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Cimetidine INN (// or //) 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.
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.
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.
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.
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'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.
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).
It has also been found to possess clinically significant 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 anti-androgen properties likely explain certain side effects seen with it such as galactorrhea and amenorrhea in women and gynecomastia and impotence in men.
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- Cimetidine as a Cause of Sexual Impotence - Cimetidine and Impotence
- Tagamet®: Discovery of Histamine H2-receptor Antagonists from American Chemical Society National Historic Chemical Landmarks
- Tagamet HB200