Cimetidine

Cimetidine

Systematic (IUPAC) name
1-cyano-2-methyl-3-(2-{[4-methyl-1H-imidazol-5-yl)methyl]sulfanyl}ethyl)guanidine
Clinical data
Pronunciation	/sᵻˈmɛtᵻdiːn/ or /saɪˈmɛtᵻdiːn/
Trade names	Tagamet
AHFS/Drugs.com	monograph
MedlinePlus	a682256
Licence data	US FDA:link
Pregnancy category	AU: B1 US: B (No risk in non-human studies)
Legal status	AU: S3 (Pharmacist only) UK: POM (Prescription only) US: Rx (although 200mg is OTC)
Routes of administration	Oral, parenteral
Pharmacokinetic data
Bioavailability	60–70%
Protein binding	15–20%
Metabolism	Hepatic
Biological half-life	2 hours
Excretion	Renal
Identifiers
CAS Number	51481-61-9 Y
ATC code	A02BA01 (WHO)
PubChem	CID: 2756
IUPHAR/BPS	1231
DrugBank	DB00501 Y
ChemSpider	2654 Y
UNII	80061L1WGD Y
KEGG	D00295 Y
ChEBI	CHEBI:3699 Y
ChEMBL	CHEMBL30 Y
Chemical data
Formula	C10H16N6S
Molecular mass	252.34 g/mol
SMILES N#CN\C(=N/C)NCCSCc1ncnc1C
InChI InChI=1S/C10H16N6S/c1-8-9(16-7-15-8)5-17-4-3-13-10(12-2)14-6-11/h7H,3-5H2,1-2H3,(H,15,16)(H2,12,13,14) Y Key:AQIXAKUUQRKLND-UHFFFAOYSA-N Y
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Cimetidine INN is a histamine H₂-receptor antagonist that inhibits stomach acid production. It is largely used in the treatment of heartburn and peptic ulcers.

Cimetidine was discovered in 1971. It has been marketed by GlaxoSmithKline (which is selling the brand to Prestige Brands) under the trade name Tagamet (sometimes Tagamet HB or Tagamet HB200). Cimetidine was approved in the UK in 1976, and was approved in the US by the Food and Drug Administration for prescriptions starting January 1, 1979.

Medical uses

Main article: H2-receptor antagonist

Other uses

Some evidence suggests cimetidine could be effective in the treatment of common warts, but more rigorous double-blind clinical trials found it to be no more effective than a placebo.

Another study used cimetidine for the treatment of chronic calcific tendinitis of the shoulder. The small-scale study took 16 individuals with calcific tendinitis in one shoulder, all of which had previously attempted other forms of therapy, including steroid injection and arthroscopic lavage. During the course of the study, 10 patients reported an elimination of pain and nine displayed a complete disappearance of calcium deposits. With results being on a small scale, cimetidine, for the treatment of chronic calcific tendinitis of the shoulder, has been recommended to be opened to large-scale clinical trials.

Tentative evidence supports a beneficial role as add on therapy in colorectal cancer.

Adverse effects

Cimetidine's side effects can include dizziness, and more rarely, headache. It is a known inhibitor of many isozymes of the cytochrome P450 enzyme system (specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). This inhibition forms the basis of the numerous drug interactions that occur between cimetidine and other drugs. For example, cimetidine may decrease metabolism of some drugs, such as those used in hormonal contraception. Cimetidine is a competitive antagonist at the dihydrotestosterone (DHT) receptor, leading to exaggerated effects of estrogens. In women, this can lead to galactorrhea, whereas in men, gynecomastia has been reported. During postmarketing surveillance in the 1980s, cases of male sexual dysfunction were also reported. Cimetidine also affects the metabolism of methadone, sometimes resulting in higher blood levels and a higher incidence of side effects, and may interact with the antimalarial medication hydroxychloroquine. Cimetidine is also known to potentiate the effects of several opioids, including tramadol, which are partially metabolized via the cytochrome P450 pathway, by inhibiting their metabolism and a temporary decrease of liver function due to reduced hepatic blood flow. This can lead to extreme plasma levels of these drugs and can easily lead to a fatal overdose.

Cimetidine can also interact with a number of psychoactive medications, including tricyclic antidepressants and selective serotonin reuptake inhibitors, causing increased blood levels of these drugs and the potential of subsequent toxicity.

Following administration of cimetidine, the half-life and AUC of zolmitriptan and its active metabolites were roughly doubled.

Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatine breakdown. Accumulation of creatinine is associated with uremia, but the symptoms of creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups.

The development of longer-acting H₂-receptor antagonists with fewer adverse effects, such as ranitidine, proved to be the downfall of cimetidine, and though it is still used, it is no longer among the more widely used of the H₂-receptor antagonists.

Like several other medications, the most obvious being erythromycin, cimetidine interferes with the body's metabolization of Viagra, causing its strength and duration to increase (therefore also its side effects to be more likely and prominent).

Pharmacology

Cimetidine's mechanism of action is as an H₂ receptor antagonist.

It has also been found to possess clinically significant albeit weak antiandrogen properties at high doses that are especially noticeable in men. It directly antagonizes the binding of testosterone and DHT to the androgen receptor in animals. In addition, also in animals, it interferes with the metabolism of estrogen and increases its serum concentrations. Accordingly, cimetidine has been found to be effective in small clinical trials for the treatment of acne and androgenic alopecia, though not in hirsutism or in sex hormone-associated cancers such as breast and prostate cancer. Cimetidine's antiandrogen properties likely explain certain side effects sometimes seen with its use such as galactorrhea and amenorrhea in women and gynecomastia and impotence in men.

History

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases. Cimetidine was the prototypical histamine H₂-receptor antagonist from which the later members of the class were developed. Cimetidine was the culmination of a project at Smith, Kline and French (SK&F; now GlaxoSmithKline) by James W. Black, C. Robin Ganellin, and others to develop a histamine receptor antagonist to suppress stomach acid secretion. This was one of the first drugs discovered using a rational drug design approach. Sir James W. Black shared the 1988 Nobel Prize in Physiology or Medicine for the discovery of propranolol and also is credited for the discovery of cimetidine.

At the time (1964), histamine was known to stimulate the secretion of stomach acid, but also that traditional antihistamines had no effect on acid production. In the process, the SK&F scientists also proved the existence of histamine H₂-receptors.

The SK&F team used a rational drug-design structure starting from the structure of histamine - the only design lead, since nothing was known of the then hypothetical H₂-receptor. Hundreds of modified compounds were synthesised in an effort to develop a model of the receptor. The first breakthrough was N^α-guanylhistamine, a partial H₂-receptor antagonist. From this lead, the receptor model was further refined and eventually led to the development of burimamide, the first H₂-receptor antagonist. Burimamide, a specific competitive antagonist at the H₂-receptor, 100 times more potent than N^α-guanylhistamine, proved the existence of the H₂-receptor.

Burimamide was still insufficiently potent for oral administration, and further modification of the structure, based on modifying the pKa of the compound, led to the development of metiamide. Metiamide was an effective agent; it was associated, however, with unacceptable nephrotoxicity and agranulocytosis. The toxicity was proposed to arise from the thiourea group, and similar guanidine-analogues were investigated until the ultimate discovery of cimetidine. The compound was synthesized in 1972 and evaluated for toxicology by 1973. It passed all trials.

Cimetidine was first marketed in the United Kingdom in 1976, and in the U.S. in August 1977; therefore, it took 12 years from initiation of the H2-receptor antagonist program to commercialization. By 1979, Tagamet was being sold in more than 100 countries and became the top-selling prescription product in the U.S., Canada, and several other countries. In November 1997, the American Chemical Society and the Royal Society of Chemistry in the U.K. jointly recognized the work as a milestone in drug discovery by designating it an International Historic Chemical Landmark during a ceremony at SmithKline Beecham's New Frontiers Science Park research facilities in Harlow, England.

The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine". Subsequent to the introduction onto the U.S. drug market, two other H₂-receptor antagonists were approved, ranitidine (Zantac, Glaxo Labs) and famotidine (Pepcid, Yamanouchi, Ltd.) Cimetidine became the first drug ever to reach more than $1 billion a year in sales, thus making it the first blockbuster drug.

In a deal expected to take effect in 2012, GlaxoSmithKline sold Tagamet and 16 other brands to Prestige Brands.

Tagamet has now been largely replaced by the proton pump inhibitors for treating peptic ulcers, but is now available as an over-the-counter medicine for heartburn in many countries.

External links

• Tagamet^®: Discovery of Histamine H₂-receptor Antagonists from American Chemical Society National Historic Chemical Landmarks