Cimetidine

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Cimetidine
Cimetidine Structural Formula V.1.svg
Cimetidine-xtal-3D-balls.png
Clinical data
Pronunciation /sɪˈmɛtɪdn/ or /sˈmɛtɪdn/
Trade names Tagamet
Synonyms cimetidine hydrochloride
SKF-92334[1]
AHFS/Drugs.com Monograph
MedlinePlus a682256
License data
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Routes of
administration
Oral, parenteral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only (although 200 mg is OTC)
Pharmacokinetic data
Bioavailability 60–70%
Protein binding 15–20%
Metabolism Hepatic
Onset of action 30 minutes[2]
Biological half-life 2 hours[2]
Duration of action 4–5 hours[2]
Excretion Renal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.052.012
Chemical and physical data
Formula C10H16N6S
Molar mass 252.34 g/mol
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][3][4] It is available over-the-counter and is mainly used in the treatment of heartburn and peptic ulcers.[1][4][5]

The development of longer-acting H2 receptor antagonists with fewer drug interactions and adverse effects, such as ranitidine and famotidine, decreased the use of cimetidine, and though it is still used, cimetidine is no longer among the more widely used of the H2-receptor antagonists.[citation needed]

Cimetidine was discovered in 1971 and came into commercial use in 1977.[6][7] Cimetidine was approved in the United Kingdom in 1976, and was approved in the United States by the Food and Drug Administration for prescriptions in 1979.[citation needed]

Medical uses[edit]

Other uses[edit]

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.[8][9][10]

Tentative evidence supports a beneficial role as add-on therapy in colorectal cancer.[11]

Cimetidine inhibits ALA synthase activity and hence may have some therapeutic value in preventing and treating acute porphyria attacks.[12][13]

Side effects[edit]

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]

Overdose[edit]

Cimetidine appears to be very safe in overdose, producing no symptoms even with massive overdoses (e.g., 20 g).[18]

Interactions[edit]

Pharmacology[edit]

Pharmacodynamics[edit]

Histamine H2 receptor antagonism[edit]

Cimetidine's mechanism of action as an antacid is as a histamine H2 receptor antagonist.[27]

Antiandrogenic and estrogenic effects[edit]

Cimetidine has been found to possess clinically significant albeit weak antiandrogen activity at high doses.[27][28][29][30] It has been found to directly and competitively displace testosterone and dihydrotestosterone (DHT) and antagonize the androgen receptor (AR) in animals.[31][32] In addition, cimetidine has been found to inhibit 2-hydroxylation of estradiol (via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increased levels of estrogen.[33][34][35][36][37][38] By increasing estrogen levels, cimetidine can also decrease testosterone and increase prolactin levels.[39]

Pharmacokinetics[edit]

Metabolism[edit]

Cimetidine is S-oxygenated by human flavin-containing monooxygenases, specifically FMO1 and FMO3.[40]

Enzyme inhibition[edit]

Cimetidine is a potent inhibitor of certain cytochrome P450 (CYP450) enzymes,[18][41] including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.[18][41][42] The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4,[43] of which it is described as a moderate inhibitor.[2] This is notable since these three CYP450 isoenzymes are involved in CYP450-mediated drug biotransformations;[44] however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative metabolism of many commonly used drugs.[45] As a result, cimetidine has the potential for a large number of pharmacokinetic interactions.[18][41][42]

Cimetidine is reported to be a competitive and reversible inhibitor of several CYP450 enzymes,[17][24][41][46] although mechanism-based (suicide) irreversible inhibition has also been identified for cimetidine's inhibition of CYP2D6.[23] It reversibly inhibits CYP450 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.[41][46][47]

History[edit]

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.[48] 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.[49] 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.[49] 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.[50]

The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine".[49] 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.[51]

In a deal expected to take effect in 2012, GlaxoSmithKline sold Tagamet and 16 other brands to Prestige Brands.[52]

Tagamet has now been largely replaced by the proton pump inhibitors for treating peptic ulcers, but is now available as an over-the-counter medicine for heartburn in many countries.[50]

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External links[edit]