Cimetidine

Cimetidine is indicated for the treatment of duodenal ulcers, gastric ulcers, gastroesophageal reflux disease, and pathological hypersecretory conditions. Cimetidine is also used to relieve or prevent heartburn. ==Side effects==

Reported side effects of cimetidine include diarrhea, rashes, dizziness, fatigue, constipation, and muscle pain, all of which are usually mild and transient. It has been reported that mental confusion may occur in the elderly. Rarely, interstitial nephritis, urticaria, and angioedema have been reported with cimetidine treatment. Cimetidine is also commonly associated with transient raised aminotransferase activity; hepatotoxicity is rare. ==Overdose==

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

Due to its non-selective inhibition of cytochrome P450 enzymes, cimetidine has numerous drug interactions. Examples of specific interactions include, but are not limited to, the following: • Cimetidine affects the metabolism of methadone, sometimes resulting in higher blood levels and a higher incidence of side effects, and may interact with the antimalarial medication hydroxychloroquine. • Cimetidine can also interact with a number of psychoactive medications, including tricyclic antidepressants and selective serotonin reuptake inhibitors, causing increased blood levels of these drugs and the potential of subsequent toxicity. • Following administration of cimetidine, the elimination half-life and area-under-curve of zolmitriptan and its active metabolites were roughly doubled. • Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatine breakdown. Accumulation of creatinine is associated with uremia, but the symptoms of creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups. • Like several other medications (e.g., erythromycin), cimetidine interferes with the body's metabolization of sildenafil, causing its strength and duration to increase and making its side effects more likely and prominent. • Clinically significant drug interactions with the CYP1A2 substrate theophylline, the CYP2C9 substrate tolbutamide, the CYP2D6 substrate desipramine, and the CYP3A4 substrate triazolam have all been demonstrated with cimetidine, and interactions with other substrates of these enzymes are likely as well. • Cimetidine has been shown clinically to reduce the clearance of mirtazapine, imipramine, timolol, nebivolol, sparteine, loratadine, nortriptyline, gabapentin, and desipramine in humans. • Cimetidine reduces the absorption of ketoconazole and itraconazole (which require a low pH). • Cimetidine is used in cancer metastasis research as a blocker of E-selectin. • Cimetidine may significantly increase the blood levels of loperamide, which can lead to serious and potentially fatal complications such as cardiac arrhythmias and cardiac arrest, especially if loperamide is taken in excessive doses. ==Pharmacology==

Pharmacodynamics Histamine H2 receptor antagonism The mechanism of action of cimetidine as an antacid is as a histamine H2 receptor antagonist. It has been found to bind to the H2 receptor with a Kd of 42 nM. Cytochrome P450 inhibition Cimetidine is a potent inhibitor of certain cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4, of which it is described as a moderate inhibitor. This is notable since these three CYP isoenzymes are involved in CYP-mediated drug biotransformations; however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative metabolism of many commonly used drugs. As a result, cimetidine has the potential for a large number of pharmacokinetic interactions. although mechanism-based (suicide) irreversible inhibition has also been identified for cimetidine's inhibition of CYP2D6. 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. Antiandrogenic and estrogenic effects Cimetidine has been found to possess weak antiandrogenic activity at high doses. It directly and competitively antagonizes the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). 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). 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 axis by androgens). 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. 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. At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men. 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. As such, its use for such indications is not recommended. Its plasma protein binding is 13 to 25% and is said to be without pharmacological significance. Cimetidine undergoes relatively little metabolism, with 56 to 85% excreted unchanged. It is metabolized in the liver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine. The major metabolite of cimetidine is the sulfoxide, which accounts for about 30% of excreted material. Cimetidine is rapidly eliminated, with an elimination half-life of 123 minutes, or about 2 hours. It has been said to have a duration of action of 4 to 8 hours. The medication is mainly eliminated in urine. ==History==

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 from which the later members of the class were developed. Cimetidine was the culmination of a project at Smith, Kline & French (SKF) 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. 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. The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine". 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. ==Lawsuit==

On 21 August 1989, Danlex Research Laboratories, Inc. filed a petition with the Filipino Bureau of Patents, Trademarks and Technology Transfer (BPTTT) for a compulsory license to manufacture, use, and sell Cimetidine, citing the provisions of the Patent Law (R.A. 165) for medicinal products. Pre-1995, the Bureau of Patents, Trademarks and Technology Transfer (BPTTT) ruled in favor of Danlex and granted the compulsory license, subject to Danlex paying a royalty of 2.5% of net sales to Smith, Kline & French. On 27 January 1995, Smith, Kline & French appealed to the Court of Appeals, but the CA affirmed the BPTTT's decision, upholding the grant of the compulsory license to Danlex. On 25 July 1995, the Court of Appeals denied Smith, Kline & French's Motion for Reconsideration. On 15 September 1995, Smith, Kline & French filed a Petition for Review on Certiorari with the Supreme Court of the Philippines, challenging the CA's decision. On 23 October 2001, the Supreme Court (G.R. No. 121267) rendered its decision, affirming the Court of Appeals and upholding the grant of the compulsory license to Danlex. This marked the final judicial resolution of the case. == 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. Tentative evidence supports a beneficial role as add-on therapy in colorectal cancer. Cimetidine inhibits ALA synthase activity and hence may have some therapeutic value in preventing and treating acute porphyria attacks. There is some evidence supporting the use of cimetidine in the treatment of PFAPA. == Veterinary use ==

In dogs, cimetidine is used as an antiemetic when treating chronic gastritis. == References ==