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More about Cimetidine

What is/are Cimetidine?

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.

History and development

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; actually, the medicinal chemists would have made the discovery.

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 Nα-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 Nα-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 is available as an over-the-counter medicine for heartburn in many countries.

Other uses

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.

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.

Another study by Yokoyama, et al., 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 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.

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 or metronomic tegafur-uracil chemotherapy for advanced epithelial cancers, with unusually long survival including for stage III colorectal cancers, 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

Cimetidine 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 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.

Antacid preparations such as cimetidine work by suppressing acid mediated break down of proteins, leads to an elevated risk of developing food or drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with only long-term use or with short-term use as well.

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:

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.

This article uses material from the Wikipedia article Cimetidine, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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