Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is available over-the-counter and is mainly used in the treatment of heartburn and peptic ulcers.
The development of longer-acting H2 receptor antagonists with fewer drug interactions and adverse effects, such as ranitidine and famotidine, decreased the use of cimetidine, and though it is still used, cimetidine is no longer among the more widely used of the H2-receptor antagonists.
Cimetidine was discovered in 1971 and came into commercial use in 1977. Cimetidine was approved in the United Kingdom in 1976, and was approved in the United States by the Food and Drug Administration for prescriptions in 1979.
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.
Reported side effects of cimetidine include diarrhea, rashes, dizziness, fatigue, constipation, and muscle pain, all of which are usually mild and transient. It has been reported that mental confusion may occur in the elderly. Because of its hormonal effects, cimetidine rarely may cause sexual dysfunction including loss of libido and erectile dysfunction and gynecomastia (0.1–0.2%) in males during long-term treatment. Rarely, interstitial nephritis, urticaria, and angioedema have been reported with cimetidine treatment. Cimetidine is also commonly associated with transient raised aminotransferase activity; hepatotoxicity is rare.
Cimetidine appears to be very safe in overdose, producing no symptoms even with massive overdoses (e.g., 20 g).Cimetidine 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 oxycodone and 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, in some cases, 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 area-under-curve 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.
Like several other medications, the most obvious being erythromycin, cimetidine interferes with the body's metabolization of sildenafil, causing its strength and duration to increase (therefore also its side effects to be more likely and prominent).
Clinically significant drug interactions with the CYP1A2 substrate theophylline, the CYP2C9 substrate tolbutamide, the CYP2D6 substrate desipramine, and the CYP3A4 substrate triazolam have all been demonstrated with cimetidine, and interactions with other substrates of these enzymes are likely as well.
Cimetidine has been shown clinically to reduce the clearance of mirtazapine, imipramine, timolol, nebivolol, sparteine, loratadine, nortriptyline, gabapentin, and desipramine in humans.
Cimetidine inhibits the renal excretion of metformin and procainamide, resulting in increased circulating levels of these drugs.
Interactions of potential clinical importance with cimetidine include warfarin, theophylline, phenytoin, carbamazepine, pethidine and other opioid analgesics, tricyclic antidepressants, lidocaine, terfenadine, amiodarone, flecainide, quinidine, fluorouracil, and benzodiazepines.
Cimetidine may decrease the effects of CYP2D6 substrates that are prodrugs, such as codeine, tramadol, and tamoxifen.
Cimetidine reduces the absorption of ketoconazole and itraconazole (which require a low pH).
Cimetidine has a theoretical but unproven benefit in paracetamol toxicity. This is because N-acetyl-p-benzoquinone imine (NAPQI), a metabolite of paracetamol (acetaminophen) that is responsible for its hepatotoxicity, is formed from it by the cytochrome P450 system (specifically, CYP1A2, CYP2E1, and CYP3A4).
Numerous other drug interactions.
Cimetidine's mechanism of action as an antacid is as a histamine H2 receptor antagonist.
Cimetidine is S-oxygenated by human flavin-containing monooxygenases, specifically FMO1 and FMO3.
Cimetidine is a potent cytochrome P450 (CYP450) enzyme inhibitor. It is not a universal inhibitor of the CYP450 oxidative system, but it inhibits a broad array of CYP450 isoforms, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The drug is said to be most potent in inhibiting CYP1A2, CYP2D6, and CYP3A4, of which it is described as a moderate inhibitor, and this is notable as these three isoenzymes are involved in the majority of CYP450-mediated drug biotransformations; also, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 have been identified as involved in the oxidative metabolism of most commonly used drugs. As such, cimetidine has the potential for a large number of drug interactions. Cimetidine is reported to be a competitive, reversible inhibitor of the CYP450 enzymes similarly to certain other inhibitors like azole antifungals and quinidine, although mechanism-based (suicide), irreversible inhibition has also been identified for at least CYP2D6. It reversibly inhibits CYP450 enzymes by binding directly with the complexed heme-iron of the active site via one of its imidazole ring nitrogen atoms, thereby blocking the oxidation of other drugs.
Cimetidine has been found to possess clinically significant albeit weak antiandrogen activity at high doses. It has been found to directly and competitively displace testosterone and dihydrotestosterone (DHT) and antagonize the androgen receptor (AR) in animals. In addition, cimetidine has been found to inhibit 2-hydroxylation of estradiol (via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increased levels of estrogen. By increasing estrogen levels, cimetidine can also decrease testosterone and increase prolactin levels. In accordance with these antiandrogen and estrogenic activities, 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. Also, these activities likely explain certain side effects that are sometimes seen with the chronic administration of cimetidine, such as galactorrhea and amenorrhea in women and gynecomastia and impotence in men.
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 synthesized 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 available as an over-the-counter medicine for heartburn in many countries.