View source for Cimetidine

{{Short description|Medication}}
{{Use dmy dates|date=November 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 456484490
| image = File:Cimetidine Structural Formula V.1.svg
| image_class = skin-invert-image
| width = 250
| alt = 
| image2 = Cimetidine-xtal-3D-balls.png
| width2 = 250
| alt2 =

<!--Clinical data-->
| pronounce = {{IPAc-en|s|ᵻ|ˈ|m|ɛ|t|ᵻ|d|iː|n}} or {{IPAc-en|s|aɪ|ˈ|m|ɛ|t|ᵻ|d|iː|n}}
| tradename = Tagamet, others
| Drugs.com = {{drugs.com|monograph|cimetidine}}
| MedlinePlus = a682256
| DailyMedID = Cimetidine
| pregnancy_AU = B1
| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection]], [[intravenous therapy|intravenous infusion]]<ref name="GuptaSingh-Radcliff2013" />
| ATC_prefix = A02
| ATC_suffix = BA01

| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| legal_US_comment = /&nbsp;OTC<ref name="Cimetidine FDA label">{{cite web | title=Cimetidine tablet, film coated | website=DailyMed | date=30 November 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=496e258d-a5fd-42da-9a86-73afc8be359b | access-date=24 June 2024}}</ref><ref name="Tagamet FDA label">{{cite web | title=Tagamet - cimetidine tablet | website=DailyMed | date=10 June 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e6401e0a-8612-42e8-bf89-2d67243f28dc | access-date=24 June 2024}}</ref>

<!--Pharmacokinetic data-->
| bioavailability = 60–70%<ref name="DowdJohnson2016">{{cite book| vauthors = Dowd FJ, Johnson B, Mariotti A |title=Pharmacology and Therapeutics for Dentistry - E-Book|url=https://books.google.com/books?id=6xT7DAAAQBAJ&pg=PA406|date=3 September 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-44595-5|pages=406–}}</ref><ref name="LeikinPaloucek1995" />
| protein_bound = 13–25%<ref name="LeikinPaloucek1995" /><ref name="AcademicPress1984">{{cite book|title=Profiles of Drug Substances, Excipients and Related Methodology|url=https://books.google.com/books?id=Fz6X-GmS-GgC&pg=PA176|date=24 October 1984|publisher=Academic Press|isbn=978-0-08-086108-1|pages=176–}}</ref>
| metabolism = [[Liver]]<ref name="LeikinPaloucek1995" />
| metabolites = • Cimetidine sulfoxide<ref name="LeikinPaloucek1995" /><br />• Hydroxycimetidine<ref name="LeikinPaloucek1995" /><br />• Guanyl urea cimetidine<ref name="LeikinPaloucek1995" />
| onset = 30 minutes<ref name="VallerandSanoski2016" />
| elimination_half-life = 123 minutes (~2 hours)<ref name="AcademicPress1984" />
| duration_of_action = 4–8 hours<ref name="GuptaSingh-Radcliff2013">{{cite book| vauthors = Gupta A, Singh-Radcliff N |title=Pharmacology in Anesthesia Practice|url=https://books.google.com/books?id=a85oAgAAQBAJ&pg=PT177|date=12 March 2013|publisher=Oxford University Press|isbn=978-0-19-934399-7|pages=177–}}</ref>
| excretion = [[Urine]]<ref name="AcademicPress1984" />

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 51481-61-9
| PubChem = 2756
| IUPHAR_ligand = 1231
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00501
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2654
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 80061L1WGD
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00295
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 3699
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 30
| synonyms = SKF-92334<ref name="Elks2014" />

<!--Chemical data-->
| IUPAC_name = 1-cyano-2-methyl-3-[2-[(5-methyl-1''H''-imidazol-4-yl)methylsulfanyl]ethyl]guanidine
| C=10 | H=16 | N=6 | S=1
| SMILES = CC1=C(N=CN1)CSCCNC(=NC)NC#N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AQIXAKUUQRKLND-UHFFFAOYSA-N
}}
<!-- Definition and medical uses -->
'''Cimetidine''', sold under the brand name '''Tagamet''' among others, is a [[histamine]] [[H2-receptor antagonist|H<sub>2</sub> receptor antagonist]] that inhibits [[stomach acid]] production.<ref name="Elks2014">{{cite book | vauthors = Elks J | title = The Dictionary of Drugs: Chemical Data: Chemical Data, Bibliographies | url = https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA275 | date = 14 November 2014 | publisher = Springer | isbn = 978-1-4757-2085-3 | pages = 275– }}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA234|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=234–}}</ref><ref name="MortonMorton1999">{{cite book | vauthors = Morton I, Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | url = https://books.google.com/books?id=mqaOMOtk61IC&pg=PA77 | date = 31 October 1999 | publisher=Springer Science & Business Media | isbn = 978-0-7514-0499-9 | pages = 77– }}</ref> It is mainly used in the treatment of [[heartburn]] and [[peptic ulcer]]s.<ref name="Elks2014" /><ref name="MortonMorton1999" /><ref name="BurchumRosenthal2014">{{cite book | vauthors = Jacqueline B, Rosenthal L | chapter = Drugs for Peptic Ulcer Disease | title = Lehne's Pharmacology for Nursing Care | chapter-url = https://books.google.com/books?id=C7_NBQAAQBAJ&pg=PA952 | date = 2 December 2014 | publisher = Elsevier Health Sciences | isbn = 978-0-323-34026-7 | pages = 952– }}</ref>

<!-- Side effects -->
With the development of [[proton pump inhibitor]]s, 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.<ref>{{Cite book | vauthors = Pino MA, Azer SA | chapter = Cimetidine | date = March 2023 | title = StatPearls [Internet]. | location = Treasure Island (FL) | publisher = StatPearls Publishing | pmid = 31334975 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK544255/ | id=Bookshelf ID: NBK544255|access-date=6 November 2023 | via = U.S. National Library of Medicine}}</ref>

<!-- History, society, and culture -->
Cimetidine was developed in 1971 and came into commercial use in 1977.<ref name="FischerGanellin2010">{{cite book | vauthors = Fischer J, Ganellin CR | title = Analogue-based Drug Discovery II | url = https://books.google.com/books?id=h2Kd8ci4Ln8C&pg=PA4 | date = 24 August 2010 | publisher = John Wiley & Sons | isbn = 978-3-527-63212-1 | pages = 4 }}</ref><ref>{{cite book| vauthors = Alapi EM, Fischer J | chapter = Table of Selected Analogue Classes | veditors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=444| chapter-url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA444}}</ref> Cimetidine was approved in the United Kingdom in 1976,{{citation needed|date=November 2023}} and was approved in the United States by the [[Food and Drug Administration]] in 1979.<ref>{{cite web | title=Tagamet: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017939 | archive-url=https://web.archive.org/web/20170430220843/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017939 | url-status=dead | archive-date=30 April 2017 | access-date=9 November 2023}}</ref>

{{TOC limit|3}}

==Medical uses==
{{Main|H2 antagonist}}

Cimetidine is indicated for the treatment of [[duodenal ulcer]]s, [[gastric ulcer]]s, [[gastroesophageal reflux disease]], and pathological hypersecretory conditions.<ref name="Cimetidine FDA label" /> Cimetidine is also used to relieve or prevent heartburn.<ref name="Tagamet FDA label" />

==Side effects==
Reported [[side effect]]s of cimetidine include [[diarrhea]], [[rash]]es, [[dizziness]], [[fatigue (medical)|fatigue]], [[constipation]], and [[myalgia|muscle pain]], all of which are usually mild and transient.<ref name="RitterLewis2008">{{cite book | vauthors = Ritter J, Lewis L, Mant T, Ferro A | chapter = Alimenary System and Liver | title = A Textbook of Clinical Pharmacology and Therapeutics | edition = 5th | chapter-url = https://books.google.com/books?id=TD59BgAAQBAJ&pg=PA250 | date = 25 April 2008 | publisher = CRC Press | isbn = 978-1-4441-1300-6 | pages = 250– }}</ref> It has been reported that [[mental confusion]] may occur in the elderly.<ref name="RitterLewis2008" /> 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.<ref name="RitterLewis2008" /><ref>{{cite journal | vauthors = Sawyer D, Conner CS, Scalley R | title = Cimetidine: adverse reactions and acute toxicity | journal = American Journal of Hospital Pharmacy | volume = 38 | issue = 2 | pages = 188–197 | date = February 1981 | pmid = 7011006 }}</ref><ref>{{cite journal | vauthors = Sabesin SM | title = Safety issues relating to long-term treatment with histamine H2-receptor antagonists | journal = Alimentary Pharmacology & Therapeutics | volume = 7 | issue = Suppl 2 | pages = 35–40 | year = 1993 | pmid = 8103374 | doi = 10.1111/j.1365-2036.1993.tb00597.x | s2cid = 42564864 }}</ref> Rarely, [[interstitial nephritis]], [[urticaria]], and [[angioedema]] have been reported with cimetidine treatment.<ref name="RitterLewis2008" /> Cimetidine is also commonly associated with transient raised [[aminotransferase]] activity; [[hepatotoxicity]] is rare.<ref name="Kelly2009" />

==Overdose==
Cimetidine appears to be very safe in [[overdose]], producing no [[symptom]]s even with massive overdoses (e.g., 20 g).<ref name="Dart2004" />

== Interactions ==

Due to its non-selective [[enzyme inhibition|inhibition]] of [[cytochrome P450]] [[enzyme]]s, cimetidine has numerous [[drug interaction]]s. Examples of specific interactions include, but are not limited to, the following:
* 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]].<ref>{{cite journal | vauthors = Furst DE | title = Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases | journal = Lupus | volume = 5 | issue = Suppl 1 | pages = S11–S15 | date = June 1996 | pmid = 8803904 | doi = 10.1177/096120339600500104 | s2cid = 44999237 }}</ref>
* Cimetidine can also interact with a number of psychoactive medications, including [[tricyclic antidepressant]]s and [[selective serotonin reuptake inhibitor]]s, causing increased blood levels of these drugs and the potential of subsequent toxicity.{{Citation needed|date=August 2016}}
* Following administration of cimetidine, the elimination half-life and [[area under the curve (pharmacokinetics)|area-under-curve]] of [[zolmitriptan]] and its [[active metabolite]]s were roughly doubled.<ref>See complete drug interactions for Zomig (zolmitriptan succinate used for migraine relief) in package insert: {{cite web | url = http://www1.astrazeneca-us.com/pi/Zomig.pdf | title = Highlights of Zomig Prescribing Information | publisher = AstraZeneca | access-date = 28 January 2010 | archive-url = https://web.archive.org/web/20150218190357/http://www1.astrazeneca-us.com/pi/Zomig.pdf | archive-date = 18 February 2015 | url-status = dead }}</ref>
* 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.<ref>{{cite journal | vauthors = Urakami Y, Kimura N, Okuda M, Masuda S, Katsura T, Inui K | title = Transcellular transport of creatinine in renal tubular epithelial cell line LLC-PK1 | journal = Drug Metabolism and Pharmacokinetics | volume = 20 | issue = 3 | pages = 200–205 | date = June 2005 | pmid = 15988122 | doi = 10.2133/dmpk.20.200 | s2cid = 13857940 }}</ref>
* Like several other medications (e.g., [[erythromycin]]), cimetidine interferes with the body's metabolization of [[sildenafil]], causing its strength and duration to increase and making its side effects more likely and prominent.{{Citation needed|date=August 2016}}
* 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.<ref name="Rodrigues2008">{{cite book | vauthors = Ogilvie BW, Usuki E, Yerino P, Parkinson A | chapter = In vitro approaches for studying the inhibition of drug-metabolizing enzymes and identifying the drug-metabolizing enzymes responsible for the metabolism of drugs (reaction phenotyping) with emphasis on cytochrome P450 | veditors = Rodrigues DA | title = Drug-Drug Interactions | edition = Second | chapter-url = https://books.google.com/books?id=rmCGQ8qAv8AC&pg=PA294 | date = 8 February 2008 | publisher = CRC Press | isbn=978-0-8493-7594-1 | pages = 277, 294 }}</ref>
* Cimetidine has been shown clinically to reduce the clearance of [[mirtazapine]], [[imipramine]], [[timolol]], [[nebivolol]], [[sparteine]], [[loratadine]], [[nortriptyline]], [[gabapentin]], and [[desipramine]] in humans.<ref name="Zhou2016" />
* Cimetidine inhibits the [[renal]] [[excretion]] of [[metformin]] and [[procainamide]], resulting in increased circulating levels of these drugs.<ref name="RitterLewis2008" />
* Interactions of potential clinical importance with cimetidine include [[warfarin]], [[theophylline]], [[phenytoin]], [[carbamazepine]], [[pethidine]] and other [[opioid]] [[analgesic]]s, [[tricyclic antidepressant]]s, [[lidocaine]], [[terfenadine]], [[amiodarone]], [[flecainide]], [[quinidine]], [[fluorouracil]], and [[benzodiazepine]]s.<ref name="RitterLewis2008" /><ref name="RosenfeldLoose2007" />
* Cimetidine may decrease the effects of CYP2D6 substrates that are [[prodrug]]s, such as [[codeine]], [[tramadol]], and [[tamoxifen]].<ref name="FullerSajatovic2005">{{cite book | vauthors = Fuller MA, Sajatovic M | title = Drug Information Handbook for Psychiatry | url = https://books.google.com/books?id=LzBtAAAAMAAJ | year = 2005 | publisher = Lexi-Comp | page = 285 | isbn = 9781591951148}}</ref>
* Cimetidine reduces the [[absorption (pharmacokinetics)|absorption]] of [[ketoconazole]] and [[itraconazole]] (which require a low [[pH]]).<ref name="RitterLewis2008" />
* Cimetidine has a theoretical but unproven benefit in [[paracetamol toxicity]].<ref name="Kelly2009" /> 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).<ref name="CameronFeuer2012">{{cite book | vauthors = Leeder JS, Okey AB | chapter = Cytochrome P450 and Liver injury | veditors = Cameron R, Feuer G, de la Iglesias F | title = Drug-Induced Hepatotoxicity | chapter-url = https://books.google.com/books?id=xZf-CAAAQBAJ&pg=PA140 | date = 6 December 2012 | publisher = Springer Science & Business Media | isbn = 978-3-642-61013-4 | pages = 140– }}</ref>
* Cimetidine is used in cancer metastasis research as a blocker of E-selectin.<ref>{{cite journal | vauthors = Coppo R, Orso F, Virga F, Dalmasso A, Baruffaldi D, Nie L, Clapero F, Dettori D, Quirico L, Grassi E, Defilippi P, Provero P, Valdembri D, Serini G, Sadeghi MM, Mazzone M, Taverna D | title = ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3 | journal = Cancer Letters | volume = 510 | pages = 13–23 | date = July 2021 | pmid = 33862151 | pmc = 8581997 | doi = 10.1016/j.canlet.2021.04.005 | hdl-access = free | hdl = 2318/1791282 }}</ref>

==Pharmacology==

===Pharmacodynamics===

====Histamine H<sub>2</sub> receptor antagonism====
The [[mechanism of action]] of cimetidine as an [[antacid]] is as a [[histamine]] [[H2 receptor|H<sub>2</sub> receptor]] [[receptor antagonist|antagonist]].<ref name="pmid6317740">{{cite journal | vauthors = Richards DA | title = Comparative pharmacodynamics and pharmacokinetics of cimetidine and ranitidine | journal = Journal of Clinical Gastroenterology | volume = 5 | issue = Suppl 1 | pages = 81–90 | year = 1983 | pmid = 6317740 | doi = 10.1097/00004836-198312001-00008 | s2cid = 24909853 }}</ref> It has been found to bind to the H<sub>2</sub> receptor with a K<sub>d</sub> of 42&nbsp;nM.<ref name="Osborne2013">{{cite journal | vauthors = Taylor JE | title = Neurochemical and neuropharmacological aspects of histamine receptors | journal = Neurochemistry International | volume = 4 | issue = 2–3 | pages = 89–96 | date = 22 October 2013 | pmid = 20487855 | url = https://books.google.com/books?id=ldnWAgAAQBAJ&pg=PA297 | publisher = Elsevier Science | doi = 10.1016/0197-0186(82)90001-8 | isbn = 978-1-4832-8635-8 | s2cid = 40069290 | veditors = Osborne NN | url-access = subscription }}</ref>

====Cytochrome P450 inhibition====
Cimetidine is a [[potency (pharmacology)|potent]] [[enzyme inhibitor|inhibitor]] of certain [[cytochrome P450]] (CYP) [[enzyme]]s,<ref name="Dart2004">{{cite book | vauthors = Whyte IM | chapter = Histaminde H<sub>2</sub> Antagonists | veditors = Dart RC | title = Medical Toxicology | chapter-url = https://books.google.com/books?id=BfdighlyGiwC&pg=PA402 | year = 2004 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-2845-4 | pages = 402– }}</ref><ref name="LemkeWilliams2008">{{cite book | vauthors = Williams DA | chapter = Drug Metabolism | veditors = Lemke TL, Williams DA | title = Foye's Principles of Medicinal Chemistry | chapter-url = https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA273 | year = 2008 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-6879-5 | pages = 273– }}</ref> including [[CYP1A2]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]], [[CYP2E1]], and [[CYP3A4]].<ref name="Dart2004" /><ref name="LemkeWilliams2008" /><ref name="KarallieddeClarke2010">{{cite book | vauthors = Karalliedde LD, Clarke SF, Collignon U, Karalliedde J | chapter = Drugs Acting on the Gastrointestinal Track | title = Adverse Drug Interactions: A Handbook for Prescribers | chapter-url = https://books.google.com/books?id=B2YwH371uzYC&pg=PA633 | date = 29 January 2010 | publisher = CRC Press | isbn = 978-0-340-92769-4 | pages = 633– }}</ref> The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4,<ref name="PriskornLarsen1997">{{cite journal | vauthors = Priskorn M, Larsen F, Segonzac A, Moulin M | title = Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects | journal = European Journal of Clinical Pharmacology | volume = 52 | issue = 3 | pages = 241–242 | year = 1997 | pmid = 9218934 | doi = 10.1007/s002280050282 | s2cid = 22540140 }}</ref> of which it is described as a moderate inhibitor.<ref name="VallerandSanoski2016">{{cite book | vauthors = Vallerand AH, Sanoski CA, Deglin JH | title = Davis's Drug Guide for Nurses | url = https://books.google.com/books?id=ORa1DAAAQBAJ&pg=PA636 | date = 25 May 2016 | publisher = F.A. Davis | isbn = 978-0-8036-5779-3 | pages = 636– }}</ref> This is notable since these three CYP [[isoenzyme]]s are involved in CYP-mediated drug [[biotransformation]]s;<ref name="MartinezAlbet1999">{{cite journal | vauthors = Martínez C, Albet C, Agúndez JA, Herrero E, Carrillo JA, Márquez M, Benítez J, Ortiz JA | title = Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists | journal = Clinical Pharmacology and Therapeutics | volume = 65 | issue = 4 | pages = 369–376 | date = April 1999 | pmid = 10223772 | doi = 10.1016/S0009-9236(99)70129-3 | s2cid = 25151710 }}</ref> however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative [[metabolism]] of many commonly used drugs.<ref name="Delafuente2003">{{cite journal | vauthors = Delafuente JC | title = Understanding and preventing drug interactions in elderly patients | journal = Critical Reviews in Oncology/Hematology | volume = 48 | issue = 2 | pages = 133–143 | date = November 2003 | pmid = 14607376 | doi = 10.1016/j.critrevonc.2003.04.004 }}</ref> As a result, cimetidine has the potential for a large number of [[pharmacokinetic interactions]].<ref name="Dart2004" /><ref name="LemkeWilliams2008" /><ref name="KarallieddeClarke2010" />

Cimetidine is reported to be a [[competitive inhibition|competitive]] and [[Enzyme inhibitor#Reversible inhibitors|reversible inhibitor]] of several CYP enzymes,<ref name="Kelly2009">{{cite book | vauthors = Murray KF | chapter = Drug-Induced Liver Disease | veditors = Kelly D | title = Diseases of the Liver and Biliary System in Children | chapter-url = https://books.google.com/books?id=z7nO3OrNXckC&pg=PA224 | date = 26 January 2009 | publisher = John Wiley & Sons | isbn = 978-1-4443-0054-3 | pages = 224– }}</ref><ref name="RosenfeldLoose2007">{{cite book | vauthors = Rosenfeld GC, Loose DS | title = Pharmacology | url = https://books.google.com/books?id=fm8kmMDjdiAC&pg=PA202 | year = 2007 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-8074-2 | pages = 202– }}</ref><ref name="LemkeWilliams2008" /><ref name="Cairns2012">{{cite book | vauthors = Cairns D | chapter = Drug Metabolism: Drug Conjugating Reactions (Phase 2) | title = Essentials of Pharmaceutical Chemistry | chapter-url = https://books.google.com/books?id=gNliFkwHYgEC&pg=PA110 | year = 2012 | publisher = Pharmaceutical Press | isbn = 978-0-85369-979-8 | pages = 110– | quote = 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.}}</ref> although [[suicide inhibition|mechanism-based]] (suicide) [[Enzyme inhibitor#Irreversible inhibitors|irreversible inhibition]] has also been identified for cimetidine's inhibition of CYP2D6.<ref name="Zhou2016">{{cite book| vauthors = Zhou S | chapter = Inhibitors of Human CYP2D6 |title=Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism | chapter-url=https://books.google.com/books?id=UJqmCwAAQBAJ&pg=PA299|date=6 April 2016|publisher=CRC Press|isbn=978-1-4665-9788-4|pages=299–}}</ref> It reversibly inhibits CYP enzymes by binding directly with the complexed [[heme]]-[[iron]] of the [[active site]] via one of its [[imidazole]] [[ring (chemistry)|ring]] [[nitrogen]] [[atom]]s, thereby blocking the oxidation of other drugs.<ref name="LemkeWilliams2008" /><ref name="Cairns2012" /><ref name="pmid9630736">{{cite journal | vauthors = Liska DJ | title = The detoxification enzyme systems | journal = Alternative Medicine Review | volume = 3 | issue = 3 | pages = 187–198 | date = June 1998 | pmid = 9630736 | quote = 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 }}</ref>

====Antiandrogenic and estrogenic effects====
Cimetidine has been found to possess weak [[antiandrogen]]ic activity at high doses.<ref name="pmid6317740" /><ref name="Becker2001">{{cite book | vauthors = Matsumoto AM | chapter = Clinical Use and Abuse of Androgens and Antiandrogens | veditors = Becker KL | title = Principles and Practice of Endocrinology and Metabolism | chapter-url = https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196 | year = 2001 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-1750-2 | pages = 1196– }}</ref><ref name="pmid6150641">{{cite journal | vauthors = Jensen RT, Collen MJ, McArthur KE, Howard JM, Maton PN, Cherner JA, Gardner JD | title = Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states | journal = The American Journal of Medicine | volume = 77 | issue = 5B | pages = 90–105 | date = November 1984 | pmid = 6150641 }}</ref><ref name="pmid3921876">{{cite journal | vauthors = Biagi P, Milani G | title = [Dysfunction of the hypothalamo-hypophyseal-gonadal axis induced by histamine H2 antagonists. Review of the literature and personal observations] | language = it | journal = Minerva Medica | volume = 76 | issue = 12 | pages = 579–586 | date = March 1985 | pmid = 3921876 }}</ref> It directly and [[competitive antagonist|competitively]] [[receptor antagonist|antagonize]]s the [[androgen receptor]] (AR), the [[biological target]] of [[androgen]]s like [[testosterone]] and [[dihydrotestosterone]] (DHT).<ref name="pmid428705">{{cite journal | vauthors = Winters SJ, Banks JL, Loriaux DL | title = Cimetidine is an antiandrogen in the rat | journal = Gastroenterology | volume = 76 | issue = 3 | pages = 504–508 | date = March 1979 | pmid = 428705 | doi = 10.1016/S0016-5085(79)80217-6 | doi-access = free }}</ref><ref name="pmid6123322">{{cite journal | vauthors = Sivelle PC, Underwood AH, Jelly JA | title = The effects of histamine H2 receptor antagonists on androgen action in vivo and dihydrotestosterone binding to the rat prostate androgen receptor in vitro | journal = Biochemical Pharmacology | volume = 31 | issue = 5 | pages = 677–684 | date = March 1982 | pmid = 6123322 | doi = 10.1016/0006-2952(82)90449-X }}</ref> However, the [[affinity (pharmacology)|affinity]] of cimetidine for the AR is very weak; in one study, it showed only 0.00084% of the [[affinity (pharmacology)|affinity]] of the [[anabolic steroid]] [[metribolone]] (100%) for the human AR (K<sub>i</sub> = 140&nbsp;μM and 1.18&nbsp;nM, respectively).<ref name="pmid6725525 b">{{cite journal | vauthors = Eil C, Edelson SK | title = The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 59 | issue = 1 | pages = 51–55 | date = July 1984 | pmid = 6725525 | doi = 10.1210/jcem-59-1-51 }}</ref> 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 gland]]s like the [[prostate gland]] and [[seminal vesicle]]s in rats, and elevated [[gonadotropin]] levels in male rats (due to reduced [[negative feedback]] on the [[hypothalamic–pituitary–gonadal axis|{{abbr|HPG|hypothalamic–pituitary–gonadal}} axis]] by androgens).<ref name="GerallMoltz2013" /><ref name="PlessisAgarwal2014">{{cite book| vauthors = Barazani Y, Sabanegh Jr ES | chapter = Risks from Medical and Therapeutic Treatments | veditors = du Plessis SS, Agarwal A, Sabanegh Jr ES |title=Male Infertility: A Complete Guide to Lifestyle and Environmental Factors| chapter-url=https://books.google.com/books?id=-I4kBAAAQBAJ&pg=PA233|date=26 July 2014|publisher=Springer|isbn=978-1-4939-1040-3|pages=233–|quote=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].}}</ref> 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.<ref name="GalbraithMichnovicz1989">{{cite journal | vauthors = Galbraith RA, Michnovicz JJ | title = The effects of cimetidine on the oxidative metabolism of estradiol | journal = The New England Journal of Medicine | volume = 321 | issue = 5 | pages = 269–274 | date = August 1989 | pmid = 2747769 | doi = 10.1056/NEJM198908033210501 }}</ref><ref name="pmid1988774">{{cite journal | vauthors = Michnovicz JJ, Galbraith RA | title = Cimetidine inhibits catechol estrogen metabolism in women | journal = Metabolism | volume = 40 | issue = 2 | pages = 170–174 | date = February 1991 | pmid = 1988774 | doi = 10.1016/0026-0495(91)90169-W }}</ref><ref name="PescovitzWalvoord2007">{{cite book | vauthors = Pescovitz OH, Walvoord EC | title = When Puberty is Precocious: Scientific and Clinical Aspects | url = https://books.google.com/books?id=seYO1f1JgzYC&pg=PA203 | date = 6 June 2007 | publisher = Springer Science & Business Media | isbn = 978-1-59745-499-5 | pages = 203– }}</ref><ref name="PolatCuhaci2014">{{cite journal | vauthors = Cuhaci N, Polat SB, Evranos B, Ersoy R, Cakir B | title = Gynecomastia: Clinical evaluation and management | journal = Indian Journal of Endocrinology and Metabolism | volume = 18 | issue = 2 | pages = 150–158 | date = March 2014 | pmid = 24741509 | pmc = 3987263 | doi = 10.4103/2230-8210.129104 | doi-access = free }}</ref><ref name="RendicCarlo2010">{{cite journal | vauthors = Rendic S, Di Carlo FJ | title = Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors | journal = Drug Metabolism Reviews | volume = 29 | issue = 1–2 | pages = 413–580 | year = 2010 | pmid = 9187528 | doi = 10.3109/03602539709037591 }}</ref> The medication has also been reported to reduce testosterone [[biosynthesis]] and increase [[prolactin]] levels in individual [[case report]]s, effects which might be secondary to increased estrogen levels.<ref name="pmid22862307">{{cite journal | vauthors = Deepinder F, Braunstein GD | title = Drug-induced gynecomastia: an evidence-based review | journal = Expert Opinion on Drug Safety | volume = 11 | issue = 5 | pages = 779–795 | date = September 2012 | pmid = 22862307 | doi = 10.1517/14740338.2012.712109 | quote = 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]. | s2cid = 22938364 }}</ref>

At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men.<ref name="GerallMoltz2013" /> 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.<ref name="GerallMoltz2013" /><ref name="PlessisAgarwal2014" /> 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%.<ref name="WattsFaingold2009">{{cite book| vauthors = Dunaway G | chapter = Androgens and Antiandrogens | veditors = Watts S, Faingold C, Dunaway G, Crespo L |title=Brody's Human Pharmacology - E-Book| chapter-url= https://books.google.com/books?id=kfsrz_-OrMQC&pg=PA472|date=1 April 2009|publisher=Elsevier Health Sciences|isbn=978-0-323-07575-6|pages=472–|quote=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.}}</ref><ref name="GerallMoltz2013">{{cite book| vauthors = Ward OB | chapter = Fetal drug exposure and sexual differentiation of males. | veditors = Gerall AA, Moltz H, Ward EL |title=Sexual Differentiation | chapter-url= https://books.google.com/books?id=4nb1BwAAQBAJ&pg=PA207|date=11 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4899-2453-7|pages=207–|quote=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).}}</ref> In one survey of over 9,000&nbsp;patients taking cimetidine, gynecomastia was the most frequent [[endocrine system|endocrine]]-related complaint but was reported in only 0.2% of patients.<ref name="GerallMoltz2013" /> At high doses however, such as those used to treat [[Zollinger–Ellison syndrome]], there may be a higher incidence of gynecomastia with cimetidine.<ref name="WattsFaingold2009" /> In one small study, a 20% incidence of gynecomastia was observed in 25&nbsp;male patients with duodenal ulcers who were treated with 1,600&nbsp;mg/day cimetidine.<ref name="pmid22862307" /> The symptoms appeared after 4&nbsp;months of treatment and regressed within a month following discontinuation of cimetidine.<ref name="pmid22862307" /> In another small study, cimetidine was reported to have induced [[breast]] changes and [[erectile dysfunction]] in 60% of 22&nbsp;men treated with it.<ref name="pmid22862307" /> These adverse effects completely resolved in all cases when the men were switched from cimetidine to [[ranitidine]].<ref name="pmid22862307" /> A study of the [[United Kingdom]] [[Clinical Practice Research Datalink#General Practice Research Database|General Practice Research Database]], which contains over 80,000&nbsp;men, found that the [[relative risk]] of gynecomastia in cimetidine users was 7.2 relative to non-users.<ref name="pmid22862307" /> People taking a dosage of cimetidine of greater than or equal to 1,000&nbsp;mg showed more than 40&nbsp;times the risk of gynecomastia than non-users.<ref name="pmid22862307" /> The risk was highest during the period of time of 7 to 12&nbsp;months after starting cimetidine.<ref name="pmid22862307" /> 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 (biology)|tissue]], although increased levels of estrogens due to inhibition of estrogen metabolism is another possible mechanism.<ref name="pmid22862307" /> 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.<ref name="PlessisAgarwal2014" /><ref name="GerallMoltz2013" /><ref name="pmid22862307" />

In accordance with the very weak nature of its AR antagonistic activity, cimetidine has shown minimal effectiveness in the treatment of [[androgen-dependent condition]]s such as [[acne]], [[hirsutism]] (excessive hair growth), and [[hyperandrogenism]] (high androgen levels) in women.<ref name="AltchekDeligdisch2003">{{cite book| vauthors = Copperman AB, Mukherjee T, Kase NG | chapter = Polycystic Ovarian Syndrome | veditors = Altchek A, Deligdisch L, Kase N |title=Diagnosis and Management of Ovarian Disorders| chapter-url = https://books.google.com/books?id=vds_TQpTIhoC&pg=PA351|date=4 September 2003|publisher=Academic Press|isbn=978-0-08-049451-7|pages=351–|quote=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.}}</ref><ref name="PreglerDeCherney2002">{{cite book| vauthors = Pregler JP, DeCherney AH | chapter = Approach to the Patient with Hirsutism |title=Women's Health: Principles and Clinical Practice| chapter-url=https://books.google.com/books?id=zC99_it1C5YC&pg=PA595|year=2002|publisher=PMPH-USA|isbn=978-1-55009-170-0|pages=595–|quote=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.}}</ref><ref name="WattsFaingold2009" /><ref name="pmid20082945">{{cite journal | vauthors = Katsambas AD, Dessinioti C | title = Hormonal therapy for acne: why not as first line therapy? facts and controversies | journal = Clinics in Dermatology | volume = 28 | issue = 1 | pages = 17–23 | date = 2010 | pmid = 20082945 | doi = 10.1016/j.clindermatol.2009.03.006 }}</ref> As such, its use for such indications is not recommended.<ref name="PreglerDeCherney2002" /><ref name="pmid20082945" />

===Pharmacokinetics===
Cimetidine is rapidly [[absorption (pharmacokinetics)|absorbed]] regardless of [[route of administration]].<ref name="AcademicPress1984" /> The [[oral administration|oral]] [[bioavailability]] of cimetidine is 60 to 70%.<ref name="DowdJohnson2016" /><ref name="LeikinPaloucek1995" /> The [[onset of action]] of cimetidine when taken orally is 30&nbsp;minutes,<ref name="VallerandSanoski2016" /> and [[Cmax (pharmacology)|peak levels]] occur within 1 to 3&nbsp;hours.<ref name="DowdJohnson2016" /> Cimetidine is widely [[distribution (pharmacology)|distributed]] throughout all [[tissue (biology)|tissue]]s.<ref name="AcademicPress1984" /> It is able to cross the [[blood–brain barrier]] and can produce effects in the [[central nervous system]] (e.g., [[headache]]s, [[dizziness]], [[somnolence]]).<ref name="GuptaSingh-Radcliff2013" /> The [[volume of distribution]] of cimetidine is 0.8&nbsp;L/kg in adults and 1.2 to 2.1&nbsp;L/kg in children.<ref name="LeikinPaloucek1995">{{cite book| vauthors = Leikin JB, Paloucek FP |title=Poisoning & Toxicology Handbook, 1995-1996|url=https://books.google.com/books?id=JpZrAAAAMAAJ|year=1995|publisher=Lexi-Comp, Incorporated|isbn=978-0-916589-08-0|page=184}}</ref> Its [[plasma protein binding]] is 13 to 25% and is said to be without pharmacological significance.<ref name="LeikinPaloucek1995" /><ref name="AcademicPress1984" /> Cimetidine undergoes relatively little [[metabolism]], with 56 to 85% [[excretion|excreted]] unchanged.<ref name="AcademicPress1984" /> It is metabolized in the [[liver]] into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine.<ref name="LeikinPaloucek1995" /> The major [[metabolite]] of cimetidine is the [[sulfoxide]], which accounts for about 30% of excreted material.<ref name="AcademicPress1984" /> Cimetidine is rapidly [[elimination (pharmacology)|eliminated]], with an [[elimination half-life]] of 123&nbsp;minutes, or about 2&nbsp;hours.<ref name="AcademicPress1984" /> It has been said to have a [[duration of action]] of 4 to 8&nbsp;hours.<ref name="GuptaSingh-Radcliff2013" /> The medication is mainly [[elimination (pharmacology)|eliminated]] in [[urine]].<ref name="AcademicPress1984" />

==History==
Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.<ref>{{cite journal | vauthors = Scheinfeld N | title = Cimetidine: a review of the recent developments and reports in cutaneous medicine | journal = Dermatology Online Journal | volume = 9 | issue = 2 | pages = 4 | date = March 2003 | pmid = 12639457 | doi = 10.5070/D33S15Q645 }}</ref> Cimetidine was the prototypical histamine [[H2-receptor antagonist|H<sub>2</sub> 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]] [[receptor antagonist|antagonist]] to suppress stomach acid secretion.<ref name="ACS Landmarks">{{cite web |url = http://portal.acs.org/portal/PublicWebSite/education/whatischemistry/landmarks/cimetidinetagamet/ |title = Tagamet: Discovery of Histamine H<sub>2</sub>-receptor Antagonists |publisher = American Chemical Society |work = National Historic Chemical Landmarks |access-date = 25 June 2012 |url-status = dead |archive-url = https://archive.today/20121209003707/http://portal.acs.org/portal/PublicWebSite/education/whatischemistry/landmarks/cimetidinetagamet/ |archive-date = 9 December 2012 }}</ref> 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 [[antihistamine]]s had no effect on acid production. In the process, the SK&F scientists also proved the existence of histamine H<sub>2</sub> 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 H<sub>2</sub> receptor. Hundreds of modified compounds were synthesized in an effort to develop a model of the receptor. The first breakthrough was ''N<sup>α</sup>''-guanylhistamine, a partial H<sub>2</sub> receptor antagonist. From this lead, the receptor model was further refined and eventually led to the development of [[burimamide]], the first H<sub>2</sub> receptor antagonist. Burimamide, a specific [[competitive antagonist]] at the H<sub>2</sub> receptor, 100 times more potent than ''N<sup>α</sup>''-guanylhistamine, proved the existence of the H<sub>2</sub> 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]].<ref name="ACS Landmarks"/> 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 H<sub>2</sub> 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.<ref name="Freemantle">{{cite web | vauthors = Fremantle M | title = Tagamet|url=http://pubs.acs.org/cen/coverstory/83/8325/8325tagamet.html | work = Chemical and Engineering news | access-date = 1 July 2013 }}</ref>

The commercial name "Tagamet" was decided upon by fusing the two words "an'''tag'''onist" and "ci'''met'''idine".<ref name="ACS Landmarks"/> Subsequent to the introduction onto the U.S. drug market, two other H<sub>2</sub> 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 [[Pharmaceutical drug#Blockbuster drug|blockbuster drug]].{{citation needed|date = March 2023}}

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.<ref name="Freemantle"/>

== Research ==
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.<ref>{{cite journal | vauthors = Fit KE, Williams PC | title = Use of histamine2-antagonists for the treatment of verruca vulgaris | journal = The Annals of Pharmacotherapy | volume = 41 | issue = 7 | pages = 1222–1226 | date = July 2007 | pmid = 17535844 | doi = 10.1345/aph.1H616 | s2cid = 19769702 }}</ref><ref>{{cite journal | vauthors = Glass AT, Solomon BA | title = Cimetidine therapy for recalcitrant warts in adults | journal = Archives of Dermatology | volume = 132 | issue = 6 | pages = 680–682 | date = June 1996 | pmid = 8651718 | doi = 10.1001/archderm.1996.03890300108014 }}</ref><ref>{{cite journal | vauthors = Karabulut AA, Sahin S, Ekşioglu M | title = Is cimetidine effective for nongenital warts: a double-blind, placebo-controlled study | journal = Archives of Dermatology | volume = 133 | issue = 4 | pages = 533–534 | date = April 1997 | pmid = 9126017 | doi = 10.1001/archderm.133.4.533 }}</ref>

Tentative evidence supports a beneficial role as add-on therapy in colorectal cancer.<ref>{{cite journal | vauthors = Deva S, Jameson M | title = Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 8 | pages = CD007814 | date = August 2012 | pmid = 22895966 | doi = 10.1002/14651858.CD007814.pub2 | pmc = 11627143 }}</ref>

Cimetidine inhibits [[ALA synthase]] activity and hence may have some therapeutic value in preventing and treating [[acute porphyria]] attacks.<ref>{{cite book | vauthors = Whatley SD, Badminton MN | veditors = 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 |title=Acute Intermittent Porphyria|date=2013|pmid=20301372|url=https://www.ncbi.nlm.nih.gov/books/NBK1193/|publisher=University of Washington, Seattle}}</ref><ref>{{cite book| vauthors = Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J | collaboration = APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine|title=Acute Pain Management: Scientific Evidence|date=2015|publisher=Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine|location=Melbourne, Australia|isbn=978-0-9873236-6-8|page=316|edition=4th|url=http://fpm.anzca.edu.au/documents/apmse4_2015_final|access-date=7 September 2017|format=PDF|archive-url=https://web.archive.org/web/20190731120330/http://fpm.anzca.edu.au/documents/apmse4_2015_final|archive-date=31 July 2019|url-status=dead}}</ref>

There is some evidence supporting the use of cimetidine in the treatment of [[Periodic fever, aphthous stomatitis, pharyngitis and adenitis|PFAPA]].<ref name="ped-rheum">{{cite journal | vauthors = Vanoni F, Theodoropoulou K, Hofer M | title = PFAPA syndrome: a review on treatment and outcome | journal = Pediatric Rheumatology Online Journal | volume = 14 | issue = 1 | pages = 38 | date = June 2016 | pmid = 27349388 | pmc = 4924332 | doi = 10.1186/s12969-016-0101-9 | doi-access = free }}</ref>

== Veterinary use ==
In dogs, cimetidine is used as an antiemetic when treating chronic gastritis.<ref>{{cite journal | vauthors = Le Traon G, Burgaud S, Horspool LJ | title = Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 32 | issue = 3 | pages = 213–218 | date = June 2009 | pmid = 19646084 | doi = 10.1111/j.1365-2885.2008.01026.x }}</ref>

== References ==
{{Reflist}}

== External links ==
* {{Commons category-inline|Cimetidine}}

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