Spironolactone 732656 226140874 2008-07-17T00:23:44Z Collabi 6095 /* Pharmacokinetics */ wl bile {{drugbox | IUPAC_name = 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone | image = Spironolactone structure.png | CAS_number = 52-01-7 | ATC_prefix = C03 | ATC_suffix = DA01 | ATC_supplemental = | PubChem = 5833 | DrugBank = APRD01234 | synonyms = Aldactone<br>Spirotone<br>Spirolactone | smiles = CC(=O)SC1CC2=CC(=O)CCC2(C3C1C4CCC5(C4(CC3)C)CCC(=O)O5)C | C=24 | H=32 | O=4 | S=1 | molecular_weight = 416.574 g/mol | bioavailability = | protein_bound = | metabolism = [[Liver|Hepatic]] | elimination_half-life = 10 minutes | excretion = [[Urine]], [[bile]] | pregnancy_AU = B3 | pregnancy_US = C | legal_UK = POM | routes_of_administration = Oral }} '''Spironolactone''' (marketed under the trade names '''Aldactone''', '''Novo-Spiroton''', '''Spiractin''', '''Spirotone''', '''Verospiron''' or '''Berlactone''') is a [[diuretic]] and is used as an [[antiandrogen]]. It is a synthetic 17-[[lactone]] drug which is a renal competitive [[aldosterone]] antagonist in a class of [[pharmaceutical]]s called [[potassium-sparing diuretic]]s, used primarily to treat [[heart failure]], [[ascites]] in patients with liver disease, low-[[renin]] [[hypertension]], [[hypokalemia]], and [[Conn's syndrome]] as well as high blood pressure. On its own, spironolactone is only a weak diuretic, but it can be combined with other diuretics. About one person in one hundred with hypertension has elevated levels of aldosterone; in these persons the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives. Due to its anti-[[androgen]] effect, it can also be used to treat [[hirsutism]], and is a common component in [[Hormone replacement therapy (trans)|hormone therapy]] for male-to-female [[Transwoman|transsexual]] and [[transgender]]ed people. It is also used for treating [[Alopecia|hair loss]] and [[acne]] in women and can be used as a [[topical]] medication for treatment of male [[baldness]]. ==Mechanism of action== Spironolactone inhibits the effect of aldosterone by competing for intracellular [[mineralocorticoid receptor|aldosterone receptor]] in the [[distal convoluted tubule|distal tubule]] cells (it actually works on aldosterone receptors in the collecting duct). This increases the excretion of water and [[sodium]], while decreasing the excretion of potassium. Spironolactone has a fairly slow onset of action, taking several days to develop and similarly the effect diminishes slowly. Spironolactone has anti-androgen activity by binding to the [[androgen receptor]] and preventing it interacting with [[dihydrotestosterone]].<ref>{{cite journal | last = Berardesca | first = E | authorlink = | coauthors = Gabba P, Ucci G, Borroni G, Rabbiosi G. | title = Topical spironolactone inhibits dihydrotestosterone receptors in human sebaceous glands: an autoradiographic study in subjects with acne vulgaris | journal = Int J Tissue React. | volume = 10 | issue = 2 | pages = 115–119 | date = 1988 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2972662&dopt=Abstract | pmid = 2972662 | accessdate = 2007-03-15 | unused_data = |publisher }}</ref> ==Pharmacokinetics== Spironolactone is fairly rapidly absorbed from the gastrointestinal tract. It is also rapidly metabolised and bound in plasma proteins. Many of its metabolites are also active and one of them, [[canrenone]] as [[potassium canrenoate]], is used parenterally when rapid effect is needed. Spironolactone's half-life is 85 minutes, but canrenone's half-life is 10 to 35 hours, depending on the dose. The main elimination route is in the urine and some also in the [[bile]]. ==Mortality and morbidity benefit in severe heart failure== Spironolactone was shown to have a significant [[death|mortality]] and [[morbidity]] benefit in the Randomized Aldactone Evaluation Study (RALES), which studied people with severe [[Heart failure|congestive heart failure]] ([[New York Heart Association Functional Classification|New York Heart Association functional class]] III or IV).<ref>{{cite journal | author = Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J | title = The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators | journal = N Engl J Med | volume = 341 | issue = 10 | pages = 709–17 | year = 1999 | url= http://content.nejm.org/cgi/content/full/341/10/709 | pmid = 10471456 | doi = 10.1056/NEJM199909023411001}}</ref> Patients in the study arm of the trial (those receiving spironolactone) had a [[relative risk]] of death (when compared to the placebo group) equal to 0.70 or a 30% [[relative risk reduction]]. Patients in the study arm also had significantly less symptoms of [[Heart failure|CHF]] and were hospitalized less frequently. The mechanism of this effect is also mediated by inhibiting aldosterone, which in heart failure leads to myocardial fibrosis, sodium retention, and vascular dysfunction. ==Adverse effects and interactions== Spironolactone is associated with an increased risk of bleeding from the [[stomach]] and [[duodenum]], but a causal relationship between the two has not been established.<ref>{{cite journal | title=Spironolactone and risk of upper gastrointestinal events: population based case-control study | journal=Brit Med J | year=2006 | author=Verhamme KMC, Mosis G, Dieleman JP, ''et al.'' | volume=333 | issue=7563 | pages=330&ndash;3 | doi=10.1136/bmj.38883.479549.2F | pmid=16840442 }}</ref> Since it also affects steroid receptors elsewhere in the body, it can cause [[gynecomastia]], menstrual irregularities and testicular atrophy. Other side effects include [[ataxia]], [[erectile dysfunction]], drowsiness and rashes. A [[carcinogen]]ic effect has been demonstrated in rats. Spironolactone has been shown to be immunosuppressive in the treatment of [[sarcoidosis]].<ref>{{cite journal | title = Aldactone in the treatment of sarcoidosis of the lungs | journal=JZ Erkr Atmungsorgane. | year=1977 | author=Wandelt-Freerksen E. | volume=149(1) | pages=156–9 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=607621&query_hl=22&itool=pubmed_DocSum | pmid = 607621 | accessdate = 2007-05-02}}</ref> There are indications that taking this drug can reduce the odds for developing Alzheimer's. "We observed the greatest reduction in AD risk specifically with potassium-sparing diuretics. It is not clear why potassium-sparing diuretics in particular should be associated with a reduced risk of AD, but it is well known that both loop and thiazide diuretics reduce plasma potassium concentration while potassium-sparing diuretics (including triamterene, spironolactone, and amiloride hydrochloride) typically lead to increased concentrations. As yet unpublished findings from the Gothenberg Study also suggest that increased potassium levels may be associated with a reduced risk of dementia. Consistent with this idea are observations that low potassium concentrations are associated with oxidative stress, inflammation, platelet aggregation, and vasoconstriction, all of which are possible contributors to AD pathogenesis." See: http://archneur.ama-assn.org/cgi/content/full/63.5.noc60013v1 People using this drug should avoid salt substitutes containing potassium.<ref>{{cite web | title = Advisory Statement | publisher = Klinge Chemicals / LoSalt | url = http://www.losalt.com/docs/lo_salt_web_advice.pdf | format = pdf | accessdate = 2007-03-15}}</ref> However, a more serious issue may be the drug's interference with antidepressant effectiveness. The drug is actually (among its other receptor interactions) a mineralocorticoid (MR) antagonist, and has been found to worsen antidepressant outcome in the treatment of major depression, presumably by interfering with normalization of the [[Hypothalamic-pituitary-adrenal_axis|hypothalamic-pituitary-adrenal axis]] in patients receiving antidepressant therapy. Given that there are many patients on this drug who are also depressed and receiving classical first-line antidepressant drugs particularly SSRIs, this becomes a poorly appreciated but potentially major issue. (See Holsboer, F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J. Psychiatr. Res. 33, 181–214 (1999) for details). ==Carcinogenicity== Studies of spironolactone and the related compound [[potassium canrenoate]] (which, like spironolactone, metabolizes to [[canrenone]]) in rats for one to two year periods show an increase in carcinogenesis in the thyroid gland, testes, liver, breasts, and myelocytic leukocytes. Mammalian cells, depending on the presence of metabolic activation, show mixed results for mutagenicity ''in vitro''.<ref>{{cite web | title = Spironolactone RX Monograph | publisher = Sandoz Inc. | url = http://dailymed.nlm.nih.gov/dailymed/fdaDrugXsl.cfm?id=2479&type=display | format = html | accessdate = 2007-05-02}}</ref> In light of this research, Sandoz has recommended that unnecessary use of spironolactone be avoided. ==See also== *[[Baldness treatments]] ==References== {{Reflist|2}} ==External links== *[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682627.html nih.gov information site] *[http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ald1010.shtml Aldactone patient info leaflet] {{Antihypertensives and diuretics}} {{Sex hormones}} [[Category:Aldosterone antagonists]] [[Category:Antiandrogens]] [[Category:Lactones]] [[Category:Hair loss]] [[de:Spironolacton]] [[es:Espironolactona]] [[hr:Spironolakton]] [[hu:Spironolakton]] [[nl:Spironolacton]] [[ja:スピロノラクトン]] [[pl:Spironolakton]] [[ru:Спиронолактон]] [[uk:Спіронолактон]]