Chemistry:Cimetidine

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Short description: Medication
Cimetidine
Cimetidine Structural Formula V.1.svg
Cimetidine-xtal-3D-balls.png
Clinical data
Pronunciation/sɪˈmɛtɪdiːn/ or /saɪˈmɛtɪdiːn/
Trade namesTagamet, others
Other namesSKF-92334[1]
AHFS/Drugs.comMonograph
MedlinePlusa682256
License data
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth, intramuscular injection, intravenous infusion[2]
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only / OTC
Pharmacokinetic data
Bioavailability60–70%[3][4]
Protein binding13–25%[4][5]
MetabolismLiver[4]
Metabolites• Cimetidine sulfoxide[4]
• Hydroxycimetidine[4]
• Guanyl urea cimetidine[4]
Onset of action30 minutes[6]
Elimination half-life123 minutes (~2 hours)[5]
Duration of action4–8 hours[2]
ExcretionUrine[5]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC10H16N6S
Molar mass252.34 g·mol−1
3D model (JSmol)
  (verify)

Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production.[1][7][8] It is mainly used in the treatment of heartburn and peptic ulcers.[1][8][9]

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.[10]

Cimetidine was developed in 1971 and came into commercial use in 1977.[11][12] Cimetidine was approved in the United Kingdom in 1976,[citation needed] and was approved in the United States by the Food and Drug Administration in 1979.[13]


Medical uses

Main page: Chemistry:H2 antagonist

Cimetidine is used to inhibit stomach acid production and is used in the treatment of heartburn and peptic ulcers.

Side effects

Reported side effects of cimetidine include diarrhea, rashes, dizziness, fatigue, constipation, and muscle pain, all of which are usually mild and transient.[14] It has been reported that mental confusion may occur in the elderly.[14] 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.[14][15][16] Rarely, interstitial nephritis, urticaria, and angioedema have been reported with cimetidine treatment.[14] Cimetidine is also commonly associated with transient raised aminotransferase activity; hepatotoxicity is rare.[17]

As of May 2021, ranitidine has been withdrawn from the market.[18]

Overdose

Cimetidine appears to be very safe in overdose, producing no symptoms even with massive overdoses (e.g., 20 g).[19]

Interactions

Due to its non-selective inhibition of cytochrome P450 enzymes, cimetidine has numerous drug interactions. Examples of specific interactions include the following:

Pharmacology

Pharmacodynamics

Histamine H2 receptor antagonism

The mechanism of action of cimetidine as an antacid is as a histamine H2 receptor antagonist.[29] It has been found to bind to the H2 receptor with a Kd of 42 nM.[30]

Cytochrome P450 inhibition

Cimetidine is a potent inhibitor of certain cytochrome P450 (CYP) enzymes,[19][31] including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.[19][31][32] The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4,[33] of which it is described as a moderate inhibitor.[6] This is notable since these three CYP isoenzymes are involved in CYP-mediated drug biotransformations;[34] however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative metabolism of many commonly used drugs.[35] As a result, cimetidine has the potential for a large number of pharmacokinetic interactions.[19][31][32]

Cimetidine is reported to be a competitive and reversible inhibitor of several CYP enzymes,[17][25][31][36] although mechanism-based (suicide) irreversible inhibition has also been identified for cimetidine's inhibition of CYP2D6.[24] It reversibly inhibits CYP 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.[31][36][37]

Antiandrogenic and estrogenic effects

Cimetidine has been found to possess weak antiandrogenic activity at high doses.[29][38][39][40] It directly and competitively antagonizes the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).[41][42] 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).[43] 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).[44][45] 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.[46][47][48][49][50] 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.[51]

At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men.[44] 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.[44][45] 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%.[52][44] 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.[44] At high doses however, such as those used to treat Zollinger–Ellison syndrome, there may be a higher incidence of gynecomastia with cimetidine.[52] 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.[51] The symptoms appeared after 4 months of treatment and regressed within a month following discontinuation of cimetidine.[51] In another small study, cimetidine was reported to have induced breast changes and erectile dysfunction in 60% of 22 men treated with it.[51] These adverse effects completely resolved in all cases when the men were switched from cimetidine to ranitidine.[51] 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.[51] 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.[51] The risk was highest during the period of time of 7 to 12 months after starting cimetidine.[51] 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.[51] 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.[45][44][51]

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.[53][54][52][55] As such, its use for such indications is not recommended.[54][55]

Pharmacokinetics

Cimetidine is rapidly absorbed regardless of route of administration.[5] The oral bioavailability of cimetidine is 60 to 70%.[3][4] The onset of action of cimetidine when taken orally is 30 minutes,[6] and peak levels occur within 1 to 3 hours.[3] Cimetidine is widely distributed throughout all tissues.[5] It is able to cross the blood–brain barrier and can produce effects in the central nervous system (e.g., headaches, dizziness, somnolence).[2] The volume of distribution of cimetidine is 0.8 L/kg in adults and 1.2 to 2.1 L/kg in children.[4] Its plasma protein binding is 13 to 25% and is said to be without pharmacological significance.[4][5] Cimetidine undergoes relatively little metabolism, with 56 to 85% excreted unchanged.[5] It is metabolized in the liver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine.[4] The major metabolite of cimetidine is the sulfoxide, which accounts for about 30% of excreted material.[5] Cimetidine is rapidly eliminated, with an elimination half-life of 123 minutes, or about 2 hours.[5] It has been said to have a duration of action of 4 to 8 hours.[2] The medication is mainly eliminated in urine.[5]

History

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.[56] 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.[57] 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.[57] 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.[58]

The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine".[57] 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.[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.[58]

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.[59][60][61]

Tentative evidence supports a beneficial role as add-on therapy in colorectal cancer.[62]

Cimetidine inhibits ALA synthase activity and hence may have some therapeutic value in preventing and treating acute porphyria attacks.[63][64]

There is some evidence supporting the use of Cimetidine in the treatment of PFAPA.[65]

Veterinary use

In dogs, cimetidine is used as an antiemetic when treating chronic gastritis.[66]

References

  1. ↑ 1.0 1.1 1.2 The Dictionary of Drugs: Chemical Data: Chemical Data, Bibliographies. Springer. 14 November 2014. pp. 275–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA275. 
  2. ↑ 2.0 2.1 2.2 2.3 Pharmacology in Anesthesia Practice. Oxford University Press. 12 March 2013. pp. 177–. ISBN 978-0-19-934399-7. https://books.google.com/books?id=a85oAgAAQBAJ&pg=PT177. 
  3. ↑ 3.0 3.1 3.2 Pharmacology and Therapeutics for Dentistry - E-Book. Elsevier Health Sciences. 3 September 2016. pp. 406–. ISBN 978-0-323-44595-5. https://books.google.com/books?id=6xT7DAAAQBAJ&pg=PA406. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 Poisoning & Toxicology Handbook, 1995-1996. Lexi-Comp, Incorporated. 1995. p. 184. ISBN 978-0-916589-08-0. https://books.google.com/books?id=JpZrAAAAMAAJ. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 Profiles of Drug Substances, Excipients and Related Methodology. Academic Press. 24 October 1984. pp. 176–. ISBN 978-0-08-086108-1. https://books.google.com/books?id=Fz6X-GmS-GgC&pg=PA176. 
  6. ↑ 6.0 6.1 6.2 Davis's Drug Guide for Nurses. F.A. Davis. 25 May 2016. pp. 636–. ISBN 978-0-8036-5779-3. https://books.google.com/books?id=ORa1DAAAQBAJ&pg=PA636. 
  7. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 234–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA234. 
  8. ↑ 8.0 8.1 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 31 October 1999. pp. 77–. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA77. 
  9. ↑ "Drugs for Peptic Ulcer Disease". Lehne's Pharmacology for Nursing Care. Elsevier Health Sciences. 2 December 2014. pp. 952–. ISBN 978-0-323-34026-7. https://books.google.com/books?id=C7_NBQAAQBAJ&pg=PA952. 
  10. ↑ "Cimetidine". StatPearls [Internet].. Treasure Island (FL): StatPearls Publishing. March 2023. Bookshelf ID: NBK544255. https://www.ncbi.nlm.nih.gov/books/NBK544255/. Retrieved 6 November 2023. 
  11. ↑ Analogue-based Drug Discovery II. John Wiley & Sons. 24 August 2010. pp. 4. ISBN 978-3-527-63212-1. https://books.google.com/books?id=h2Kd8ci4Ln8C&pg=PA4. 
  12. ↑ "Table of Selected Analogue Classes". Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 444. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA444. 
  13. ↑ "Tagamet: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017939. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 "Alimenary System and Liver". A Textbook of Clinical Pharmacology and Therapeutics (5th ed.). CRC Press. 25 April 2008. pp. 250–. ISBN 978-1-4441-1300-6. https://books.google.com/books?id=TD59BgAAQBAJ&pg=PA250. 
  15. ↑ "Cimetidine: adverse reactions and acute toxicity". American Journal of Hospital Pharmacy 38 (2): 188–197. February 1981. PMID 7011006. 
  16. ↑ "Safety issues relating to long-term treatment with histamine H2-receptor antagonists". Alimentary Pharmacology & Therapeutics 7 (Suppl 2): 35–40. 1993. doi:10.1111/j.1365-2036.1993.tb00597.x. PMID 8103374. 
  17. ↑ 17.0 17.1 17.2 "Drug-Induced Liver Disease". Diseases of the Liver and Biliary System in Children. John Wiley & Sons. 26 January 2009. pp. 224–. ISBN 978-1-4443-0054-3. https://books.google.com/books?id=z7nO3OrNXckC&pg=PA224. 
  18. ↑ "Is this the end for ranitidine? NDMA presence continues to confound". Clinical and Translational Science 14 (4): 1197–1200. July 2021. doi:10.1111/cts.12995. PMID 33934515. 
  19. ↑ 19.0 19.1 19.2 19.3 "Histaminde H2 Antagonists". Medical Toxicology. Lippincott Williams & Wilkins. 2004. pp. 402–. ISBN 978-0-7817-2845-4. https://books.google.com/books?id=BfdighlyGiwC&pg=PA402. 
  20. ↑ "Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases". Lupus 5 (Suppl 1): S11–S15. June 1996. doi:10.1177/096120339600500104. PMID 8803904. 
  21. ↑ See complete drug interactions for Zomig (zolmitriptan succinate used for migraine relief) in package insert: "Highlights of Zomig Prescribing Information". AstraZeneca. http://www1.astrazeneca-us.com/pi/Zomig.pdf. 
  22. ↑ "Transcellular transport of creatinine in renal tubular epithelial cell line LLC-PK1". Drug Metabolism and Pharmacokinetics 20 (3): 200–205. June 2005. doi:10.2133/dmpk.20.200. PMID 15988122. 
  23. ↑ "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". Drug-Drug Interactions (Second ed.). CRC Press. 8 February 2008. pp. 277, 294. ISBN 978-0-8493-7594-1. https://books.google.com/books?id=rmCGQ8qAv8AC&pg=PA294. 
  24. ↑ 24.0 24.1 "Inhibitors of Human CYP2D6". Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism. CRC Press. 6 April 2016. pp. 299–. ISBN 978-1-4665-9788-4. https://books.google.com/books?id=UJqmCwAAQBAJ&pg=PA299. 
  25. ↑ 25.0 25.1 Pharmacology. Lippincott Williams & Wilkins. 2007. pp. 202–. ISBN 978-0-7817-8074-2. https://books.google.com/books?id=fm8kmMDjdiAC&pg=PA202. 
  26. ↑ Drug Information Handbook for Psychiatry. Lexi-Comp. 2005. p. 285. ISBN 9781591951148. https://books.google.com/books?id=LzBtAAAAMAAJ. 
  27. ↑ "Cytochrome P450 and Liver injury". Drug-Induced Hepatotoxicity. Springer Science & Business Media. 6 December 2012. pp. 140–. ISBN 978-3-642-61013-4. https://books.google.com/books?id=xZf-CAAAQBAJ&pg=PA140. 
  28. ↑ "ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3". Cancer Letters 510: 13–23. July 2021. doi:10.1016/j.canlet.2021.04.005. PMID 33862151. 
  29. ↑ 29.0 29.1 "Comparative pharmacodynamics and pharmacokinetics of cimetidine and ranitidine". Journal of Clinical Gastroenterology 5 (Suppl 1): 81–90. 1983. doi:10.1097/00004836-198312001-00008. PMID 6317740. 
  30. ↑ "Neurochemical and neuropharmacological aspects of histamine receptors". Neurochemistry International (Elsevier Science) 4 (2–3): 89–96. 22 October 2013. doi:10.1016/0197-0186(82)90001-8. ISBN 978-1-4832-8635-8. PMID 20487855. https://books.google.com/books?id=ldnWAgAAQBAJ&pg=PA297. 
  31. ↑ 31.0 31.1 31.2 31.3 31.4 "Drug Metabolism". Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 2008. pp. 273–. ISBN 978-0-7817-6879-5. https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA273. 
  32. ↑ 32.0 32.1 "Drugs Acting on the Gastrointestinal Track". Adverse Drug Interactions: A Handbook for Prescribers. CRC Press. 29 January 2010. pp. 633–. ISBN 978-0-340-92769-4. https://books.google.com/books?id=B2YwH371uzYC&pg=PA633. 
  33. ↑ "Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects". European Journal of Clinical Pharmacology 52 (3): 241–242. 1997. doi:10.1007/s002280050282. PMID 9218934. 
  34. ↑ "Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists". Clinical Pharmacology and Therapeutics 65 (4): 369–376. April 1999. doi:10.1016/S0009-9236(99)70129-3. PMID 10223772. 
  35. ↑ "Understanding and preventing drug interactions in elderly patients". Critical Reviews in Oncology/Hematology 48 (2): 133–143. November 2003. doi:10.1016/j.critrevonc.2003.04.004. PMID 14607376. 
  36. ↑ 36.0 36.1 "Drug Metabolism: Drug Conjugating Reactions (Phase 2)". Essentials of Pharmaceutical Chemistry. Pharmaceutical Press. 2012. pp. 110–. ISBN 978-0-85369-979-8. https://books.google.com/books?id=gNliFkwHYgEC&pg=PA110. "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." 
  37. ↑ "The detoxification enzyme systems". Alternative Medicine Review 3 (3): 187–198. June 1998. PMID 9630736. "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". 
  38. ↑ "Clinical Use and Abuse of Androgens and Antiandrogens". Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. 2001. pp. 1196–. ISBN 978-0-7817-1750-2. https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196. 
  39. ↑ "Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states". The American Journal of Medicine 77 (5B): 90–105. November 1984. PMID 6150641. 
  40. ↑ "[Dysfunction of the hypothalamo-hypophyseal-gonadal axis induced by histamine H2 antagonists. Review of the literature and personal observations]" (in it). Minerva Medica 76 (12): 579–586. March 1985. PMID 3921876. 
  41. ↑ "Cimetidine is an antiandrogen in the rat". Gastroenterology 76 (3): 504–508. March 1979. doi:10.1016/S0016-5085(79)80217-6. PMID 428705. 
  42. ↑ "The effects of histamine H2 receptor antagonists on androgen action in vivo and dihydrotestosterone binding to the rat prostate androgen receptor in vitro". Biochemical Pharmacology 31 (5): 677–684. March 1982. doi:10.1016/0006-2952(82)90449-X. PMID 6123322. 
  43. ↑ "The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors". The Journal of Clinical Endocrinology and Metabolism 59 (1): 51–55. July 1984. doi:10.1210/jcem-59-1-51. PMID 6725525. 
  44. ↑ 44.0 44.1 44.2 44.3 44.4 44.5 "Fetal drug exposure and sexual differentiation of males.". Sexual Differentiation. Springer Science & Business Media. 11 November 2013. pp. 207–. ISBN 978-1-4899-2453-7. https://books.google.com/books?id=4nb1BwAAQBAJ&pg=PA207. "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)." 
  45. ↑ 45.0 45.1 45.2 "Risks from Medical and Therapeutic Treatments". Male Infertility: A Complete Guide to Lifestyle and Environmental Factors. Springer. 26 July 2014. pp. 233–. ISBN 978-1-4939-1040-3. https://books.google.com/books?id=-I4kBAAAQBAJ&pg=PA233. "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]." 
  46. ↑ "The effects of cimetidine on the oxidative metabolism of estradiol". The New England Journal of Medicine 321 (5): 269–274. August 1989. doi:10.1056/NEJM198908033210501. PMID 2747769. 
  47. ↑ "Cimetidine inhibits catechol estrogen metabolism in women". Metabolism 40 (2): 170–174. February 1991. doi:10.1016/0026-0495(91)90169-W. PMID 1988774. 
  48. ↑ When Puberty is Precocious: Scientific and Clinical Aspects. Springer Science & Business Media. 6 June 2007. pp. 203–. ISBN 978-1-59745-499-5. https://books.google.com/books?id=seYO1f1JgzYC&pg=PA203. 
  49. ↑ "Gynecomastia: Clinical evaluation and management". Indian Journal of Endocrinology and Metabolism 18 (2): 150–158. March 2014. doi:10.4103/2230-8210.129104. PMID 24741509. 
  50. ↑ "Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors". Drug Metabolism Reviews 29 (1–2): 413–580. 2010. doi:10.3109/03602539709037591. PMID 9187528. 
  51. ↑ 51.0 51.1 51.2 51.3 51.4 51.5 51.6 51.7 51.8 51.9 "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety 11 (5): 779–795. September 2012. doi:10.1517/14740338.2012.712109. PMID 22862307. "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].". 
  52. ↑ 52.0 52.1 52.2 "Androgens and Antiandrogens". Brody's Human Pharmacology - E-Book. Elsevier Health Sciences. 1 April 2009. pp. 472–. ISBN 978-0-323-07575-6. https://books.google.com/books?id=kfsrz_-OrMQC&pg=PA472. "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." 
  53. ↑ "Polycystic Ovarian Syndrome". Diagnosis and Management of Ovarian Disorders. Academic Press. 4 September 2003. pp. 351–. ISBN 978-0-08-049451-7. https://books.google.com/books?id=vds_TQpTIhoC&pg=PA351. "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." 
  54. ↑ 54.0 54.1 "Approach to the Patient with Hirsutism". Women's Health: Principles and Clinical Practice. PMPH-USA. 2002. pp. 595–. ISBN 978-1-55009-170-0. https://books.google.com/books?id=zC99_it1C5YC&pg=PA595. "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." 
  55. ↑ 55.0 55.1 "Hormonal therapy for acne: why not as first line therapy? facts and controversies". Clinics in Dermatology 28 (1): 17–23. 2010. doi:10.1016/j.clindermatol.2009.03.006. PMID 20082945. 
  56. ↑ "Cimetidine: a review of the recent developments and reports in cutaneous medicine". Dermatology Online Journal 9 (2): 4. March 2003. doi:10.5070/D33S15Q645. PMID 12639457. 
  57. ↑ 57.0 57.1 57.2 "Tagamet: Discovery of Histamine H2-receptor Antagonists". National Historic Chemical Landmarks. American Chemical Society. http://portal.acs.org/portal/PublicWebSite/education/whatischemistry/landmarks/cimetidinetagamet/. 
  58. ↑ 58.0 58.1 "Tagamet". Chemical and Engineering news. http://pubs.acs.org/cen/coverstory/83/8325/8325tagamet.html. 
  59. ↑ "Use of histamine2-antagonists for the treatment of verruca vulgaris". The Annals of Pharmacotherapy 41 (7): 1222–1226. July 2007. doi:10.1345/aph.1H616. PMID 17535844. 
  60. ↑ "Cimetidine therapy for recalcitrant warts in adults". Archives of Dermatology 132 (6): 680–682. June 1996. doi:10.1001/archderm.1996.03890300108014. PMID 8651718. 
  61. ↑ "Is cimetidine effective for nongenital warts: a double-blind, placebo-controlled study". Archives of Dermatology 133 (4): 533–534. April 1997. doi:10.1001/archderm.133.4.533. PMID 9126017. 
  62. ↑ "Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer". The Cochrane Database of Systematic Reviews 8 (8): CD007814. August 2012. doi:10.1002/14651858.CD007814.pub2. PMID 22895966. 
  63. ↑ Acute Intermittent Porphyria. University of Washington, Seattle. 2013. https://www.ncbi.nlm.nih.gov/books/NBK1193/. 
  64. ↑ (PDF) Acute Pain Management: Scientific Evidence (4th ed.). Melbourne, Australia: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. 2015. p. 316. ISBN 978-0-9873236-6-8. http://fpm.anzca.edu.au/documents/apmse4_2015_final. Retrieved 7 September 2017. 
  65. ↑ "PFAPA syndrome: a review on treatment and outcome". Pediatric Rheumatology Online Journal 14 (1): 38. June 2016. doi:10.1186/s12969-016-0101-9. PMID 27349388. 
  66. ↑ Le Traon, G; Burgaud, S; Horspool, LJI (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. PMID 19646084. 

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