Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Triamterene: Difference between pages

{{short description|Chemical compound}}

{{redirect-distinguish|Ademine|adenine}}

{{more citations needed section|date=June 2012}}

| verifiedrevid = 470613031

| image2 = Triamterene substance photo.jpg

| tradename = Dyrenium, others

| pregnancy_AU = C

| pregnancy_US = C

| pregnancy_category =

| legal_AU = S4

| legal_UK = POM

| legal_status =

| routes_of_administration = By mouth

| metabolism = [[hydroxylation]] to para-hydroxytriamterene

| ATC_supplemental =

| IUPHAR_ligand = 4329

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| KEGG = D00386

| C=12 | H=11 | N=7

'''Triamterene''' (traded under names such as '''Dyrenium''' and Dytac) is a [[potassium-sparing diuretic]] often used in combination with [[thiazide]] diuretics for the treatment of [[hypertension|high blood pressure]] or [[edema|swelling]]. The combination with [[hydrochlorothiazide]], is known as [[hydrochlorothiazide/triamterene]].

== Side effects ==

Common [[adverse drug reaction|side effects]] may include a depletion of [[sodium]], [[folic acid]], and [[calcium]], nausea, vomiting, diarrhea, headache, dizziness, fatigue, and dry mouth. Serious side effects may include heart palpitations, tingling/numbness, fever, chills, sore throat, rash, and back pain. Triamterene can also cause [[kidney stones]] through direct crystallization or by seeding [[calcium oxalate]] stones. Triamterene is best avoided in patients with chronic kidney disease due to the possibility of [[hyperkalemia]]. People using this drug should use [[salt substitute]] cautiously.<ref>{{cite web | work = LoSalt | url = http://www.losalt.com/docs/lo_salt_web_advice.pdf | title = Advisory Statement | archive-url = https://web.archive.org/web/20051210181911/http://www.losalt.com/docs/lo_salt_web_advice.pdf | archive-date= 10 December 2005}}</ref>

Triamterene may impart a blue fluorescent color to the urine.

== Caution with certain disease states ==

[[Diabetes]]: Use with caution in people with prediabetes or diabetes mellitus as there may be a change in glucose control.

[[Hepatic impairment|Liver impairment]]: Use with caution in people with severe liver dysfunction; in [[cirrhosis]], avoid electrolyte and acid/base imbalances that might lead to [[hepatic encephalopathy]].

[[Kidney failure]]: combined triamterene and [[indomethacin]] therapy caused reversible [[acute kidney injury]] in some people.<ref>{{cite journal | vauthors = Favre L, Glasson P, Vallotton MB | title = Reversible acute renal failure from combined triamterene and indomethacin: a study in healthy subjects | journal = Annals of Internal Medicine | volume = 96 | issue = 3 | pages = 317–320 | date = March 1982 | pmid = 6949485 | doi = 10.7326/0003-4819-96-3-317 }}</ref>

[[Kidney stones]]: Use with caution in people with kidney stones.

Use should be avoided if the creatinine clearance is less than 10 ml/minute.

== Mechanism of action ==

Triamterene directly blocks the [[epithelial sodium channel]]<ref name="pmid8772124">{{cite journal | vauthors = Busch AE, Suessbrich H, Kunzelmann K, Hipper A, Greger R, Waldegger S, Mutschler E, Lindemann B, Lang F | display-authors = 6 | title = Blockade of epithelial Na+ channels by triamterenes - underlying mechanisms and molecular basis | journal = Pflügers Archiv | volume = 432 | issue = 5 | pages = 760–766 | date = September 1996 | pmid = 8772124 | doi = 10.1007/s004240050196 | s2cid = 10489391 }}</ref> (ENaC) on the lumen side of the kidney [[collecting tubule]].<ref name=Burger/>{{rp|127}} Other diuretics cause a decrease in the sodium concentration of the forming urine due to the entry of sodium into the cell via the ENaC, and the concomitant exit of potassium from the [[principal cell]] into the forming urine. Blocking ENaC prevents this from happening. [[Amiloride]] works in the same way. Sodium channel blockers directly inhibit the entry of sodium into the sodium channels.

== With hydrochlorothiazide ==

{{main|Hydrochlorothiazide/triamterene}}

Triamterene is commonly prepared in combination with [[hydrochlorothiazide]] for treatment of [[hypertension]] (high blood pressure) and [[edema]] (water retention). This combination is in a class of medications called [[diuretic]]s or 'water pills', and causes the [[kidney]]s to get rid of the body's unneeded water and [[sodium]] through the [[urine]].<ref>{{cite web | url = https://www.nlm.nih.gov/medlineplus/druginfo/meds/a601125.html | title = Triamterene and Hydrochlorothiazide | work = MedlinePlus | publisher = [[United States National Library of Medicine|U.S. National Library of Medicine]]. [[National Institutes of Health]] | date = 1 September 2008 }}</ref>

==History==

The triamterene ring system is found in many naturally occurring compounds, such as folic acid and riboflavin. The observation that the naturally occurring compound [[xanthopterin]] had renal affects led scientists at [[Smith Kline and French]] Laboratories in Philadelphia to begin a medicinal chemistry campaign to discover potential drugs, as part of a program to discover potassium-sparing diuretics.<ref name=Burger>{{cite book| vauthors = Fink CA, McKenna JM, Werner LH | veditors = Abraham DJ |title=Burger's medicinal chemistry and drug discovery. Volume 3: Cardiovascular Agents and Endocrines|date=2003|publisher=Wiley|isbn=978-0471370291|pages=55–154|edition=6th|chapter=Diuretic and Uricosuric Agents}}</ref>{{rp|125}} The first clinical studies were published in 1961 and the first trials combining it with [[hydrochlorothiazide]] were published the next year.<ref name=Burger/>{{rp|126}}<ref>{{cite journal | vauthors = Crosley AP, Ronquillo LM, Strickland WH, Alexander F | title = Triamterene, a new natruretic agent. Preliminary observations in man | journal = Annals of Internal Medicine | volume = 56 | issue = 2 | pages = 241–251 | date = February 1962 | pmid = 13882367 | doi = 10.7326/0003-4819-56-2-241 }}</ref><ref>{{cite journal | vauthors = Heath WC, Freis ED | title = Triamterene with Hydrochlorothiazide in the Treatment of Hypertension | journal = JAMA | volume = 186 | issue = 2 | pages = 119–122 | date = October 1963 | pmid = 14056525 | doi = 10.1001/jama.1963.03710020039012 }}</ref>

Smith Kline & French launched it as a single agent under the brand Dyrenium in 1964.<ref>{{cite book | vauthors = Landau R, Achilladelis B, Scriabine A | title = Pharmaceutical Innovation: Revolutionizing Human Health. | volume = 2 | series = Chemical Heritage Foundation series in innovation and entrepreneurship. | publisher = Chemical Heritage Foundation | date = 1999 | isbn = 9780941901215 }}</ref>{{rp|83}} The [[combination drug]] with hydrochlorothiazide, Dyazide, was first approved in the US in 1965 and the first generic, brought by Bolar Pharmaceutical Co., was approved in 1987.<ref name=DyazideApprovalHist>FDA

{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=016042&DrugName=DYAZIDE&ActiveIngred=HYDROCHLOROTHIAZIDE%3B%20TRIAMTERENE&SponsorApplicant=GLAXOSMITHKLINE%20LLC&ProductMktStatus=1&goto=Search.Label_ApprovalHistory | title = Approval History NDA 016042: Dyazide | publisher = U.S. Food and Drug Administration | access-date = 8 September 2016 }}</ref><ref name=Philly1987>{{cite book | vauthors = Wolf R | work = The Philadelphia Inquirer | date = 22 August 1987 | url = http://articles.philly.com/1987-08-22/news/26170137_1_smithkline-stock-smithkline-earnings-generic-version | title = Smithkline Loses Exclusive Rights To Drug }}</ref> In 1986 Dyazide was the most prescribed drug in the US and had $325 million in sales, making it SmithKline Beckman's second-biggest seller behind [[Tagamet]].<ref name=Philly1987/>

The patents had expired on Dyazide in 1980, but complications arose with the introductions of generics, because the formulation of Dyazide resulted in variable batches that made it impossible for generic manufacturers to show that their versions were bioequivalent.<ref>{{cite journal | vauthors = Boehm G, Yao L, Han L, Zheng Q |title=Development of the generic drug industry in the US after the Hatch-Waxman Act of 1984 |journal=Acta Pharmaceutica Sinica B |date=September 2013 |volume=3 |issue=5 |pages=297–311 |doi=10.1016/j.apsb.2013.07.004 |doi-access=free }}</ref><ref name=MylanHistDyazide>{{cite book | vauthors = Seaman J, Landry JT | title = Mylan 50 Years of Unconventional Success. | publisher = University Press of New England | date = 2011 | isbn = 9781611682700 | url = https://books.google.com/books?id=Q4OHtqPMjvYC&pg=PT50 | page = 50 }}</ref>

Bolar Pharmaceutical was in the running to be the first to bring a generic, but its application was delayed by these concerns about whether its formulation provided the same amount of each drug; these were complicated by accusations that Bolar had fraudulently substituted Dyazide for its own version to conduct studies that were submitted to the FDA.<ref name=Philly1987/> Shortly after Bolar's generic was approved, further concerns were raised with regard to Bolar's applications to market generics more generally; these findings among others raised widespread concern among doctors and the public over whether generics were really the same as branded drugs.<ref>{{cite news | vauthors = Strickland C |title=Bolar: A Drug Company Under Siege |url= https://www.nytimes.com/1989/10/15/nyregion/bolar-a-drug-company-under-siege.html?pagewanted=all |work=The New York Times |date=15 October 1989}}</ref><ref>{{cite news | vauthors = Cimons M |title=FDA to Lift OK of Last Dyazide Generic Version |url= http://articles.latimes.com/1989-08-29/news/mn-1184_1_generic-drug |work=Los Angeles Times|date=29 August 1989 }}</ref> Bolar ended up recalling its generic form of Dyazide and withdrawing the product in 1990.<ref>{{cite news|title=Bolar Recalls Generic Version Of Dyazide And Extended Release Phenytoin, Saying "Bioequivalence Cannot Be Assured"; Products; Represent 52% of Sales|url=https://pink.pharmamedtechbi.com/PS016884/BOLAR-RECALLS-GENERIC-VERSION-OF-DYAZIDE-AND-EXTENDED-RELEASE-PHENYTOIN-SAYING-BIOEQUIVALENCE-CANNOT-BE-ASSURED-PRODUCTSampnbspREPRESENT-52-OF-SALES|work=Pink Sheet|date=February 5, 1990}}</ref> In 1991 the US Justice Department on behalf of the FDA filed 20 criminal charges against Bolar for its fraud,<ref>{{cite news| vauthors = Shaw D |title=U.S. Charges Bolar Pharmaceutical With Misrepresenting Its Products|url=http://articles.philly.com/1991-02-27/business/25775782_1_generic-drug-generic-drug-industry-bolar-pharmaceutical|work=The Philadelphia Inquirer|date=February 27, 1991}}</ref> and early the next year Bolar pled guilty and agreed to pay a $10M fine.<ref>{{cite news| vauthors = Freudenheim M |title=Bolar Plans Guilty Plea On Generics|url=https://www.nytimes.com/1991/02/28/business/bolar-plans-guilty-plea-on-generics.html|work=The New York Times|date=28 February 1991}}</ref> Public concern over the safety of generic drugs was further exacerbated by a Congressional investigation into bribery at the FDA by generics companies that found pervasive corruption; the investigation had been spurred by the generics company [[Mylan]], which had hired private investigators based on its beliefs that competitors were getting unfair advantages in getting their generics approved.<ref name=NYTexpose1989>{{Cite news|url = https://www.nytimes.com/1989/09/10/business/exposing-the-fda.html?pagewanted=all|title = Exposing the F.D.A.| vauthors = Freudenheim M |date = 10 September 1989|work = The New York Times}}</ref>

[[Mylan]] itself developed a version of a triamterene/hydrochlorothiazide combination drug after the Dyazide patent expired, and used a different, more stable formulation<ref name=MylanHistDyazide/> as well as different dosages of each active ingredient (50&nbsp;mg hydrochlorothiazide and 75&nbsp;mg triamterene, compared with Dyazide's 25&nbsp;mg hydrochlorothiazide and 50&nbsp;mg triamterene) so it had to get approval as a new drug, as opposed to a generic; their product was called Maxzide and was approved in 1984.<ref>{{cite web | publisher = U.S. Food and Drug Administration | url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=019129&DrugName=MAXZIDE&ActiveIngred=HYDROCHLOROTHIAZIDE%3B%20TRIAMTERENE&SponsorApplicant=MYLAN%20PHARMS%20INC&ProductMktStatus=1&goto=Search.Label_ApprovalHistory | title = Approval History NDA 019129: Maxzide | access-date = 8 September 2016 }}</ref><ref name=MaxApprovable>{{cite web | work = Pink Sheet | date = 22 October 1984 | url = https://pink.pharmamedtechbi.com/PS007364/MYLANs-MAXZIDE-IS-APPROVABLE-AT-FDA-LEDERLE-TO-MARKET-BRAND-COMPETITION-TO-SMITHKLINEs-No-3RANKED-DYAZIDE-FINAL-APPROVAL-ANTICIPATED-IMMINENTLY | title = Mylan's Maxzide is "Approvable" at FDA: Lederle To Market Brand Competition to Smithkline's No. 3-Ranked Dyazide; Final Approval Anticipated "Imminently" }}</ref> The higher dose allowed once per day dosing, which Mylan and its marketing partner, Lederle, believed would help it compete against Dyazide, which had $210M in sales in 1983.<ref name=MaxApprovable/>

Mylan's patents on the drug were declared invalid in court, and its marketing exclusivity expired in 1987, prompting a rush of generic competition and litigation by two of them, American Therapeutics Inc. and Vitarine Pharmaceuticals, with the FDA.<ref>{{cite news| vauthors = Reid K |title=US Judge to Rule on Drug Marketing|url=http://www.joc.com/us-judge-rule-drug-marketing_19871117.html|publisher=Journal of Commerce|date=November 17, 1987}}</ref> Vitarine, along with [[Par Pharmaceutical]], were two of the companies that Mylan had targeted in its investigation into corruption and it turned out that Par and Vitarine had each used Mylan's Maxzide to obtain its bioequivalence data, leading both companies to withdraw its generic competitor to Mylan's product.<ref name=NYTexpose1989/><ref>{{cite news| vauthors = Andrews EL |title=F.D.A. Inquiry on Generic Drugs Focuses on Changes in Ingredients|url=https://www.nytimes.com/1989/07/31/us/fda-inquiry-on-generic-drugs-focuses-on-changes-in-ingredients.html|work=The New York Times|date=31 July 1989}}</ref> Generics eventually entered the market.<ref>{{cite web | work = Drugs.com | url = https://www.drugs.com/availability/generic-maxzide-25.html | title = Generic Maxzide | access-date = 8 September 2016 }}</ref>

== Research ==

While there is a lack of [[randomized controlled trial]]s evaluating the use of triamterene in the treatment of [[Ménière's disease]], the typical treatment is 37.5&nbsp;mg of triamterene with 25&nbsp;mg of [[hydrochlorothiazide]] 1–2 capsules daily.<ref name="pmid15791890">{{cite journal | vauthors = Swartz R, Longwell P | title = Treatment of vertigo | journal = American Family Physician | volume = 71 | issue = 6 | pages = 1115–1122 | date = March 2005 | pmid = 15791890 | url = http://www.aafp.org/afp/2005/0315/p1115.pdf }}</ref><ref name="pmid11346317">{{cite journal | vauthors = Sloane PD, Coeytaux RR, Beck RS, Dallara J | title = Dizziness: state of the science | journal = Annals of Internal Medicine | volume = 134 | issue = 9 Pt 2 | pages = 823–832 | date = May 2001 | pmid = 11346317 | doi = 10.7326/0003-4819-134-9_Part_2-200105011-00005 | s2cid = 6762911 }}</ref> This recommendation was given a Strength of Recommendation Taxonomy (SORT) grade of C.{{citation needed|date=June 2012}}

== References ==

{{Reflist|32em}}

== External links ==

{{Sodium channel blockers}}

{{Diuretics}}

[[Category:IARC Group 2B carcinogens]]

[[Category:Potassium-sparing diuretics]]

[[Category:Pteridines]]

[[Category:World Anti-Doping Agency prohibited substances]]