Cimetidine

Template:Short description Template:Use dmy dates Template:Cs1 config Template:Main other {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0

|preview=

}}{{Infobox drug/maintenance categoriesTemplate:Yesno | drug_name = | INN = | _drugtype =

| _has_physiological_data= | _has_gene_therapy=

| vaccine_type= | mab_type= | _number_of_combo_chemicals={{#invoke:ParameterCount |main |component1 |component2 |component3 |component4|component5|component6 }} | _vaccine_data= | _mab_data= | _mab_vaccine_data= | _mab_other_data=10166CC1=C(N=CN1)CSCCNC(=NC)NC#N1S/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)AQIXAKUUQRKLND-UHFFFAOYSA-NTemplate:StdinchiciteTemplate:Stdinchicite | _combo_data= | _physiological_data= | _clinical_data=Template:Drugs.coma682256Cimetidine B1By mouth, intramuscular injection, intravenous infusion<ref name="GuptaSingh-Radcliff2013" />Tagamet, othersA02 | _legal_data=S4POM/ OTC<ref name="Cimetidine FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Tagamet FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-only

| _other_data=1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine

| _image_0_or_2 = File:Cimetidine Structural Formula V.1.svgCimetidine-xtal-3D-balls.png | _image_LR =

| _datapage = Cimetidine (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=S4POMRx-only | _ATC_prefix_supplemental=A02 | _has_EMA_link = | CAS_number=51481-61-9 | PubChem=2756 | ChemSpiderID=2654 | ChEBI=3699 | ChEMBL=30 | DrugBank=DB00501 | KEGG=D00295 | _hasInChI_or_Key={{#if: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)AQIXAKUUQRKLND-UHFFFAOYSA-N |yes}} | UNII=80061L1WGD | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields=changed |verifiedrevid=456484490}} Cimetidine, sold under the brand name Tagamet among others, is a histamine H₂ receptor antagonist that inhibits stomach acid production.<ref name="Elks2014">Template:Cite book</ref><ref name="IndexNominum2000">Template:Cite book</ref><ref name="MortonMorton1999">Template:Cite book</ref> It is mainly used in the treatment of heartburn and peptic ulcers.<ref name="Elks2014" /><ref name="MortonMorton1999" /><ref name="BurchumRosenthal2014">Template:Cite book</ref>

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.<ref>Template:Cite book</ref>

Cimetidine was developed in 1971 and came into commercial use in 1977.<ref name="FischerGanellin2010">Template:Cite book</ref><ref>Template:Cite book</ref> Cimetidine was approved in the United Kingdom in 1976,Template:Citation needed and was approved in the United States by the Food and Drug Administration in 1979.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Cimetidine is indicated for the treatment of duodenal ulcers, gastric ulcers, gastroesophageal reflux disease, and pathological hypersecretory conditions.<ref name="Cimetidine FDA label" /> Cimetidine is also used to relieve or prevent heartburn.<ref name="Tagamet FDA label" />

Side effects

Reported side effects of cimetidine include diarrhea, rashes, dizziness, fatigue, constipation, and muscle pain, all of which are usually mild and transient.<ref name="RitterLewis2008">Template:Cite book</ref> It has been reported that mental confusion may occur in the elderly.<ref name="RitterLewis2008" /> 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.<ref name="RitterLewis2008" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Rarely, interstitial nephritis, urticaria, and angioedema have been reported with cimetidine treatment.<ref name="RitterLewis2008" /> Cimetidine is also commonly associated with transient raised aminotransferase activity; hepatotoxicity is rare.<ref name="Kelly2009" />

Overdose

Cimetidine appears to be very safe in overdose, producing no symptoms even with massive overdoses (e.g., 20 g).<ref name="Dart2004" />

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.<ref>Template:Cite journal</ref>
• 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.Template:Citation needed
• Following administration of cimetidine, the elimination half-life and area-under-curve of zolmitriptan and its active metabolites were roughly doubled.<ref>See complete drug interactions for Zomig (zolmitriptan succinate used for migraine relief) in package insert: {{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• 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.<ref>Template:Cite journal</ref>
• 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.Template:Citation needed
• 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.<ref name="Rodrigues2008">Template:Cite book</ref>
• Cimetidine has been shown clinically to reduce the clearance of mirtazapine, imipramine, timolol, nebivolol, sparteine, loratadine, nortriptyline, gabapentin, and desipramine in humans.<ref name="Zhou2016" />
• Cimetidine inhibits the renal excretion of metformin and procainamide, resulting in increased circulating levels of these drugs.<ref name="RitterLewis2008" />
• Interactions of potential clinical importance with cimetidine include warfarin, theophylline, phenytoin, carbamazepine, pethidine and other opioid analgesics, tricyclic antidepressants, lidocaine, terfenadine, amiodarone, flecainide, quinidine, fluorouracil, and benzodiazepines.<ref name="RitterLewis2008" /><ref name="RosenfeldLoose2007" />
• Cimetidine may decrease the effects of CYP2D6 substrates that are prodrugs, such as codeine, tramadol, and tamoxifen.<ref name="FullerSajatovic2005">Template:Cite book</ref>
• Cimetidine reduces the absorption of ketoconazole and itraconazole (which require a low pH).<ref name="RitterLewis2008" />
• Cimetidine has a theoretical but unproven benefit in paracetamol toxicity.<ref name="Kelly2009" /> This is because N-acetyl-p-benzoquinone imine (NAPQI), a metabolite of paracetamol (acetaminophen) that is responsible for its hepatotoxicity, is formed from it by the cytochrome P450 system (specifically, CYP1A2, CYP2E1, and CYP3A4).<ref name="CameronFeuer2012">Template:Cite book</ref>
• Cimetidine is used in cancer metastasis research as a blocker of E-selectin.<ref>Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

Histamine H₂ receptor antagonism

The mechanism of action of cimetidine as an antacid is as a histamine H₂ receptor antagonist.<ref name="pmid6317740">Template:Cite journal</ref> It has been found to bind to the H₂ receptor with a K_d of 42 nM.<ref name="Osborne2013">Template:Cite journal</ref>

Cytochrome P450 inhibition

Cimetidine is a potent inhibitor of certain cytochrome P450 (CYP) enzymes,<ref name="Dart2004">Template:Cite book</ref><ref name="LemkeWilliams2008">Template:Cite book</ref> including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.<ref name="Dart2004" /><ref name="LemkeWilliams2008" /><ref name="KarallieddeClarke2010">Template:Cite book</ref> The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4,<ref name="PriskornLarsen1997">Template:Cite journal</ref> of which it is described as a moderate inhibitor.<ref name="VallerandSanoski2016">Template:Cite book</ref> This is notable since these three CYP isoenzymes are involved in CYP-mediated drug biotransformations;<ref name="MartinezAlbet1999">Template:Cite journal</ref> however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative metabolism of many commonly used drugs.<ref name="Delafuente2003">Template:Cite journal</ref> As a result, cimetidine has the potential for a large number of pharmacokinetic interactions.<ref name="Dart2004" /><ref name="LemkeWilliams2008" /><ref name="KarallieddeClarke2010" />

Cimetidine is reported to be a competitive and reversible inhibitor of several CYP enzymes,<ref name="Kelly2009">Template:Cite book</ref><ref name="RosenfeldLoose2007">Template:Cite book</ref><ref name="LemkeWilliams2008" /><ref name="Cairns2012">Template:Cite book</ref> although mechanism-based (suicide) irreversible inhibition has also been identified for cimetidine's inhibition of CYP2D6.<ref name="Zhou2016">Template:Cite book</ref> 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.<ref name="LemkeWilliams2008" /><ref name="Cairns2012" /><ref name="pmid9630736">Template:Cite journal</ref>

Antiandrogenic and estrogenic effects

Cimetidine has been found to possess weak antiandrogenic activity at high doses.<ref name="pmid6317740" /><ref name="Becker2001">Template:Cite book</ref><ref name="pmid6150641">Template:Cite journal</ref><ref name="pmid3921876">Template:Cite journal</ref> It directly and competitively antagonizes the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).<ref name="pmid428705">Template:Cite journal</ref><ref name="pmid6123322">Template:Cite journal</ref> 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 (K_i = 140 μM and 1.18 nM, respectively).<ref name="pmid6725525 b">Template:Cite journal</ref> 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 [[hypothalamic–pituitary–gonadal axis|Template:Abbr axis]] by androgens).<ref name="GerallMoltz2013" /><ref name="PlessisAgarwal2014">Template:Cite book</ref> 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.<ref name="GalbraithMichnovicz1989">Template:Cite journal</ref><ref name="pmid1988774">Template:Cite journal</ref><ref name="PescovitzWalvoord2007">Template:Cite book</ref><ref name="PolatCuhaci2014">Template:Cite journal</ref><ref name="RendicCarlo2010">Template:Cite journal</ref> 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.<ref name="pmid22862307">Template:Cite journal</ref>

At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men.<ref name="GerallMoltz2013" /> 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.<ref name="GerallMoltz2013" /><ref name="PlessisAgarwal2014" /> 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%.<ref name="WattsFaingold2009">Template:Cite book</ref><ref name="GerallMoltz2013">Template:Cite book</ref> 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.<ref name="GerallMoltz2013" /> At high doses however, such as those used to treat Zollinger–Ellison syndrome, there may be a higher incidence of gynecomastia with cimetidine.<ref name="WattsFaingold2009" /> 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.<ref name="pmid22862307" /> The symptoms appeared after 4 months of treatment and regressed within a month following discontinuation of cimetidine.<ref name="pmid22862307" /> In another small study, cimetidine was reported to have induced breast changes and erectile dysfunction in 60% of 22 men treated with it.<ref name="pmid22862307" /> These adverse effects completely resolved in all cases when the men were switched from cimetidine to ranitidine.<ref name="pmid22862307" /> 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.<ref name="pmid22862307" /> 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.<ref name="pmid22862307" /> The risk was highest during the period of time of 7 to 12 months after starting cimetidine.<ref name="pmid22862307" /> 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.<ref name="pmid22862307" /> 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.<ref name="PlessisAgarwal2014" /><ref name="GerallMoltz2013" /><ref name="pmid22862307" />

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.<ref name="AltchekDeligdisch2003">Template:Cite book</ref><ref name="PreglerDeCherney2002">Template:Cite book</ref><ref name="WattsFaingold2009" /><ref name="pmid20082945">Template:Cite journal</ref> As such, its use for such indications is not recommended.<ref name="PreglerDeCherney2002" /><ref name="pmid20082945" />

Pharmacokinetics

Cimetidine is rapidly absorbed regardless of route of administration.<ref name="AcademicPress1984" /> The oral bioavailability of cimetidine is 60 to 70%.<ref name="DowdJohnson2016" /><ref name="LeikinPaloucek1995" /> The onset of action of cimetidine when taken orally is 30 minutes,<ref name="VallerandSanoski2016" /> and peak levels occur within 1 to 3 hours.<ref name="DowdJohnson2016" /> Cimetidine is widely distributed throughout all tissues.<ref name="AcademicPress1984" /> It is able to cross the blood–brain barrier and can produce effects in the central nervous system (e.g., headaches, dizziness, somnolence).<ref name="GuptaSingh-Radcliff2013" /> The volume of distribution of cimetidine is 0.8 L/kg in adults and 1.2 to 2.1 L/kg in children.<ref name="LeikinPaloucek1995">Template:Cite book</ref> Its plasma protein binding is 13 to 25% and is said to be without pharmacological significance.<ref name="LeikinPaloucek1995" /><ref name="AcademicPress1984" /> Cimetidine undergoes relatively little metabolism, with 56 to 85% excreted unchanged.<ref name="AcademicPress1984" /> It is metabolized in the liver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine.<ref name="LeikinPaloucek1995" /> The major metabolite of cimetidine is the sulfoxide, which accounts for about 30% of excreted material.<ref name="AcademicPress1984" /> Cimetidine is rapidly eliminated, with an elimination half-life of 123 minutes, or about 2 hours.<ref name="AcademicPress1984" /> It has been said to have a duration of action of 4 to 8 hours.<ref name="GuptaSingh-Radcliff2013" /> The medication is mainly eliminated in urine.<ref name="AcademicPress1984" />

History

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.<ref>Template:Cite journal</ref> 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.<ref name="ACS Landmarks">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 N^α-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 N^α-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.<ref name="ACS Landmarks"/> 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.<ref name="Freemantle">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine".<ref name="ACS Landmarks"/> 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.Template: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.<ref name="Freemantle"/>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Tentative evidence supports a beneficial role as add-on therapy in colorectal cancer.<ref>Template:Cite journal</ref>

Cimetidine inhibits ALA synthase activity and hence may have some therapeutic value in preventing and treating acute porphyria attacks.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

There is some evidence supporting the use of cimetidine in the treatment of PFAPA.<ref name="ped-rheum">Template:Cite journal</ref>

Veterinary use

In dogs, cimetidine is used as an antiemetic when treating chronic gastritis.<ref>Template:Cite journal</ref>

External links

• Template:Commons category-inline