|Pronunciation||// or //|
|Trade names||Tagamet, others|
|By mouth, intramuscular injection, intravenous infusion|
|Metabolites||• Cimetidine sulfoxide|
• Guanyl urea cimetidine
|Onset of action||30 minutes|
|Elimination half-life||123 minutes (~2 hours)|
|Duration of action||4–8 hours|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||252.34 g/mol g·mol−1|
|3D model (JSmol)|
Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It 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 developed 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.
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 is a potent inhibitor of certain cytochrome P450 (CYP450) enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4, of which it is described as a moderate inhibitor. This is notable since these three CYP450 isoenzymes are involved in CYP450-mediated drug biotransformations; however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative metabolism of many commonly used drugs. As a result, cimetidine has the potential for a large number of pharmacokinetic interactions.
Cimetidine is reported to be a competitive and reversible inhibitor of several CYP450 enzymes, although mechanism-based (suicide) irreversible inhibition has also been identified for cimetidine's inhibition of 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 weak antiandrogenic activity at high doses. It directly and competitively antagonizes the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). However, the affinity of cimetidine for the AR is very weak; in one study, it showed only 0.00084% of the affinity of the anabolic steroid metribolone (100%) for the human AR (Ki = 140 μM and 1.18 nM, respectively). In any case, at sufficiently high doses, cimetidine has demonstrated weak but significant antiandrogenic effects in animals, including antiandrogenic effects in the rat ventral prostate and mouse kidney, reductions in the weights of the male accessory glands like the prostate gland and seminal vesicles in rats, and elevated gonadotropin levels in male rats (due to reduced negative feedback on the HPG axis by androgens). In addition to AR antagonism, cimetidine has been found to inhibit the 2-hydroxylation of estradiol (via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increased estrogen levels. The medication has also been reported to reduce testosterone biosynthesis and increase prolactin levels in individual case reports, effects which might be secondary to increased estrogen levels.
At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men. Any increases in testosterone levels with cimetidine have been attributed to the loss of negative feedback on the HPG axis that results due to AR antagonism. At typical clinical dosages, such as those used to treat peptic ulcer disease, the incidence of gynecomastia (breast development) with cimetidine is very low at less than 1%. In one survey of over 9,000 patients taking cimetidine, gynecomastia was the most frequent endocrine-related complaint but was reported in only 0.2% of patients. At high doses however, such as those used to treat Zollinger–Ellison syndrome, there may be a higher incidence of gynecomastia with cimetidine. In one small study, a 20% incidence of gynecomastia was observed in 25 male patients with duodenal ulcers who were treated with 1,600 mg/day cimetidine. The symptoms appeared after 4 months of treatment and regressed within a month following discontinuation of cimetidine. In another small study, cimetidine was reported to have induced breast changes and erectile dysfunction in 60% of 22 men treated with it. These adverse effects completely resolved in all cases when the men were switched from cimetidine to ranitidine. A study of the United Kingdom General Practice Research Database, which contains over 80,000 men, found that the relative risk of gynecomastia in cimetidine users was 7.2 relative to non-users. People taking a dosage of cimetidine of greater than or equal to 1,000 mg showed more than 40 times the risk of gynecomastia than non-users. The risk was highest during the period of time of 7 to 12 months after starting cimetidine. The gynecomastia associated with cimetidine is thought to be due to blockade of ARs in the breasts, which results in estrogen action unopposed by androgens in this tissue, although increased levels of estrogens due to inhibition of estrogen metabolism is another possible mechanism. Cimetidine has also been associated with oligospermia (decreased sperm count) and sexual dysfunction (e.g., decreased libido, erectile dysfunction) in men in some research, which are hormonally related similarly.
In accordance with the very weak nature of its AR antagonistic activity, cimetidine has shown minimal effectiveness in the treatment of androgen-dependent conditions such as acne, hirsutism (excessive hair growth), and hyperandrogenism (high androgen levels) in women. As such, its use for such indications is not recommended.
|Compound||AR RBA (%)||AR Ki (nM)|
|Notes: (1) Human skin fibroblasts used for assays. (2) Situation in vivo is different for flutamide and spironolactone due biotransformation. (3) Conflicting findings for spironolactone. Sources: See template.|
Cimetidine is rapidly absorbed regardless of route of administration. The oral bioavailability of cimetidine is 60 to 70%. The onset of action of cimetidine when taken orally is 30 minutes, and peak levels occur within 1 to 3 hours. Cimetidine is widely distributed throughout all tissues. It is able to cross the blood–brain barrier and can produce effects in the central nervous system (e.g., headaches, dizziness, somnolence). The volume of distribution of cimetidine is 0.8 L/kg in adults and 1.2 to 2.1 L/kg in children. Its plasma protein binding is 13 to 25% and is said to be without pharmacological significance. Cimetidine undergoes relatively little metabolism, with 56 to 85% excreted unchanged. It is metabolized in the liver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine. The major metabolite of cimetidine is the sulfoxide, which accounts for about 30% of excreted material. Cimetidine is rapidly eliminated, with an elimination half-life of 123 minutes, or about 2 hours. It has been said to have a duration of action of 4 to 8 hours. The medication is mainly eliminated in urine.
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) Laboratories in Welwyn Garden City (now part of 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.
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.
Drugs interacting in this way with CYP450 include the histamine H2-receptor antagonist cimetidine, [...] Reversible inhibitors, such as cimetidine, which interact with the complexed iron at the active site of the enzyme to inhibit oxidation of other drugs. The inhibition occurs before any oxidation of the inhibitor occurs and is reversible once the inhibitor is removed.
Cimetidine is an example of a compound that can bind directly to the heme iron of the cytochrome P450 reactive site to inhibit all cytochrome-dependent Phase I enzyme activities.13
In high concentrations cimetidine acts as a weak antiandrogen by competitively binding to cytosol androgen receptors, as has been demonstrated in rat ventral prostate (Foldesy, Vanderhoof, & Hahn, 1985; Sivelle, Underwood, & Jelly, 1982) and mouse kidney tissue (Funder & Mercer, 1979). In vivo, cimetidine, in high dose levels, causes reductions in prostate and seminal vesicle weights in male rats (Foldesy et al., 1985; Leslie & Walker, 1977; Sivelle et al., 1982). After 6 weeks of daily cimetidine administration to male rats, reduced weights of accessory sexual organs were accompanied by elevated gonadotropin levels (Baba, Paul, Pollow, Janetschek, & Jacobi, 1981). At therapeutic levels in men, cimetidine either has no effect on plasma T levels (Spona et al., 1987; Stubbs et al., 1983) or causes small increases in T (Peden, Boyd, Browning, Saunders, & Wormsley, 1981; Van Thiel, Gavaler, Smith, & Paul, 1979; Wang, Lai, Lam, & Yeung, 1982). The increases in T have been attributed to cimetidine's antagonism of the normal negative feedback that androgens exert on gonadotropin secretion (Peden, Cargill, Browning, Saunders, & Wormsley, 1979). Gynecomastia and even loss of libido that progressed to impotence have occasionally been reported in men taking cimetidine (Peden et al., 1979; Spence & Celestin, 1979), but the occurrence of these disorders is very rare (Gifford, Aeugle, Myerson, & Tannenbaum, 1980). In one survey, gynecomastia, the most frequent endocrine-related complaint, was reported in only 0.2% of over 9,000 patients taking cimetidine (Gifford et al., 1980).
Like other antiandrogens, [cimetidine] leads to elevated gonadotropin levels by antagonizing the negative feedback control of gonadotropin secretion by testosterone [1, 34]. Cimetidine has been reported to have antiandrogenic effects ranging from gynecomastia to oligospermia . In one clinical study, men administered cimetidine exhibited a significant reduction in sperm concentration compared to placebo-treated controls . In another study of men receiving cimetidine for chronic duodenal ulcers, testosterone and FSH were elevated during treatment with cimetidine compared to both pre- and posttreatment levels. Moreover, these hormonal effects were associated with a reduction in mean sperm count compared to the period after drug withdrawal .
Cimetidine. Spence and Celestin reported a 20% incidence of gynecomastia in a prospective study of 25 male duodenal ulcer patients treated with cimetidine 1.6 g/day . Symptoms developed after 4 months of treatment and regressed within a month of stopping therapy. In another prospective cohort study involving 22 patients, cimetidine caused breast changes and erectile dysfunction in 60% of men which resolved completely in all cases when switched to ranitidine . In the UK general practice database of over 80,000 men, the relative risk (RR) of gynecomastia among cimetidine users was 7.2 (95% confidence interval (CI 4.5 -- 11.3)) as compared with the non-users. Users with a daily dose ‡ 1000 mg had more than 40 times the risk of developing gynecomastia than the non-users. The period of highest risk was 7 -- 12 months after starting cimetidine treatment . Cimetidine blocks the androgen receptors in the breast leading to decreased androgen action causing the growth of breast tissue because of ‘unopposed’ estrogen action . Another possible mechanism includes decreased 2-hydroxylation of estrogen leading to elevated serum estrogen levels . There also are reports of cimetidine blocking testosterone biosynthesis and causing elevated prolactin levels in individual cases .
The histamine receptor antagonist cimetidine, used to decrease gastric acid secretion in treatment of peptic ulcer disease and esophagitis (see Chapter 14), also acts as an antiandrogen. Thus it has been reported to produce gynecomastia when given in large doses, such as those used in the treatment of patients with Zollinger-Ellison syndrome. Gynecomastia occurs in less than 1% of patients treated with the doses used in peptic ulcer disease. Cimetidine interacts with ARs approximately 0.01% as effectively as testosterone and has been used with limited effectiveness to treat hirsutism in women.
Cimetidine is a weak androgen receptor antagonist. A controlled clinical study has not found cimetidine to be effective in the treatment of hyperandrogenism.[123, 124] 5.
Cimetidine is a histamine type 2 blocker, which also binds to the androgen receptor to inhibit its function." However, this antiandrogen activity of cimetidine is weak, and the clinical benefit of its use in women with hirsutism is minimal. Thus, this drug is not recommended for the treatment of hyperandrogenism.