Cimetidine

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Cimetidine
Cimetidine Structural Formula V.1.svg
Cimetidine-xtal-3D-balls.png
Clinical data
Pronunciation /sɪˈmɛtɪdiːn/ or /saɪˈmɛtɪdiːn/
Trade names Tagamet, others
Other namesSKF-92334 [1]
AHFS/Drugs.com Monograph
MedlinePlus a682256
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
Bioavailability 60–70% [3] [4]
Protein binding 13–25% [4] [5]
Metabolism Liver [4]
Metabolites • Cimetidine sulfoxide [4]
• Hydroxycimetidine [4]
• Guanyl urea cimetidine [4]
Onset of action 30 minutes [6]
Elimination half-life 123 minutes (~2 hours) [5]
Duration of action 4–8 hours [2]
Excretion Urine [5]
Identifiers
  • 1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.052.012 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H16N6S
Molar mass 252.34 g·mol−1
3D model (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) Yes check.svgY
  • Key:AQIXAKUUQRKLND-UHFFFAOYSA-N Yes check.svgY
   (verify)

Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. [1] [7] [8] It is mainly used in the treatment of heartburn and peptic ulcers. [1] [8] [9]

Contents

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

Cimetidine is used to inhibit stomach acid production and is used in the treatment of heartburn and peptic ulcers.[ medical citation needed ]

Side effects

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

Cimetidine appears to be very safe in overdose, producing no 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 mechanism of action of cimetidine as an antacid is as a histamine 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 potent inhibitor of certain cytochrome P450 (CYP) enzymes, [18] [30] including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. [18] [30] [31] The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4, [32] of which it is described as a moderate inhibitor. [6] This is notable since these three CYP isoenzymes are involved in CYP-mediated drug biotransformations; [33] however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative metabolism of many commonly used drugs. [34] As a result, cimetidine has the potential for a large number of 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 antiandrogenic activity at high doses. [28] [37] [38] [39] It directly and competitively antagonizes the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). [40] [41] However, the affinity of cimetidine for the AR is very weak; in one study, it showed only 0.00084% of the affinity of the anabolic steroid metribolone (100%) for the human AR (Ki = 140 μM and 1.18 nM, respectively). [42] In any case, at sufficiently high doses, cimetidine has demonstrated weak but significant antiandrogenic effects in animals, including antiandrogenic effects in the rat ventral prostate and mouse kidney, reductions in the weights of the male accessory glands like the prostate gland and 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. [43] Any increases in testosterone levels with cimetidine have been attributed to the loss of negative feedback on the HPG axis that results due to AR antagonism. [43] [44] At typical clinical dosages, such as those used to treat peptic ulcer disease, the incidence of gynecomastia (breast development) with cimetidine is very low at less than 1%. [51] [43] In one survey of over 9,000 patients taking cimetidine, gynecomastia was the most frequent endocrine-related complaint but was reported in only 0.2% of patients. [43] At high doses however, such as those used to treat Zollinger–Ellison syndrome, there may be a higher incidence of gynecomastia with cimetidine. [51] In one small study, a 20% incidence of gynecomastia was observed in 25 male patients with duodenal ulcers who were treated with 1,600 mg/day cimetidine. [50] The symptoms appeared after 4 months of treatment and regressed within a month following discontinuation of cimetidine. [50] In another small study, cimetidine was reported to have induced breast changes and erectile dysfunction in 60% of 22 men treated with it. [50] These adverse effects completely resolved in all cases when the men were switched from cimetidine to ranitidine. [50] A study of the United Kingdom General Practice Research Database, which contains over 80,000 men, found that the relative risk of gynecomastia in cimetidine users was 7.2 relative to non-users. [50] People taking a dosage of cimetidine of greater than or equal to 1,000 mg showed more than 40 times the risk of gynecomastia than non-users. [50] The risk was highest during the period of time of 7 to 12 months after starting cimetidine. [50] The gynecomastia associated with cimetidine is thought to be due to blockade of ARs in the breasts, which results in estrogen action unopposed by androgens in this tissue, although increased levels of estrogens due to inhibition of estrogen metabolism is another possible mechanism. [50] Cimetidine has also been associated with oligospermia (decreased sperm count) and sexual dysfunction (e.g., 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 absorbed regardless of route of administration. [5] The oral bioavailability of cimetidine is 60 to 70%. [3] [4] The onset of action of cimetidine when taken orally is 30 minutes, [6] and peak levels occur within 1 to 3 hours. [3] Cimetidine is widely distributed throughout all tissues. [5] It is able to cross the blood–brain barrier and can produce effects in the central nervous system (e.g., headaches, dizziness, somnolence). [2] The volume of distribution of cimetidine is 0.8 L/kg in adults and 1.2 to 2.1 L/kg in children. [4] Its plasma protein binding is 13 to 25% and is said to be without pharmacological significance. [4] [5] Cimetidine undergoes relatively little metabolism, with 56 to 85% excreted unchanged. [5] It is metabolized in the liver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine. [4] The major metabolite of cimetidine is the sulfoxide, which accounts for about 30% of excreted material. [5] Cimetidine is rapidly eliminated, with an elimination half-life of 123 minutes, or about 2 hours. [5] It has been said to have a 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. [55] 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. [56] 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. [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". [56] 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.[ 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 ALA synthase activity and hence may have some therapeutic value in preventing and treating 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]

Related Research Articles

H<sub>2</sub> receptor antagonist Class of medications

H2 antagonists, sometimes referred to as H2RAs and also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of stomach acid. H2 antagonists can be used in the treatment of dyspepsia, peptic ulcers and gastroesophageal reflux disease. They have been surpassed by proton pump inhibitors (PPIs). The PPI omeprazole was found to be more effective at both healing and alleviating symptoms of ulcers and reflux oesophagitis than the H2 blockers ranitidine and cimetidine.

<span class="mw-page-title-main">Anastrozole</span> Chemical compound

Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast cancer in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Famotidine</span> Medication that reduces stomach acid

Famotidine, sold under the brand name Pepcid among others, is a histamine H2 receptor antagonist medication that decreases stomach acid production. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. It is taken by mouth or by injection into a vein. It begins working within an hour.

<span class="mw-page-title-main">CYP3A4</span> Enzyme that metabolizes substances by oxidation

Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

<span class="mw-page-title-main">Dextrorphan</span> Psychoactive cough suppressant medication

Dextrorphan (DXO) is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and in high doses a dissociative hallucinogen. It is the dextrorotatory enantiomer of racemorphan; the levorotatory enantiomer is levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6. Dextrorphan is an NMDA antagonist and contributes to the psychoactive effects of dextromethorphan.

<span class="mw-page-title-main">Bicalutamide</span> Prostate cancer treatment

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.

<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

<span class="mw-page-title-main">Nortriptyline</span> Antidepressant medication

Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. As with many antidepressants, its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18–24 population initiating treatment. Nortriptyline is a less preferred treatment for ADHD and stopping smoking. It is taken by mouth.

<span class="mw-page-title-main">Doxepin</span> Medication to treat depressive disorder, anxiety disorders, chronic hives, and trouble sleeping

Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.

<span class="mw-page-title-main">Metiamide</span> Chemical compound

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 (Tagamet).

<span class="mw-page-title-main">Antihistamine</span> Drug that blocks histamine or histamine agonists

Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic drug that can be bought without a prescription and provides relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection. Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.

Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.

Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.

<span class="mw-page-title-main">Afimoxifene</span> Chemical compound

Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.

<span class="mw-page-title-main">Benorterone</span> Chemical compound

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<span class="mw-page-title-main">Zanoterone</span> Chemical compound

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<span class="mw-page-title-main">Nonsteroidal antiandrogen</span> Antiandrogen with a nonsteroidal chemical structure

A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

<span class="mw-page-title-main">Bifluranol</span> Mixture of two compounds

Bifluranol is a synthetic nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol that has been used as an antiandrogen in the United Kingdom in the treatment of benign prostatic hyperplasia. The drug is described as a weak estrogen, and possesses about one-eighth the potency of diethylstilbestrol.

<span class="mw-page-title-main">Pharmacodynamics of spironolactone</span> Mechanisms of action

The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.

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  29. ↑ Taylor JE (22 October 2013). Osborne NN (ed.). "Neurochemical and neuropharmacological aspects of histamine receptors" . Neurochemistry International. 4 (2–3). Elsevier Science: 89–96. doi:10.1016/0197-0186(82)90001-8. ISBN   978-1-4832-8635-8. PMID   20487855. S2CID   40069290.
  30. 1 2 3 4 5 Williams DA (2008). "Drug Metabolism". In Lemke TL, Williams DA (eds.). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 273–. ISBN   978-0-7817-6879-5.
  31. 1 2 Karalliedde LD, Clarke SF, Collignon U, Karalliedde J (29 January 2010). "Drugs Acting on the Gastrointestinal Track". Adverse Drug Interactions: A Handbook for Prescribers. CRC Press. pp. 633–. ISBN   978-0-340-92769-4.
  32. ↑ Priskorn M, Larsen F, Segonzac A, Moulin M (1997). "Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects". European Journal of Clinical Pharmacology. 52 (3): 241–242. doi:10.1007/s002280050282. PMID   9218934. S2CID   22540140.
  33. ↑ Martínez C, Albet C, Agúndez JA, Herrero E, Carrillo JA, Márquez M, et al. (April 1999). "Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists". Clinical Pharmacology and Therapeutics. 65 (4): 369–376. doi:10.1016/S0009-9236(99)70129-3. PMID   10223772. S2CID   25151710.
  34. ↑ Delafuente JC (November 2003). "Understanding and preventing drug interactions in elderly patients". Critical Reviews in Oncology/Hematology. 48 (2): 133–143. doi:10.1016/j.critrevonc.2003.04.004. PMID   14607376.
  35. 1 2 Cairns D (2012). "Drug Metabolism: Drug Conjugating Reactions (Phase 2)". Essentials of Pharmaceutical Chemistry. Pharmaceutical Press. pp. 110–. ISBN   978-0-85369-979-8. 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. ↑ Liska DJ (June 1998). "The detoxification enzyme systems". Alternative Medicine Review. 3 (3): 187–198. 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
  37. ↑ Matsumoto AM (2001). "Clinical Use and Abuse of Androgens and Antiandrogens". In Becker KL (ed.). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1196–. ISBN   978-0-7817-1750-2.
  38. ↑ Jensen RT, Collen MJ, McArthur KE, Howard JM, Maton PN, Cherner JA, 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.
  39. ↑ 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): 579–586. PMID   3921876.
  40. ↑ Winters SJ, Banks JL, Loriaux DL (March 1979). "Cimetidine is an antiandrogen in the rat". Gastroenterology. 76 (3): 504–508. doi: 10.1016/S0016-5085(79)80217-6 . PMID   428705.
  41. ↑ 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): 677–684. doi:10.1016/0006-2952(82)90449-X. PMID   6123322.
  42. ↑ Eil C, Edelson SK (July 1984). "The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors". The Journal of Clinical Endocrinology and Metabolism. 59 (1): 51–55. doi:10.1210/jcem-59-1-51. PMID   6725525.
  43. 1 2 3 4 5 6 Ward OB (11 November 2013). "Fetal drug exposure and sexual differentiation of males.". In Gerall AA, Moltz H, Ward EL (eds.). Sexual Differentiation. Springer Science & Business Media. pp. 207–. ISBN   978-1-4899-2453-7. 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. 1 2 3 Barazani Y, Sabanegh Jr ES (26 July 2014). "Risks from Medical and Therapeutic Treatments". In du Plessis SS, Agarwal A, Sabanegh Jr ES (eds.). Male Infertility: A Complete Guide to Lifestyle and Environmental Factors. Springer. pp. 233–. ISBN   978-1-4939-1040-3. 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].
  45. ↑ Galbraith RA, Michnovicz JJ (August 1989). "The effects of cimetidine on the oxidative metabolism of estradiol". The New England Journal of Medicine. 321 (5): 269–274. doi:10.1056/NEJM198908033210501. PMID   2747769.
  46. ↑ Michnovicz JJ, Galbraith RA (February 1991). "Cimetidine inhibits catechol estrogen metabolism in women". Metabolism. 40 (2): 170–174. doi:10.1016/0026-0495(91)90169-W. PMID   1988774.
  47. ↑ Pescovitz OH, Walvoord EC (6 June 2007). When Puberty is Precocious: Scientific and Clinical Aspects. Springer Science & Business Media. pp. 203–. ISBN   978-1-59745-499-5.
  48. ↑ Cuhaci N, Polat SB, Evranos B, Ersoy R, Cakir B (March 2014). "Gynecomastia: Clinical evaluation and management". Indian Journal of Endocrinology and Metabolism. 18 (2): 150–158. doi: 10.4103/2230-8210.129104 . PMC   3987263 . PMID   24741509.
  49. ↑ Rendic S, Di Carlo FJ (2010). "Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors". Drug Metabolism Reviews. 29 (1–2): 413–580. doi:10.3109/03602539709037591. PMID   9187528.
  50. 1 2 3 4 5 6 7 8 9 10 Deepinder F, Braunstein GD (September 2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–795. doi:10.1517/14740338.2012.712109. PMID   22862307. S2CID   22938364. 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. 1 2 3 Dunaway G (1 April 2009). "Androgens and Antiandrogens". In Watts S, Faingold C, Dunaway G, Crespo L (eds.). Brody's Human Pharmacology - E-Book. Elsevier Health Sciences. pp. 472–. ISBN   978-0-323-07575-6. 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.
  52. ↑ Copperman AB, Mukherjee T, Kase NG (4 September 2003). "Polycystic Ovarian Syndrome". In Altchek A, Deligdisch L, Kase N (eds.). Diagnosis and Management of Ovarian Disorders. Academic Press. pp. 351–. ISBN   978-0-08-049451-7. 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. 1 2 Pregler JP, DeCherney AH (2002). "Approach to the Patient with Hirsutism". Women's Health: Principles and Clinical Practice. PMPH-USA. pp. 595–. ISBN   978-1-55009-170-0. 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.
  54. 1 2 Katsambas AD, Dessinioti C (2010). "Hormonal therapy for acne: why not as first line therapy? facts and controversies". Clinics in Dermatology. 28 (1): 17–23. doi:10.1016/j.clindermatol.2009.03.006. PMID   20082945.
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  59. ↑ Glass AT, Solomon BA (June 1996). "Cimetidine therapy for recalcitrant warts in adults". Archives of Dermatology. 132 (6): 680–682. doi:10.1001/archderm.1996.03890300108014. PMID   8651718.
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  61. ↑ Deva S, Jameson M (August 2012). "Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer". The Cochrane Database of Systematic Reviews. 8 (8): CD007814. doi:10.1002/14651858.CD007814.pub2. PMID   22895966.
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  64. ↑ Vanoni F, Theodoropoulou K, Hofer M (June 2016). "PFAPA syndrome: a review on treatment and outcome". Pediatric Rheumatology Online Journal. 14 (1): 38. doi: 10.1186/s12969-016-0101-9 . PMC   4924332 . PMID   27349388.
  65. ↑ Le Traon G, Burgaud S, Horspool LJ (June 2009). "Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets". Journal of Veterinary Pharmacology and Therapeutics. 32 (3): 213–218. doi:10.1111/j.1365-2885.2008.01026.x. PMID   19646084.
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