Wikipedia

Cimetidine

(Redirected fromTagamet)

Cimetidine,sold under the brand nameTagametamong others, is ahistamineH2receptor antagonistthat inhibitsstomach acidproduction.[1][9][10]It is mainly used in the treatment ofheartburnandpeptic ulcers.[1][10][11]

Cimetidine
Clinical data
Pronunciation/sɪˈmɛtɪdiːn/or/saɪˈmɛtɪdiːn/
Trade namesTagamet, others
Other namesSKF-92334[1]
AHFS/DrugsMonograph
MedlinePlusa682256
License data
Pregnancy
category
  • AU:B1
Routes of
administration		By mouth,intramuscular injection,intravenous infusion[2]
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability60–70%[5][6]
Protein binding13–25%[6][7]
MetabolismLiver[6]
Metabolites• Cimetidine sulfoxide[6]
• Hydroxycimetidine[6]
• Guanyl urea cimetidine[6]
Onset of action30 minutes[8]
Eliminationhalf-life123 minutes (~2 hours)[7]
Duration of action4–8 hours[2]
ExcretionUrine[7]
Identifiers
  • 1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.052.012Edit this at Wikidata
Chemical and physical data
FormulaC10H16N6S
Molar mass252.34g·mol−1
3D model (JSmol)
  • CC1=C(N=CN1)CSCCNC(=NC)NC#N
  • InChI=1S/C10H16N6S/c1-8-9(16-7-15-8)5-17-4-3-13-10(12-2)14-6-11/h7H,3-5H2,1-2H3,(H,15,16)(H2,12,13,14)checkY
  • Key:AQIXAKUUQRKLND-UHFFFAOYSA-NcheckY
(verify)

With the development of proton pump inhibitors, such as omeprazole, 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 Administrationin 1979.[15]

Medical uses

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Main article:H2 antagonist

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]

Side effects

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Reportedside effectsof cimetidine includediarrhea,rashes,dizziness,fatigue,constipation,andmuscle pain,all of which are usually mild and transient.[16]It has been reported thatmental confusionmay occur in the elderly.[16]Because of its hormonal effects, cimetidine rarely may causesexual dysfunctionincluding loss oflibidoanderectile dysfunctionandgynecomastia(0.1–0.2%) in males during long-term treatment.[16][17][18]Rarely,interstitial nephritis,urticaria,andangioedemahave been reported with cimetidine treatment.[16]Cimetidine is also commonly associated with transient raisedaminotransferaseactivity;hepatotoxicityis rare.[19]

Overdose

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Cimetidine appears to be very safe inoverdose,producing nosymptomseven with massive overdoses (e.g., 20 g).[20]

Interactions

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Due to its non-selectiveinhibitionofcytochrome P450enzymes,cimetidine has numerousdrug interactions.Examples of specific interactions include the following:

Pharmacology

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Pharmacodynamics

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Histamine H2receptor antagonism

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Themechanism of actionof cimetidine as anantacidis as ahistamineH2receptorantagonist.[30]It has been found to bind to the H2receptor with a Kdof 42 nM.[31]

Cytochrome P450 inhibition

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Cimetidine is apotentinhibitorof certaincytochrome P450(CYP)enzymes,[20][32]includingCYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP2E1,andCYP3A4.[20][32][33]The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4,[34]of which it is described as a moderate inhibitor.[8]This is notable since these three CYPisoenzymesare involved in CYP-mediated drugbiotransformations;[35]however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidativemetabolismof many commonly used drugs.[36]As a result, cimetidine has the potential for a large number ofpharmacokinetic interactions.[20][32][33]

Cimetidine is reported to be acompetitiveandreversible inhibitorof several CYP enzymes,[19][26][32][37]althoughmechanism-based(suicide)irreversible inhibitionhas also been identified for cimetidine's inhibition of CYP2D6.[25]It reversibly inhibits CYP enzymes by binding directly with the complexedheme-ironof theactive sitevia one of itsimidazoleringnitrogenatoms,thereby blocking the oxidation of other drugs.[32][37][38]

Antiandrogenic and estrogenic effects

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Cimetidine has been found to possess weakantiandrogenicactivity at high doses.[30][39][40][41]It directly andcompetitivelyantagonizestheandrogen receptor(AR), thebiological targetofandrogensliketestosteroneanddihydrotestosterone(DHT).[42][43]However, theaffinityof cimetidine for the AR is very weak; in one study, it showed only 0.00084% of theaffinityof theanabolic steroidmetribolone(100%) for the human AR (Ki= 140 μM and 1.18 nM, respectively).[44]In any case, at sufficiently high doses, cimetidine has demonstrated weak but significant antiandrogenic effects in animals, including antiandrogenic effects in the ratventral prostateand mousekidney,reductions in the weights of themale accessory glandslike theprostate glandandseminal vesiclesin rats, and elevatedgonadotropinlevels in male rats (due to reducednegative feedbackon theHPGaxisby androgens).[45][46]In addition to AR antagonism, cimetidine has been found to inhibit the 2-hydroxylationofestradiol(via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increasedestrogenlevels.[47][48][49][50][51]The medication has also been reported to reduce testosteronebiosynthesisand increaseprolactinlevels in individualcase reports,effects which might be secondary to increased estrogen levels.[52]

At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men.[45]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.[45][46]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%.[53][45]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.[45]At high doses however, such as those used to treatZollinger–Ellison syndrome,there may be a higher incidence of gynecomastia with cimetidine.[53]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.[52]The symptoms appeared after 4 months of treatment and regressed within a month following discontinuation of cimetidine.[52]In another small study, cimetidine was reported to have inducedbreastchanges anderectile dysfunctionin 60% of 22 men treated with it.[52]These adverse effects completely resolved in all cases when the men were switched from cimetidine toranitidine.[52]A study of theUnited KingdomGeneral Practice Research Database,which contains over 80,000 men, found that therelative riskof gynecomastia in cimetidine users was 7.2 relative to non-users.[52]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.[52]The risk was highest during the period of time of 7 to 12 months after starting cimetidine.[52]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.[52]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.[46][45][52]

In accordance with the very weak nature of its AR antagonistic activity, cimetidine has shown minimal effectiveness in the treatment ofandrogen-dependent conditionssuch asacne,hirsutism(excessive hair growth), andhyperandrogenism(high androgen levels) in women.[54][55][53][56]As such, its use for such indications is not recommended.[55][56]

Pharmacokinetics

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Cimetidine is rapidlyabsorbedregardless ofroute of administration.[7]Theoralbioavailabilityof cimetidine is 60 to 70%.[5][6]Theonset of actionof cimetidine when taken orally is 30 minutes,[8]andpeak levelsoccur within 1 to 3 hours.[5]Cimetidine is widelydistributedthroughout alltissues.[7]It is able to cross theblood–brain barrierand can produce effects in thecentral nervous system(e.g.,headaches,dizziness,somnolence).[2]Thevolume of distributionof cimetidine is 0.8 L/kg in adults and 1.2 to 2.1 L/kg in children.[6]Itsplasma protein bindingis 13 to 25% and is said to be without pharmacological significance.[6][7]Cimetidine undergoes relatively littlemetabolism,with 56 to 85%excretedunchanged.[7]It is metabolized in theliverinto cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine.[6]The majormetaboliteof cimetidine is thesulfoxide,which accounts for about 30% of excreted material.[7]Cimetidine is rapidlyeliminated,with anelimination half-lifeof 123 minutes, or about 2 hours.[7]It has been said to have aduration of actionof 4 to 8 hours.[2]The medication is mainlyeliminatedinurine.[7]

History

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Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.[57]Cimetidine was the prototypical histamineH2receptor antagonistfrom 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 receptorantagonistto suppress stomach acid secretion.[58]This was one of the first drugs discovered using arational drug designapproach. Sir James W. Black shared the 1988 Nobel Prize in Physiology or Medicine for the discovery ofpropranololand also is credited for the discovery of cimetidine.

At the time (1964),histaminewas known to stimulate the secretion of stomach acid, but also that traditionalantihistamineshad no effect on acid production. In the process, the SK&F scientists also proved the existence of histamine H2receptors.

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 H2receptor. Hundreds of modified compounds were synthesized in an effort to develop a model of the receptor. The first breakthrough wasNα-guanylhistamine, a partial H2receptor antagonist. From this lead, the receptor model was further refined and eventually led to the development ofburimamide,the first H2receptor antagonist. Burimamide, a specificcompetitive antagonistat the H2receptor, 100 times more potent thanNα-guanylhistamine, proved the existence of the H2receptor.

Burimamide was still insufficiently potent for oral administration, and further modification of the structure, based on modifying thepKaof the compound, led to the development ofmetiamide.Metiamide was an effective agent; it was associated, however, with unacceptablenephrotoxicityandagranulocytosis.[58]The toxicity was proposed to arise from thethioureagroup, and similarguanidineanalogues 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 H2receptor 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.[59]

The commercial name "Tagamet" was decided upon by fusing the two words "antagonist "and" cimetidine ".[58]Subsequent to the introduction onto the U.S. drug market, two other H2receptor 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.[59]

Research

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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.[60][61][62]

Tentative evidence supports a beneficial role as add-on therapy in colorectal cancer.[63]

Cimetidine inhibitsALA synthaseactivity and hence may have some therapeutic value in preventing and treatingacute porphyriaattacks.[64][65]

There is some evidence supporting the use of Cimetidine in the treatment ofPFAPA.[66]

Veterinary use

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In dogs, cimetidine is used as an antiemetic when treating chronic gastritis.[67]

References

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  51. ^Rendic S, Di Carlo FJ (2010). "Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors".Drug Metabolism Reviews.29(1–2): 413–580.doi:10.3109/03602539709037591.PMID9187528.
  52. ^abcdefghijDeepinder F, Braunstein GD (September 2012). "Drug-induced gynecomastia: an evidence-based review".Expert Opinion on Drug Safety.11(5): 779–795.doi:10.1517/14740338.2012.712109.PMID22862307.S2CID22938364.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].
  53. ^abcDunaway G (1 April 2009)."Androgens and Antiandrogens".In Watts S, Faingold C, Dunaway G, Crespo L (eds.).Brody's Human Pharmacology - E-Book.Elsevier Health Sciences. pp. 472–.ISBN978-0-323-07575-6.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.
  54. ^Copperman AB, Mukherjee T, Kase NG (4 September 2003)."Polycystic Ovarian Syndrome".In Altchek A, Deligdisch L, Kase N (eds.).Diagnosis and Management of Ovarian Disorders.Academic Press. pp. 351–.ISBN978-0-08-049451-7.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.
  55. ^abPregler JP, DeCherney AH (2002)."Approach to the Patient with Hirsutism".Women's Health: Principles and Clinical Practice.PMPH-USA. pp. 595–.ISBN978-1-55009-170-0.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.
  56. ^abKatsambas AD, Dessinioti C (2010). "Hormonal therapy for acne: why not as first line therapy? facts and controversies".Clinics in Dermatology.28(1): 17–23.doi:10.1016/j.clindermatol.2009.03.006.PMID20082945.
  57. ^Scheinfeld N (March 2003). "Cimetidine: a review of the recent developments and reports in cutaneous medicine".Dermatology Online Journal.9(2): 4.doi:10.5070/D33S15Q645.PMID12639457.
  58. ^abc"Tagamet: Discovery of Histamine H2-receptor Antagonists ".National Historic Chemical Landmarks.American Chemical Society. Archived fromthe originalon 9 December 2012.Retrieved25 June2012.
  59. ^abFremantle M."Tagamet".Chemical and Engineering news.Retrieved1 July2013.
  60. ^Fit KE, Williams PC (July 2007). "Use of histamine2-antagonists for the treatment of verruca vulgaris".The Annals of Pharmacotherapy.41(7): 1222–1226.doi:10.1345/aph.1H616.PMID17535844.S2CID19769702.
  61. ^Glass AT, Solomon BA (June 1996). "Cimetidine therapy for recalcitrant warts in adults".Archives of Dermatology.132(6): 680–682.doi:10.1001/archderm.1996.03890300108014.PMID8651718.
  62. ^Karabulut AA, Sahin S, Ekşioglu M (April 1997). "Is cimetidine effective for nongenital warts: a double-blind, placebo-controlled study".Archives of Dermatology.133(4): 533–534.doi:10.1001/archderm.133.4.533.PMID9126017.
  63. ^Deva S, Jameson M (August 2012). "Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer".The Cochrane Database of Systematic Reviews.8(8): CD007814.doi:10.1002/14651858.CD007814.pub2.PMID22895966.
  64. ^Whatley SD, Badminton MN (2013). Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A, Bird TD, Ledbetter N, Mefford HC, Smith RJ, Stephens K (eds.).Acute Intermittent Porphyria.University of Washington, Seattle.PMID20301372.
  65. ^Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J, et al. (APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine) (2015).Acute Pain Management: Scientific Evidence(4th ed.). Melbourne, Australia: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. p. 316.ISBN978-0-9873236-6-8.Archived fromthe original(PDF)on 31 July 2019.Retrieved7 September2017.
  66. ^Vanoni F, Theodoropoulou K, Hofer M (June 2016)."PFAPA syndrome: a review on treatment and outcome".Pediatric Rheumatology Online Journal.14(1): 38.doi:10.1186/s12969-016-0101-9.PMC4924332.PMID27349388.
  67. ^Le Traon G, Burgaud S, Horspool LJ (June 2009). "Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets".Journal of Veterinary Pharmacology and Therapeutics.32(3): 213–218.doi:10.1111/j.1365-2885.2008.01026.x.PMID19646084.
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