Cimetidine

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Cimetidine
Cimetidine2DACS.svg
Cimetidine-xtal-3D-balls.png
Systematic (IUPAC) name
2-cyano- 1-methyl- 3-(2-[(5-methyl- 1H-imidazol- 4-yl)methylthio]ethyl)guanidine
Clinical data
Trade names Tagamet
AHFS/Drugs.com monograph
MedlinePlus a682256
Licence data US FDA:link
Pregnancy cat. B1 (AU) B (US)
Legal status Pharmacist Only (S3) (AU) POM (UK) Rx (although 200mg is OTC) (US)
Routes Oral, parenteral
Pharmacokinetic data
Bioavailability 60–70%
Protein binding 15–20%
Metabolism Hepatic
Half-life 2 hours
Excretion Renal
Identifiers
CAS number 51481-61-9 YesY
ATC code A02BA01
PubChem CID 2756
IUPHAR ligand 1231
DrugBank DB00501
ChemSpider 2654 YesY
UNII 80061L1WGD YesY
KEGG D00295 YesY
ChEBI CHEBI:3699 YesY
ChEMBL CHEMBL30 YesY
Chemical data
Formula C10H16N6S 
Mol. mass 252.34 g/mol
 YesY (what is this?)  (verify)

Cimetidine INN (/sɨˈmɛtɨdn/ or /sˈmɛtɨdn/) is a histamine H2-receptor antagonist that inhibits stomach acid production. It is largely used in the treatment of heartburn and peptic ulcers. It has been marketed by GlaxoSmithKline (which is selling the brand to Prestige Brands) under the trade name Tagamet (sometimes Tagamet HB or Tagamet HB200). Cimetidine was approved in the UK in 1976 and was approved in the US by the Food and Drug Administration for prescriptions starting January 1, 1979.

Clinical use[edit]

History and development[edit]

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.[1] 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; now GlaxoSmithKline) by James W. Black, C. Robin Ganellin, and others to develop a histamine receptor antagonist to suppress stomach acid secretion.[2] 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 synthesised 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.[2] 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.[3]

The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine".[2] 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.[4]

In a deal expected to take effect in 2012, GlaxoSmithKline sold Tagamet and 16 other brands to Prestige Brands.[5]

Tagamet has now been largely replaced by the proton pump inhibitors for treating peptic ulcers, but is now is available as an over-the-counter medicine for heartburn in many countries.[3]

Other uses[edit]

In some studies, cimetidine has been found to reduce the debilitating pain and symptoms of herpes zoster, presumably by blocking the H2-receptors of T-lymphocyte suppressor cells.[6]

There has been some evidence to suggest cimetidine could be effective in the treatment of common warts, but more rigorous double-blind clinical trials suggested it to be no more effective than a placebo.[7][8][9]

Another study by Yokoyama, et al., used cimetidine for the treatment of chronic calcific tendinitis of the shoulder.[10] The small scale study took 16 individuals with calcific tendinitis in one shoulder, all of which had previously attempted other forms of therapy, including steroid injection and arthroscopic lavage. During the course of the study, 10 patients reported an elimination of pain and 9 displayed a complete disappearance of calcium deposits. With results being on a small scale, cimetidine, for the treatment of chronic calcific tendinitis of the shoulder, has been recommended to be opened to large scale clinical trials.[11]

In Asia, cimetidine, which molecularly targets EGF, VEGF and e-selectin associated with sialylated Lewis biomarkers and metastasis, has been combined with long term, continuous low dose 5FU[12] or metronomic tegafur-uracil chemotherapy for advanced epithelial cancers, with unusually long survival[13] including for stage III colorectal cancers,[14] as well as refractory and recurrent cancers.

Cimetidine has been reported for use as an analgesic in experimental treatments of interstitial cystitis.

Pretreatment with cimetidine improves the accuracy of measured creatinine clearance testing when using urine collection analysis.

Adverse effects and interactions[edit]

Cimetidine's side effects can include dizziness, and more rarely, headache. It is a known inhibitor of many isozymes of the cytochrome P450 enzyme system[15] (specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). This inhibition forms the basis of the numerous drug interactions that occur between cimetidine and other drugs. For example, cimetidine may decrease metabolism of some drugs, such as those used in hormonal contraception. Cimetidine is a competitive antagonist at the dihydrotestosterone (DHT) receptor, leading to exaggerated effects of estrogens. In women, this can lead to galactorrhea, whereas in men, gynecomastia has been reported.[16] During postmarketing surveillance in the 1980s, cases of male sexual dysfunction were also reported.[17][18] Cimetidine also 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.[19] Cimetidine is also known to potentiate the effects of several opioids, including tramadol, which are partially metabolized via the cytochrome P450 pathway, via inhibiting their metabolism and a temporary decrease of liver function due to reduced hepatic blood flow. This can lead to extreme plasma levels of these drugs and can easily lead to a fatal overdose.[20]

Antacid preparations such as cimetidine suppress the acid-mediated break down of proteins, leading to an elevated risk of developing food or drug allergies due to undigested proteins passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs only with long-term use, or with short-term use as well.[21]

Cimetidine can also interact with a number of psychoactive medications, including tricyclic antidepressants and selective serotonin reuptake inhibitors, causing increased blood levels of these drugs and the potential of subsequent toxicity.

Following administration of cimetidine, the half-life and AUC of zolmitriptan and its active metabolites were approximately doubled (see CLINICAL PHARMACOLOGY). See complete drug interactions for Zomig (triptan succinate used for migraine relief) in package insert: http://www1.astrazeneca-us.com/pi/Zomig.pdf

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.[22]

The development of longer-acting H2-receptor antagonists with fewer adverse effects, such as ranitidine, proved to be the downfall of cimetidine and, though it is still used, it is no longer among the more widely used of the H2-receptor antagonists.

Like several other medication, the most obvious being erythromycin, Cimetidine interferes with the body's metabolization of Viagra, causing its strength and duration to increase (therefore also its side-effects to be more likely and prominent).

Pharmacology[edit]

Cimetidine's mechanism of action is as an H2 receptor antagonist.[23]

Cimetidine has also been found to possess clinically significant anti-androgen properties at high doses that are especially noticeable in men.[23][24][25] It directly antagonizes the binding of testosterone and DHT to the androgen receptor in animals.[26][27] In addition, also in animals, it interferes with the metabolism of estrogen and increases its serum concentrations.[28] Accordingly, cimetidine has been found to be effective in small clinical trials for the treatment of acne and androgenic alopecia,[29][30] though not in hirsutism or in sex hormone-associated cancers such as breast and prostate cancer.[31][32] Cimetidine's anti-androgen properties likely explain certain side effects seen with it such as galactorrhea and amenorrhea in women and gynecomastia and impotence in men.[25][25][33]

Synthesis[edit]

Cimetidine synthesis 01.svg [34]

References[edit]

  1. ^ Scheinfeld N (March 2003). "Cimetidine: a review of the recent developments and reports in cutaneous medicine". Dermatol. Online J. 9 (2): 4. PMID 12639457. 
  2. ^ a b c "Tagamet®: Discovery of Histamine H2-receptor Antagonists". National Historic Chemical Landmarks. American Chemical Society. Retrieved June 25, 2012. 
  3. ^ a b Freemantle, Michael. "Tagamet". Chemical and Engineering news. Retrieved 1 July 2013. 
  4. ^ Whitney, Jake (February 2006). "Pharmaceutical Sales 101: Me-Too Drugs". Guernica. Retrieved 2008-07-31. 
  5. ^ Ranii, David (21 December 2011). "GSK sells BC, Goody's and other brands". News & Observer. 
  6. ^ Faloon, William; Kitchen, Kate (March 2001). "Tagemet to Treat Herpes and Shingles". Life Extension Magazine. Retrieved 2009-03-05. 
  7. ^ Fit KE, Williams PC (July 2007). "Use of histamine2-antagonists for the treatment of verruca vulgaris". Ann Pharmacother 41 (7): 1222–6. doi:10.1345/aph.1H616. PMID 17535844. 
  8. ^ Glass AT, Solomon BA. Cimetidine therapy for recalcitrant warts in adults Arch Dermatol 1996;132:680-2.
  9. ^ Karabulut AA, Sahin S, Eksioglu M. Is cimetidine effective for nongenital warts: A double-blind, placebo-controlled study. Arch Dematol 1997;133:533-5.
  10. ^ Yokoyama M, Aono H, Takeda A, Morita K (2003). "Cimetidine for chronic calcifying tendinitis of the shoulder". Reg Anesth Pain Med 28 (3): 248–52. doi:10.1053/rapm.2003.50048. PMID 12772145. 
  11. ^ "Musculoskeletal Pain". Retrieved 2008-10-22. [dead link]
  12. ^ S Matsumoto, Y Imaeda, S Umemoto, K Kobayashi, H Suzuki1 and T Okamoto S (21 January 2002). doi=10.1038/sj.bjc.6600048 "Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells". British Journal of Cancer 86 (1): 161–167. doi:10.1038/sj.bjc.6600048. PMC 2375187. PMID 11870500. 
  13. ^ Matsumoto S, Hayashi A, Kobayashi K, Imaeda Y, Umemoto S (February 2004). Cimetidine blocking of E-selectin expression inhibits sialyl Lewis-X-positive cancer cells from adhering to vascular endothelium. 
  14. ^ Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Okamoto T (January 2002). "Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells". British Journal of Cancer 86 (6): 161–167. doi:10.1038/sj.bjc.6600048. PMC 2375187. PMID 11870500. 
  15. ^ Levine M, Law EY, Bandiera SM, Chang TK, Bellward GD (February 1998). "In vivo cimetidine inhibits hepatic CYP2C6 and CYP2C11 but not CYP1A1 in adult male rats". The Journal of Pharmacology and Experimental Therapeutics 284 (2): 493–9. PMID 9454789. 
  16. ^ Michnovicz JJ, Galbraith RA (February 1991). "Cimetidine inhibits catechol estrogen metabolism in women". Metabolism: clinical and experimental 40 (2): 170–4. doi:10.1016/0026-0495(91)90169-W. PMID 1988774. 
  17. ^ Sawyer D, Conner CS, Scalley R (February 1981). "Cimetidine: adverse reactions and acute toxicity". Am J Hosp Pharm 38 (2): 188–97. PMID 7011006. 
  18. ^ Sabesin SM (1993). "Safety issues relating to long-term treatment with histamine H2-receptor antagonists". Aliment Pharmacol Ther. 7 Suppl 2: 35–40. PMID 8103374. 
  19. ^ Furst DE (June 1996). "Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases". Lupus. 5 Suppl 1: S11–5. doi:10.1177/096120339600500104. PMID 8803904. 
  20. ^ Sorkin, E.M.; D.L. Darvey (1983-02-01). "Review of cimetidine drug interactions". Annals of Pharmacotherapy 17 (2): 110–120. PMID 6130930. Retrieved 2012-04-28. 
  21. ^ Pali-Schöll I, Jensen-Jarolim E (April 2011). "Anti-acid medication as a risk factor for food allergy". Allergy 66 (4): 469–77. doi:10.1111/j.1398-9995.2010.02511.x. PMID 21121928. 
  22. ^ Transcellular Transport of Creatinine in Renal Tubular Epithelial Cell Line LLC-PK1. Drug Metab. Pharmacokinet. 20(3): 200-205 (2005)
  23. ^ a b Richards DA (1983). "Comparative pharmacodynamics and pharmacokinetics of cimetidine and ranitidine". Journal of Clinical Gastroenterology. 5 Suppl 1: 81–90. doi:10.1097/00004836-198312001-00008. PMID 6317740. 
  24. ^ Jensen RT, Collen MJ, McArthur KE, et al. (November 1984). "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. PMID 6150641. 
  25. ^ a b c Biagi P, Milani G (March 1985). "[Dysfunction of the hypothalamo-hypophyseal-gonadal axis induced by histamine H2 antagonists. Review of the literature and personal observations]". Minerva Medica (in Italian) 76 (12): 579–86. PMID 3921876. 
  26. ^ Winters SJ, Banks JL, Loriaux DL (March 1979). "Cimetidine is an antiandrogen in the rat". Gastroenterology 76 (3): 504–8. PMID 428705. 
  27. ^ Sivelle PC, Underwood AH, Jelly JA (March 1982). "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): 677–84. doi:10.1016/0006-2952(82)90449-X. PMID 6123322. 
  28. ^ Galbraith RA, Michnovicz JJ (August 1989). "The effects of cimetidine on the oxidative metabolism of estradiol". The New England Journal of Medicine 321 (5): 269–74. doi:10.1056/NEJM198908033210501. PMID 2747769. 
  29. ^ Hatwal A, Bhatt RP, Agrawal JK, Singh G, Bajpai HS (1988). "Spironolactone and cimetidine in treatment of acne". Acta Dermato-venereologica 68 (1): 84–7. PMID 2449021. 
  30. ^ Aram H (March 1987). "Treatment of female androgenetic alopecia with cimetidine". International Journal of Dermatology 26 (2): 128–30. doi:10.1111/j.1365-4362.1987.tb00546.x. PMID 3570585. 
  31. ^ Golditch IM, Price VH (June 1990). "Treatment of hirsutism with cimetidine". Obstetrics and Gynecology 75 (6): 911–3. PMID 2342735. 
  32. ^ Rossing MA, Scholes D, Cushing-Haugen KL, Voigt LF (March 2000). "Cimetidine use and risk of prostate and breast cancer". Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 9 (3): 319–23. PMID 10750671. 
  33. ^ Funder JW, Mercer JE (February 1979). "Cimetidine, a histamine H2 receptor antagonist, occupies androgen receptors". The Journal of Clinical Endocrinology and Metabolism 48 (2): 189–91. doi:10.1210/jcem-48-2-189. PMID 429472. 
  34. ^ Clayden, Jonathan (2005). Organic chemistry (Reprinted (with corrections). ed.). Oxford [u.a.]: Oxford Univ. Press. p. 587. ISBN 0198503466. 

External links[edit]