Cimetidine

Source: Wikipedia, the free encyclopedia.

Cimetidine
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
  • 1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine
JSmol)
  • CC1=C(N=CN1)CSCCNC(=NC)NC#N
  • InChI=1S/C10H16N6S/c1-8-9(16-7-15-8)5-17-4-3-13-10(12-2)14-6-11/h7H,3-5H2,1-2H3,(H,15,16)(H2,12,13,14) checkY
  • Key:AQIXAKUUQRKLND-UHFFFAOYSA-N checkY
  (verify)

Cimetidine, sold under the brand name Tagamet among others, is a

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 article:
H2 antagonist

Cimetidine is used to inhibit

peptic ulcers.[medical citation needed
]

Side effects

Reported

aminotransferase activity; hepatotoxicity is rare.[17]

Overdose

Cimetidine appears to be very safe in

symptoms even with massive overdoses (e.g., 20 g).[18]

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

H2 receptor antagonist.[28] It has been found to bind to the H2 receptor with a Kd of 42 nM.[29]

Cytochrome P450 inhibition

Cimetidine is a

pharmacokinetic interactions.[18][30][31]

Cimetidine is reported to be a competitive and reversible inhibitor of several CYP enzymes,[17][24][30][35] although mechanism-based (suicide) irreversible inhibition has also been identified for cimetidine's inhibition of CYP2D6.[23] 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.[30][35][36]

Antiandrogenic and estrogenic effects

Cimetidine has been found to possess weak

seminal vesicles in rats, and elevated gonadotropin levels in male rats (due to reduced negative feedback on the HPG axis by androgens).[43][44] 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.[45][46][47][48][49] 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.[50]

At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men.

decreased libido, erectile dysfunction) in men in some research, which are hormonally related similarly.[44][43][50]

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.[52][53][51][54] As such, its use for such indications is not recommended.[53][54]

Pharmacokinetics

Cimetidine is rapidly

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.

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

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.[56] 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.[57]

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

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.[57]

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.[58][59][60]

Tentative evidence supports a beneficial role as add-on therapy in colorectal cancer.[61]

Cimetidine inhibits

acute porphyria attacks.[62][63]

There is some evidence supporting the use of Cimetidine in the treatment of PFAPA.[64]

Veterinary use

In dogs, cimetidine is used as an antiemetic when treating chronic gastritis.[65]

References

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    . 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.
  36. 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
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    . 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).
  44. ^
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    . 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].
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    . 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].
  51. ^
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    . 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.
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    . 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.
  53. ^
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    . 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.
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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Cimetidine&oldid=1216888095"