Cimetidine
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| Routes of administration | Oral, parenteral |
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| Pharmacokinetic data | |
| Bioavailability | 60–70% |
| Protein binding | 15–20% |
| Metabolism | Hepatic |
| Elimination half-life | 2 hours |
| Excretion | Renal |
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| ECHA InfoCard | 100.052.012 |
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| Formula | C10H16N6S |
| Molar mass | 252.34 g/mol g·mol−1 |
Cimetidine (INN) (Template:PronEng) is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet (sometimes Tagamet HB or Tagamet HB200) and was approved by the Food & Drug Administration for prescriptions starting January 1, 1979.
Clinical use
Main article:H2-receptor antagonist
History and development
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 & French (SK&F; now GlaxoSmithKline) to develop a histamine receptor antagonist to suppress stomach acid secretion. This was one of the first drugs discovered using a rational drug design approach, thanks to the valiant efforts of medicinal chemists C. Robin Ganellin and Graham Durant and pharmacologist James Black at Smith, Kline, & French Laboratories(now GlaxoSmithKline; 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 this drug; actually, the medicinal chemists would have made the discovery). (The Organic Chemistry of Drug Design and Drug Action, Richard B. Silverman, page 159)
At the time (1964) it was known that histamine was able 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, lead to the development of metiamide. Metiamide was an effective agent, however it was associated with unacceptable nephrotoxicity and agranulocytosis. It was proposed that the toxicity arose from the thiourea group, and similar guanidine-analogues were investigated until the ultimate discovery of cimetidine.
Cimetidine was first marketed in the United Kingdom in 1976; therefore, it took 12 years from initiation of the H2-receptor antagonist program to commercialization. Subsequent to the introduction onto the U.S. drug market, two other H2-receptor antagonists were approved, ranitidine (Zantac, Glaxo Labs) and famotidine (Pepcide, 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.
Other uses
A number of "open label" studies showed that cimetidine was effective in the treatment of common warts, but more rigorous double-blinded clinical trials showed it to be no more effective than a placebo. [1]
Another study by Yokoyama et al used Cimetidine for the treatment of Chronic Calcifying Tendonitis of the shoulder. The small scale study took 16 individuals with calcifying tendonitis 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, it has been recommended that Cimetidine, for the treatment of chronic calcifying tendonitis of the shoulder, be opened to large scale clinical trials. [1]
Cimetidine has also been reported for use in treatment of colorectal cancer - it is however not approved in the US by the FDA for cancer treatment.
Shortcomings and side effects
Cimetidine is a known inhibitor of many isozymes of the cytochrome P450 enzyme system (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 interferes with metabolism of the hormone estrogen, enhancing estrogen activity. In women, this can lead to galactorrhea, whereas in men gynecomastia and a reduced sperm count can result[citation needed]. Adverse drug reactions were also found to be relatively common with Cimetidine, including interactions with the antimalarial medication Hydroxychloroquine[citation needed].
The development of longer-acting H2-receptor antagonists with reduced adverse effects such as ranitidine proved to be the downfall of cimetidine and, whilst it is still used, it is no longer amongst the more widely used H2-receptor antagonists. Cimetidine should be used with caution in cases of hepatic impairment and cardiovascular disease[citation needed]. Side effects can include dizziness, and more rarely, headache. BIOAVAILABILITY: The observed bioavailibility of cimetidine is almost 60%.
References
- Michnovicz JJ, Galbraith RA .Cimetidine inhibits catechol estrogen metabolism in women. Metabolism. 1991 Feb;40(2):170-4. PMID 1988774
The Organic Chemistry of Drug Design and Drug Action, Richard B. Silverman 3.2G "Case History of Rational Drug Design of a Receptor Antagonist: Cimetidine." Pages 159-165)
External links
- American Chemical Society - National Historic Chemical Landmarks - Tagamet: A medicine that changed people's lives
- Tagamet HB200