of the limbs.

Warnings

This drug contains cimetidine hence one should not ingest Tagamet HB if they are hypersensitive to the drug or its constituents. Cimetidine should be kept out of reach of children.
Cimetidine is an antiandrogen hence it may result in sexual dysfunction and feminization in men. The drug is considered safe for use amongst pregnant women, but since it can be absorbed into breast milk, lactating mothers should refrain from Cimetidine.
People with kidney or liver disease may be at a higher risk of experiencing intense side effects if Cimetidine is administered without appropriate advice from a medical practitioner. The doctor should indicate how the drug may influence the pre-existing liver or kidney disease, and whether the patient may require additional monitoring.

References

https://www.drugbank.ca/drugs/DB00501
https://en.wikipedia.org/wiki/Cimetidine

Description

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

Chemical Properties

White Solid

Originator

Tagamet,SKF,UK,1977

Uses

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

Uses

antibacterial

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.

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.

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.

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.

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.

storage

Store at RT

Dosage forms

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

Cimetidine(51481-61-9)Related Product Information

• Thioacetic acid
• Thiophanate-methyl
• Bensulfuron methyl
• Kresoxim-methyl
• Sodium thiosulfate pentahydrate
• Thioacetamide
• 2-Thiobarbituric acid
• ETHYL 2-CYANOACRYLATE
• Methylparaben
• Methyl acrylate
• Sitagliptin
• Methyl
• S,S-DIMETHYL-N-CYANODITHIOIMINO CARBONATE [DIMETHYL-N-CYANOTHIOCARBONATE]CIMETIDINE
• N-Cyano-N-[2-(5-methylimidazole-4-methylthio)ethyl]-S-methyl isothiourea
• (5-Ethyl-1H-imidazol-4-yl)methanol
• N-CYANO-N',N'-DIMETHYLGUANIDINE
• Cimetidine Amide Dihydrochloride
• N-Cyano-3-(cyanoaMino)-N'-Methyl-7,8-dithia-2,4,11-triazadodec-2-en-12-iMidaMide (CiMetidine IMpurity)