Cimetidine, sold under the brand nameTagamet among others, is ahistamineH2 receptor antagonist that inhibitsstomach acid production.[1][9][10] It is mainly used in the treatment ofheartburn andpeptic ulcers.[1][10][11]
With the development ofproton pump inhibitors, such asomeprazole, approved for the same indications, cimetidine is available as an over-the-counter formulation to prevent heartburn or acid indigestion, along with the other H2-receptor antagonists.[12]
Cimetidine was developed in 1971 and came into commercial use in 1977.[13][14] Cimetidine was approved in the United Kingdom in 1976,[citation needed] and was approved in the United States by theFood and Drug Administration in 1979.[15]
Cimetidine is indicated for the treatment ofduodenal ulcers,gastric ulcers,gastroesophageal reflux disease, and pathological hypersecretory conditions.[3] Cimetidine is also used to relieve or prevent heartburn.[4]
Reportedside effects of cimetidine includediarrhea,rashes,dizziness,fatigue,constipation, andmuscle pain, all of which are usually mild and transient.[16] It has been reported thatmental confusion may occur in the elderly.[16] Because of its hormonal effects, cimetidine rarely may causesexual dysfunction including loss oflibido anderectile dysfunction andgynecomastia (0.1–0.2%) in males during long-term treatment.[16][17][18] Rarely,interstitial nephritis,urticaria, andangioedema have been reported with cimetidine treatment.[16] Cimetidine is also commonly associated with transient raisedaminotransferase activity;hepatotoxicity is rare.[19]
Cimetidine appears to be very safe inoverdose, producing nosymptoms even with massive overdoses (e.g., 20 g).[20]
Due to its non-selectiveinhibition ofcytochrome P450enzymes, cimetidine has numerousdrug interactions. Examples of specific interactions include, but are not limited to, the following:
Themechanism of action of cimetidine as anantacid is as ahistamineH2 receptorantagonist.[31] It has been found to bind to the H2 receptor with a Kd of 42 nM.[32]
Cimetidine is apotentinhibitor of certaincytochrome P450 (CYP)enzymes,[20][33] includingCYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP2E1, andCYP3A4.[20][33][34] The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4,[35] of which it is described as a moderate inhibitor.[8] This is notable since these three CYPisoenzymes are involved in CYP-mediated drugbiotransformations;[36] however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidativemetabolism of many commonly used drugs.[37] As a result, cimetidine has the potential for a large number ofpharmacokinetic interactions.[20][33][34]
Cimetidine is reported to be acompetitive andreversible inhibitor of several CYP enzymes,[19][26][33][38] althoughmechanism-based (suicide)irreversible inhibition has also been identified for cimetidine's inhibition of CYP2D6.[25] It reversibly inhibits CYP enzymes by binding directly with the complexedheme-iron of theactive site via one of itsimidazoleringnitrogenatoms, thereby blocking the oxidation of other drugs.[33][38][39]
Cimetidine has been found to possess weakantiandrogenic activity at high doses.[31][40][41][42] It directly andcompetitivelyantagonizes theandrogen receptor (AR), thebiological target ofandrogens liketestosterone anddihydrotestosterone (DHT).[43][44] However, theaffinity of cimetidine for the AR is very weak; in one study, it showed only 0.00084% of theaffinity of theanabolic steroidmetribolone (100%) for the human AR (Ki = 140 μM and 1.18 nM, respectively).[45] In any case, at sufficiently high doses, cimetidine has demonstrated weak but significant antiandrogenic effects in animals, including antiandrogenic effects in the ratventral prostate and mousekidney, reductions in the weights of themale accessory glands like theprostate gland andseminal vesicles in rats, and elevatedgonadotropin levels in male rats (due to reducednegative feedback on theHPG axis by androgens).[46][47] In addition to AR antagonism, cimetidine has been found to inhibit the 2-hydroxylation ofestradiol (via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increasedestrogen levels.[48][49][50][51][52] The medication has also been reported to reduce testosteronebiosynthesis and increaseprolactin levels in individualcase reports, effects which might be secondary to increased estrogen levels.[53]
At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men.[46] 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.[46][47] At typical clinical dosages, such as those used to treat peptic ulcer disease, the incidence ofgynecomastia (breast development) with cimetidine is very low at less than 1%.[54][46] In one survey of over 9,000 patients taking cimetidine, gynecomastia was the most frequentendocrine-related complaint but was reported in only 0.2% of patients.[46] At high doses however, such as those used to treatZollinger–Ellison syndrome, there may be a higher incidence of gynecomastia with cimetidine.[54] 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.[53] The symptoms appeared after 4 months of treatment and regressed within a month following discontinuation of cimetidine.[53] In another small study, cimetidine was reported to have inducedbreast changes anderectile dysfunction in 60% of 22 men treated with it.[53] These adverse effects completely resolved in all cases when the men were switched from cimetidine toranitidine.[53] A study of theUnited KingdomGeneral Practice Research Database, which contains over 80,000 men, found that therelative risk of gynecomastia in cimetidine users was 7.2 relative to non-users.[53] 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.[53] The risk was highest during the period of time of 7 to 12 months after starting cimetidine.[53] 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 thistissue, although increased levels of estrogens due to inhibition of estrogen metabolism is another possible mechanism.[53] Cimetidine has also been associated witholigospermia (decreasedsperm count) andsexual dysfunction (e.g.,decreased libido, erectile dysfunction) in men in some research, which are hormonally related similarly.[47][46][53]
In accordance with the very weak nature of its AR antagonistic activity, cimetidine has shown minimal effectiveness in the treatment ofandrogen-dependent conditions such asacne,hirsutism (excessive hair growth), andhyperandrogenism (high androgen levels) in women.[55][56][54][57] As such, its use for such indications is not recommended.[56][57]
Cimetidine is rapidlyabsorbed regardless ofroute of administration.[7] Theoralbioavailability of cimetidine is 60 to 70%.[5][6] Theonset of action of cimetidine when taken orally is 30 minutes,[8] andpeak levels occur within 1 to 3 hours.[5] Cimetidine is widelydistributed throughout alltissues.[7] It is able to cross theblood–brain barrier and can produce effects in thecentral nervous system (e.g.,headaches,dizziness,somnolence).[2] Thevolume of distribution of cimetidine is 0.8 L/kg in adults and 1.2 to 2.1 L/kg in children.[6] Itsplasma protein binding is 13 to 25% and is said to be without pharmacological significance.[6][7] Cimetidine undergoes relatively littlemetabolism, with 56 to 85%excreted unchanged.[7] It is metabolized in theliver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine.[6] The majormetabolite of cimetidine is thesulfoxide, which accounts for about 30% of excreted material.[7] Cimetidine is rapidlyeliminated, with anelimination half-life of 123 minutes, or about 2 hours.[7] It has been said to have aduration of action of 4 to 8 hours.[2] The medication is mainlyeliminated inurine.[7]
Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.[58] Cimetidine was the prototypical histamineH2 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 ofGlaxoSmithKline) byJames W. Black,C. Robin Ganellin, and others to develop ahistamine receptorantagonist to suppress stomach acid secretion.[59] This was one of the first drugs discovered using arational drug design approach. Sir James W. Black shared the 1988 Nobel Prize in Physiology or Medicine for the discovery ofpropranolol 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 traditionalantihistamines 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 wasNα-guanylhistamine, a partial H2 receptor antagonist. From this lead, the receptor model was further refined and eventually led to the development ofburimamide, the first H2 receptor antagonist. Burimamide, a specificcompetitive antagonist at the H2 receptor, 100 times more potent thanNα-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 thepKa of the compound, led to the development ofmetiamide. Metiamide was an effective agent; it was associated, however, with unacceptablenephrotoxicity andagranulocytosis.[59] The toxicity was proposed to arise from thethiourea group, and similarguanidine 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.[60]
The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine".[59] Subsequent to the introduction onto the U.S. drug market, two other H2 receptor antagonists were approved,ranitidine (Zantac, Glaxo Labs) andfamotidine (Pepcid, Yamanouchi, Ltd.) Cimetidine became the first drug ever to reach more than $1 billion a year in sales, thus making it the firstblockbuster drug.[citation needed]
Tagamet has been largely replaced by proton pump inhibitors for treating peptic ulcers, but is available as an over-the-counter medicine for heartburn in many countries.[60]
In August 12, 1989, Danlex Research Laboratories, Inc. filed a petition with the Bureau of Patents, Trademarks and Technology Transfer (BPTTT) for a compulsory license to manufacture, use, and sell Cimetidine, citing the provisions of the Patent Law (R.A. 165) for medicinal products. Pre-1995, the Bureau of Patents, Trademarks and Technology Transfer (BPTTT) ruled in favor of Danlex and granted the compulsory license, subject to Danlex paying a royalty of 2.5% of net sales toSmith, Kline & French. January 27, 1995,Smith, Kline & French appealed to the Court of Appeals, but the CA affirmed the BPTTT's decision, upholding the grant of the compulsory license to Danlex. July 25, 1995, the Court of Appeals deniedSmith, Kline & French's Motion for Reconsideration. September 15, 1995,Smith, Kline & French filed a Petition for Review on Certiorari with the Supreme Court of the Philippines, challenging the CA's decision. October 23, 2001, The Supreme Court (G.R. No. 121267) rendered its decision, affirming the Court of Appeals and upholding the grant of the compulsory license to Danlex. This marked the final judicial resolution of the case.[61]
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.[62][63][64]
Tentative evidence supports a beneficial role as add-on therapy in colorectal cancer.[65]
Cimetidine inhibitsALA synthase activity and hence may have some therapeutic value in preventing and treatingacute porphyria attacks.[66][67]
There is some evidence supporting the use of cimetidine in the treatment ofPFAPA.[68]
In dogs, cimetidine is used as an antiemetic when treating chronic gastritis.[69]
Drugs interacting in this way with CYP 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 [4]. In one clinical study, men administered cimetidine exhibited a significant reduction in sperm concentration compared to placebo-treated controls [35]. 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 [34].
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 [13]. 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 [14]. 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 [15]. Cimetidine blocks the androgen receptors in the breast leading to decreased androgen action causing the growth of breast tissue because of 'unopposed' estrogen action [16]. Another possible mechanism includes decreased 2-hydroxylation of estrogen leading to elevated serum estrogen levels [17]. There also are reports of cimetidine blocking testosterone biosynthesis and causing elevated prolactin levels in individual cases [18].
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.
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