Cimetidine
Encyclopedia
Cimetidine INN
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...

 (icon or s) is a histamine H2-receptor antagonist
H2-receptor antagonist
The H2 receptor antagonists are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. H2 antagonists are used in the treatment of dyspepsia, although they have been surpassed in popularity by the more effective ...

 that inhibits the production of acid in the stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

. It is largely used in the treatment of heartburn
Heartburn
Heartburn, also known as pyrosis or acid indigestion is a burning sensation in the chest, just behind the breastbone or in the epigastrium...

 and peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...

s. It is marketed by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

 under the trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....

 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 for prescriptions starting January 1, 1979.

History and development

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases. Cimetidine was the prototypical histamine H2-receptor antagonist
H2-receptor antagonist
The H2 receptor antagonists are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. H2 antagonists are used in the treatment of dyspepsia, although they have been surpassed in popularity by the more effective ...

 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
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

) by James W. Black
James W. Black
Sir James Whyte Black, OM, FRS, FRSE, FRCP was a Scottish doctor and pharmacologist. He spent his career both as researcher and as an academic at several universities. Black established the physiology department at the University of Glasgow, where he became interested in the effects of adrenaline...

, C. Robin Ganellin
C. Robin Ganellin
Charon Robin Ganellin is a British born medicinal chemist. He has contributed much to the field of drug discovery and development. His most outstanding achievement was the discovery of cimetidine, a drug used to combat stomach ulcers, when he was working at Smith Kline and French...

, and others to develop a histamine receptor
Histamine receptor
The histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...

 antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

 to suppress stomach acid secretion. 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; actually, the medicinal chemists would have made the discovery.

At the time (1964), histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

 was known to stimulate the secretion of stomach acid, but also that traditional antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...

s 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
Burimamide
Burimamide is an antagonist at the H2 and H3 histamine receptors. It is largely inactive as an H2 antagonist at physiological pH, but its H3 affinity is 100x higher. It is a thiourea derivative....

, the first H2-receptor antagonist. Burimamide, a specific competitive antagonist
Competitive antagonist
A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor...

 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
PKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...

 of the compound, led to the development of metiamide
Metiamide
Metiamide is a histamine H2-receptor antagonist developed from another H2 antagonist, burimamide. It was an intermediate compound in the development of the successful anti-ulcer drug cimetidine .-Development of metiamide from burimamide:...

. Metiamide was an effective agent; it was associated, however, with unacceptable nephrotoxicity
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...

 and agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...

. The toxicity was proposed to arise from the thiourea
Thiourea
Thiourea is an organosulfur compound of with the formula SC2 . It is structurally similar to urea, except that the oxygen atom is replaced by a sulfur atom, but the properties of urea and thiourea differ significantly. Thiourea is a reagent in organic synthesis. "Thioureas" refers to a broad...

 group, and similar guanidine
Guanidine
Guanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. It is used in the manufacture of plastics and explosives. It is found in urine as a normal product of protein metabolism. The molecule was first synthesized in 1861 by the oxidative degradation of an...

-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. The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine". Subsequent to the introduction onto the U.S. drug market, two other H2-receptor antagonists were approved, ranitidine
Ranitidine
Ranitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions...

 (Zantac, Glaxo Labs) and famotidine
Famotidine
Famotidine is a histamine H2-receptor antagonist that inhibits stomach acid production, and it is commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease . It is commonly marketed by Johnson & Johnson/Merck under the trade names Pepcidine and Pepcid and by...

 (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.

Other uses

In some studies, cimetidine has been found to reduce the debilitating pain and symptoms of herpes zoster
Herpes zoster
Herpes zoster , commonly known as shingles and also known as zona, is a viral disease characterized by a painful skin rash with blisters in a limited area on one side of the body, often in a stripe...

, presumably by blocking the H2-receptors of T-lymphocyte suppressor cells.

A number of "open label" studies showed cimetidine was effective in the treatment of common warts, but more rigorous double-blind clinical trials suggested it to be no more effective than a placebo. However, the researchers in this study admit their results may not be sound, due to small sample size, and did not explore higher dosing options.

Another study by Yokoyama, et al., used cimetidine for the treatment of chronic calcific tendinitis
Calcific tendinitis
Calcific tendinitis , a form of tendinitis, is a disorder characterized by deposits of hydroxyapatite in any tendon of the...

 of the shoulder. 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
Arthroscopic lavage
"Lavage" means 'washing'. To lavage a joint means to wash out any blood, fluid or loose debris from inside the joint space.Arthroscopic lavage is generally combined with arthroscopic debridement, where fronds of joint material or degenerative tissue are removed using a combination of injected fluid...

. 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.

Cimetidine has been reported for use in treatment of colorectal cancer; it is not approved, however, in the US by the FDA for cancer treatment.

In Asia, cimetidine, which molecularly targets EGF
EGF
EGF can refer to several things:*Epidermal growth factor, a growth factor in biology*Exponential generating function, a function in mathematics*European Gendarmerie Force, a European intervention force...

, VEGF and e-selectin
E-selectin
E-selectin, also known as CD62 antigen-like family member E , endothelial-leukocyte adhesion molecule 1 , or leukocyte-endothelial cell adhesion molecule 2 , is a cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in...

 associated with sialylated Lewis biomarkers and metastasis, has been combined with long term, continuous low dose 5FU or metronomic tegafur-uracil
Tegafur-uracil
Tegafur-uracil is a chemotherapy drug used in the treatment of cancer, primarily bowel cancer. It is also called UFT or UFUR.-Development and regulation:...

 chemotherapy for advanced epithelial cancers, with unusually long survival including for stage III colorectal cancers, 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.

Cimetidine reduces or inhibits production of liver enzymes responsible for the metabolization of opiates and benzodiazepines. Therefore, patients who are prescribed these medications may find that taking cimetidine in conjunction with the opiate and/or benzodiazepine will extend the latter drug's effectiveness, duration of action, or both, potentially allowing the patient to require a smaller dose of these habit-forming medicines while still getting equivalent relief of their symptoms.

Adverse effects and interactions

Cimetidine is a known inhibitor of many isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...

s of the cytochrome P450 enzyme system (specifically CYP1A2
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...

, CYP2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...

, CYP2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...

, CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...

, CYP2E1
CYP2E1
Cytochrome P450 2E1 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene...

, and CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...

). This inhibition forms the basis of the numerous drug interaction
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...

s that occur between cimetidine and other drugs. For example, cimetidine may decrease metabolism of some drugs, such as those used in hormonal contraception
Hormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...

. Cimetidine interferes with metabolism of the hormone estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...

, enhancing estrogen activity. In women, this can lead to galactorrhea
Galactorrhea
Galactorrhea or galactorrhoea is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.Contemporary Maternal-Newborn Nursing Care defines galactorrhea as "nipple discharge." -Causes:...

, whereas in men, gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...

 has been reported; during postmarketing surveillance
Postmarketing surveillance
Postmarketing surveillance is the practice of monitoring the safety of a pharmaceutical drug or device after it has been released on the market and is an important part of the science of pharmacovigilance...

 in the 1980s, cases of male sexual dysfunction were also reported. Cimetidine also affects the metabolism of methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...

, sometimes resulting in higher blood levels and a higher incidence of side effects, and may interact with the antimalarial medication hydroxychloroquine
Hydroxychloroquine
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...

.

It is also important to recognize that cimetidine can interact with a number of different psychoactive medications, including those in the classes of Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors, causing increased blood levels of these drugs and subsequent toxicity.

The development of longer-acting H2-receptor antagonists with reduced adverse effects, such as ranitidine
Ranitidine
Ranitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions...

, proved to be the downfall of cimetidine and, though it is still used, it is no longer among the more widely used H2-receptor antagonists. Side effects can include dizziness, and more rarely, headache.

Following administration of cimetidine, the half-life and AUC of zolmitriptan
Zolmitriptan
Zolmitriptan is a selective serotonin receptor agonist of the 1B and 1D subtypes. It is a triptan, used in the acute treatment of migraine attacks with or without aura and cluster headaches....

 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

External links

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