Cimetidine

Systematic (IUPAC) name
2-cyano- 1-methyl- 3-(2-[(5-methyl- 1H-imidazol- 4-yl)methylthio]ethyl)guanidine
Clinical data
Trade names	Tagamet
AHFS/Drugs.com	monograph
MedlinePlus	a682256
Licence data	US FDA:link
Pregnancy cat.	B1 (AU) B (US)
Legal status	Prescription Only (S4) (AU) POM (UK) OTC/℞-only (U.S., depending on dosage strength)
Routes	Oral, parenteral
Pharmacokinetic data
Bioavailability	60–70%
Protein binding	15–20%
Metabolism	Hepatic
Half-life	2 hours
Excretion	Renal
Identifiers
CAS number	51481-61-9 Y
ATC code	A02BA01
PubChem	CID 2756
IUPHAR ligand	1231
DrugBank	DB00501
ChemSpider	2654 Y
UNII	80061L1WGD Y
KEGG	D00295 Y
ChEBI	CHEBI:3699 Y
ChEMBL	CHEMBL30 Y
Chemical data
Formula	C10H16N6S
Mol. mass	252.34 g/mol
SMILES	eMolecules & PubChem
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
Y (what is this?)  (verify)

Cimetidine INN ( /sɨˈmɛtɨdiːn/ or /saɪˈmɛtɨdiːn/) is a histamine H₂-receptor antagonist that inhibits stomach acid production. It is largely used in the treatment of heartburn and peptic ulcers. 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.

Clinical use[link]

History and development[link]

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.^[1] 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.^[2] 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; actually, the medicinal chemists would have made the discovery.^[3]

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.^[2] The toxicity was proposed to arise from the thiourea group, and similar guanidine-analogues were investigated until the ultimate discovery of cimetidine.

Cimetidine was first marketed in the United Kingdom in 1976; therefore, it took 12 years from initiation of the H2-receptor antagonist program to commercialization. The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine".^[2] 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.^[4]

In a deal expected to take effect in 2012, GlaxoSmithKline sold Tagamet and 16 other brands to Prestige Brands.^[5]

Other uses[link]

In some studies, cimetidine has been found to reduce the debilitating pain and symptoms of herpes zoster, presumably by blocking the H₂-receptors of T-lymphocyte suppressor cells.^[6]

A number of "open label" studies showed cimetidine was effective in the treatment of common warts, but more rigorous double-blind clinical trials suggested it to be no more effective than a placebo. However, the researchers in this study admit their results may not be sound, due to small sample size, and did not explore higher dosing options.^[7]

Another study by Yokoyama, et al., used cimetidine for the treatment of chronic calcific tendinitis of the shoulder.^[8] 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 9 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.^[9]

In Asia, cimetidine, which molecularly targets EGF, VEGF and e-selectin associated with sialylated Lewis biomarkers and metastasis, has been combined with long term, continuous low dose 5FU^[10] or metronomic tegafur-uracil chemotherapy for advanced epithelial cancers, with unusually long survival^[11] including for stage III colorectal cancers,^[12] as well as refractory and recurrent cancers.

Cimetidine has been reported for use as an analgesic in experimental treatments of interstitial cystitis.

Pretreatment with cimetidine improves the accuracy of measured creatinine clearance testing when using urine collection analysis.

Adverse effects and interactions[link]

Cimetidine is a known inhibitor of many isozymes of the cytochrome P450 enzyme system^[13] (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 interferes with metabolism of the hormone estrogen, enhancing estrogen activity. In women, this can lead to galactorrhea, whereas in men, gynecomastia has been reported;^[14] during postmarketing surveillance in the 1980s, cases of male sexual dysfunction were also reported.^[15][16] 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.^[17] Cimetidine is also known to Potentiator the effects of several opiods which are partially metabolized via the cytochrome P450 pathway via 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.^[18]

It is also important to recognize that cimetidine can interact with a number of different psychoactive medications, including those in the classes of Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors, causing increased blood levels of these drugs and subsequent toxicity.

The development of longer-acting H₂-receptor antagonists with reduced 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 H₂-receptor antagonists. Side effects can include dizziness, and more rarely, headache.

Following administration of cimetidine, the half-life and AUC of zolmitriptan and its active metabolites were approximately doubled (see CLINICAL PHARMACOLOGY). See complete drug interactions for Zomig (triptan succinate used for migraine relief) in package insert: http://www1.astrazeneca-us.com/pi/Zomig.pdf

Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatinine breakdown. Accumulation of creatinine is associated with uremia. The symptoms of puts creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups.^[19]

Pharmacology[link]

Cimetidine's mechanism of action is as an H₂ receptor antagonist.^[20]

Cimetidine has also been found to possess clinically significant anti-androgen properties at high doses that are especially noticeable in men.^[20][21][22] It directly antagonizes the binding of testosterone and DHT to the androgen receptor in animals.^[23][24] In addition, also in animals, it interferes with the metabolism of estrogen and increases its serum concentrations.^[25] Accordingly, cimetidine has been found to be effective in small clinical trials for the treatment of acne and androgenic alopecia,^[26][27] though not in hirsutism or in sex hormone-associated cancers such as breast and prostate cancer.^[28][29] Cimetidine's anti-androgen properties likely explain certain side effects seen with it such as galactorrhea and amenorrhea in women and gynecomastia and impotence in men.^[30][22][22]

References[link]

External links[link]

• Cimetidine as a Cause of Sexual Impotence - Cimetidine and Impotence
• American Chemical Society - National Historic Chemical Landmarks - Tagamet: A medicine that changed people's lives
• Tagamet HB200