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Spironolactone
Indications
Spironolactone has indications in both certain cardiovascular diseases and non-cardiovascular disease entities. Spironolactone is FDA approved for the treatment of heart failure with reduced ejection fraction (HFrEF), resistant hypertension, primary hyperaldosteronism, edema secondary to cirrhosis, edema secondary to a nephrotic syndrome that is not adequately controlled using alternative therapies, and hypokalemia. The Randomized Aldactone Evaluation Study (RALES) was a landmark trial that used spironolactone in New York Heart Association (NYHA) class III-IV HFrEF patients with an ejection fraction less than 35%, and the trial was stopped early due to but not limited to positive findings including a 30% relative risk reduction in all-cause mortality.[1] In the 2017 American College of Cardiology heart failure guidelines, spironolactone is indicated in NYHA class II-IV HFrEF patients who have a creatinine clearance greater than 30 mL/min and a serum potassium level less than 5 mEq/L, and the guidelines also mention that select heart failure with preserved ejection fraction (HFpEF) patients may benefit from spironolactone use to help in reducing the number of hospitalizations.[2] There is some evidence that spironolactone may reduce myocardial fibrosis, reduce left ventricular mass, and decrease the amount of extracellular volume expansion in HFpEF patients.[3] This medication is not yet generally recommended for end-stage renal disease patients either on or not on dialysis; even though more large randomized controlled trials are needed, some reports do suggest that it would be well tolerated in chronic kidney disease patients if clinicians carefully manage the risk of hyperkalemia.[4][5] The definition of resistant hypertension is elevated blood pressure above the goal despite a patient being on optimal doses of three different antihypertensive agents of which one is a diuretic is another condition for which clinicians can prescribe spironolactone. The typical triple antihypertensive regimen in these patients is a thiazide diuretic, calcium channel blocker, and wither an angiotensin-converting enzyme inhibitor or an aldosterone receptor antagonist. Researchers tested low dose spironolactone as an agent added on in both White race and African American patients with resistant hypertension with and without primary hyperaldosteronism, and results showed it to help lower blood pressure when added to these patients' multidrug antihypertensive regimens.[6] Spironolactone was also tested against bisoprolol and doxazosin to determine which of the three was the most effective fourth agent for treating resistant hypertension, and research showed spironolactone to be superior to the other two in reducing systolic home blood pressure in these patients.[7] A study tested spironolactone against clonidine as the fourth agent in treating resistant hypertension and found to be non-inferior base on the primary endpoints of the trial and preferable to clonidine based on secondary endpoints of 24-hour systolic and diastolic blood pressure as well as diastolic daytime ambulatory blood pressure being lowered greater by spironolactone than by clonidine.[8] Spironolactone is considered the main option for the treatment of ascites in cirrhosis after the dietary salt restriction is not sufficient.[9] The typical starting dose ratio of oral furosemide to spironolactone is 40 mg to 100 mg, respectively. A study in children with severe edema secondary to nephrotic syndrome showed that oral spironolactone in conjunction with intravenous furosemide was safe and helpful in treating these children who had edema with volume expansion.[10] Spironolactone was studied concurrently with metolazone in patients with cirrhosis and nephrotic syndrome and found to be effective adjunctively, and it mitigated the hypokalemia associated with metolazone use.[11]
Off-label, non-FDA approved indications include the treatment of acne vulgaris and hirsutism. Spironolactone has off label use as an alternative agent used to treat acne vulgaris in adult females with persistent and/or late-onset acne.[12] Spironolactone has been considered as a possible alternative to the guideline-based recommendation of a three-month course of oral antibiotics, specifically the tetracycline class of antibiotics, for chronic treatment of moderate to severe acne because it may reduce the risk of antibiotic resistance in patients on very long periods of antibiotics and provide clinically relevant improvement in acne.[13] It is important to note that there is a lack of high-level evidence for this indication, so patients who are to receive this drug should undergo careful selection after first attempting primary therapy options for acne vulgaris, and there has been full consideration of the benefits and risks of using spironolactone. The role of spironolactone in androgen excess syndromes such as hirsutism is to reduce the rate of testosterone production and increase the metabolic clearance of testosterone, which supports its use in select patients adjunctively with dexamethasone and oral contraceptives.[14]
Mechanism of Action
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Mechanism of Action
Spironolactone belongs to the drug class of mineralocorticoid receptor antagonists, and it is a nonselective antagonist that can bind to androgen and progesterone receptors. Aldosterone, a component of the renin-angiotensin-aldosterone system, binds to its receptors at the distal tubules and collecting duct and causes sodium reabsorption and potassium secretion, increased vascular stiffness and remodeling, and increased cardiac inflammation, fibrosis, and remodeling. Spironolactone specifically works by competitively blocking aldosterone receptor-mediated action. The effect of the blockade is that sodium reabsorption with water retention does not occur, and there is increased potassium retention. In the treatment of acne vulgaris, spironolactone may reduce sebum production by blocking the binding of dihydrotestosterone to its androgen receptors, thereby inhibiting sebocyte proliferation.[12]
Administration
Spironolactone oral dosing is as an oral tablet in 25 mg, 50 mg, or 100 mg doses and the maximum daily is dependent on the indication as follows: 1) 50 mg daily for HFrEF 2) 100 mg daily for resistant hypertension 3) 400 mg daily for edema due to cirrhosis or 200mg daily for edema due to nephrotic syndrome 4) 400 mg daily for primary hyperaldosteronism 5) 200 mg daily for diuretic-induced hypokalemia 6) 200 mg daily for hirsutism 7) 200 mg daily for acne vulgaris. Dosing can also is possible as an oral suspension at a dose of 5 mg/mL with varying doses based on the indication. The frequency of administration and adjustments in the dose are based on the clinical indication and presence of renal impairment.
Adverse Effects
The most common non-electrolyte and electrolyte adverse effects of spironolactone are breast complaints and hyperkalemia, respectively. Men specifically may experience gynecomastia, loss of libido, and general feminization; the drug is a category C pregnancy drug because animal studies showed that the feminization of male fetuses is a concern.[13] Meanwhile, women can experience menstrual irregularities.[15] One study mentions the following additional adverse effects in order from more to less common: dehydration, hyponatremia, gastrointestinal problems (nausea, vomiting, diarrhea or anorexia), neurological abnormalities (headache, drowsiness, asterixis, confusion, or coma), and skin rashes.[16]
Contraindications
Hyperkalemia is an adverse effect of spironolactone. This drug is contraindicated in patients with hyperkalemia and in those at increased risk of developing hyperkalemia. It is also contraindicated in patients with renal impairment. As per the 2017 American College of Cardiology heart failure guidelines, patients should not receive spironolactone if their serum creatinine is greater than 2.5 mg/dL in men or greater than 2.0 mg/dL in women, the estimated glomerular filtration rate is less than 30 mL/min, and the serum potassium exceeds 5.0 mEq/L.[2]
Monitoring
Hyperkalemia can be due to spironolactone alone or a synergistic side effect from multiple medications such as beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers that clinicians often prescribe to patients for indications such as hypertension or heart failure. Routine blood work is necessary to evaluate serum potassium levels and any decline in renal function. Additional urine studies to assess kidney function may also be a requirement.
Toxicity
There are rare reports of spironolactone causing liver toxicity that can manifest as elevations in serum aminotransferases and alkaline phosphatase in a hepatocellular mixed pattern after nearly one month of taking spironolactone, and this resolves over time after discontinuation of the drug.[17]
Enhancing Healthcare Team Outcomes
The use of spironolactone for various FDA and non-FDA approved conditions has been reported, but clinicians must be careful when prescribing the drug. Communication between doctor and pharmacists is essential; the pharmacist should perform a thorough medical reconciliation of a patient's entire medication list. In doing so, healthcare professionals can identify multidrug related potentiation of adverse effects specific to spironolactone and thereby avoid starting the drug or discontinuing it versus switching to eplerenone if clinically appropriate. For example, cohort studies have identified beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers being co-administered with spironolactone as risks for the development of severe hyperkalemia, which would help decide the appropriateness of spironolactone.[18] Baseline patient characteristics also require assessment. Additional features that could also contribute to spironolactone related hyperkalemia include advanced age, high dose spironolactone use, decreased renal function, and diabetes mellitus type 2.[19] [Level 3] Patients on spironolactone require careful management using multi-specialty physician care; endocrinologists can assist with optimizing diabetes management, and nephrologists would help track a decline in renal function and progression of chronic kidney disease to end-stage renal disease, which can impact the appropriate use of spironolactone.
References
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. The New England journal of medicine. 1999 Sep 2:341(10):709-17 [PubMed PMID: 10471456]
Level 1 (high-level) evidenceYancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Journal of cardiac failure. 2017 Aug:23(8):628-651. doi: 10.1016/j.cardfail.2017.04.014. Epub 2017 Apr 28 [PubMed PMID: 28461259]
Level 3 (low-level) evidenceMcDiarmid AK, Swoboda PP, Erhayiem B, Bounford KA, Bijsterveld P, Tyndall K, Fent GJ, Garg P, Dobson LE, Musa TA, Foley JRJ, Witte KK, Kearney MT, Greenwood JP, Plein S. Myocardial Effects of Aldosterone Antagonism in Heart Failure With Preserved Ejection Fraction. Journal of the American Heart Association. 2020 Jan 7:9(1):e011521. doi: 10.1161/JAHA.118.011521. Epub 2019 Dec 19 [PubMed PMID: 31852424]
Agrawal S, Agrawal N, Garg J, Mohandas R, Gupta T, Segal M. Heart failure and chronic kidney disease: should we use spironolactone? The American journal of the medical sciences. 2015 Aug:350(2):147-51. doi: 10.1097/MAJ.0000000000000514. Epub [PubMed PMID: 26086152]
Yang CT, Kor CT, Hsieh YP. Long-Term Effects of Spironolactone on Kidney Function and Hyperkalemia-Associated Hospitalization in Patients with Chronic Kidney Disease. Journal of clinical medicine. 2018 Nov 21:7(11):. doi: 10.3390/jcm7110459. Epub 2018 Nov 21 [PubMed PMID: 30469400]
Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. American journal of hypertension. 2003 Nov:16(11 Pt 1):925-30 [PubMed PMID: 14573330]
Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ, British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet (London, England). 2015 Nov 21:386(10008):2059-2068. doi: 10.1016/S0140-6736(15)00257-3. Epub 2015 Sep 20 [PubMed PMID: 26414968]
Level 1 (high-level) evidenceKrieger EM, Drager LF, Giorgi DMA, Pereira AC, Barreto-Filho JAS, Nogueira AR, Mill JG, Lotufo PA, Amodeo C, Batista MC, Bodanese LC, Carvalho ACC, Castro I, Chaves H, Costa EAS, Feitosa GS, Franco RJS, Fuchs FD, Guimarães AC, Jardim PC, Machado CA, Magalhães ME, Mion D Jr, Nascimento RM, Nobre F, Nóbrega AC, Ribeiro ALP, Rodrigues-Sobrinho CR, Sanjuliani AF, Teixeira MDCB, Krieger JE, ReHOT Investigators. Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment). Hypertension (Dallas, Tex. : 1979). 2018 Apr:71(4):681-690. doi: 10.1161/HYPERTENSIONAHA.117.10662. Epub 2018 Feb 20 [PubMed PMID: 29463627]
Level 1 (high-level) evidenceMoore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006 Oct:55 Suppl 6(Suppl 6):vi1-12 [PubMed PMID: 16966752]
Kapur G, Valentini RP, Imam AA, Mattoo TK. Treatment of severe edema in children with nephrotic syndrome with diuretics alone--a prospective study. Clinical journal of the American Society of Nephrology : CJASN. 2009 May:4(5):907-13. doi: 10.2215/CJN.04390808. Epub 2009 Apr 30 [PubMed PMID: 19406963]
Lang GR, Westenfelder C, Nascimento L, Dhupelia VB, Arruda JA, Kane RE. Metolazone and spironolactone in cirrhosis and the nephrotic syndrome. Clinical pharmacology and therapeutics. 1977 Feb:21(2):234-43 [PubMed PMID: 319937]
Layton AM, Eady EA, Whitehouse H, Del Rosso JQ, Fedorowicz Z, van Zuuren EJ. Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. American journal of clinical dermatology. 2017 Apr:18(2):169-191. doi: 10.1007/s40257-016-0245-x. Epub [PubMed PMID: 28155090]
Level 1 (high-level) evidenceCharny JW, Choi JK, James WD. Spironolactone for the treatment of acne in women, a retrospective study of 110 patients. International journal of women's dermatology. 2017 Jun:3(2):111-115. doi: 10.1016/j.ijwd.2016.12.002. Epub 2017 Mar 13 [PubMed PMID: 28560306]
Level 2 (mid-level) evidenceCumming DC. Use of spironolactone in treatment of hirsutism. Cleveland Clinic journal of medicine. 1990 May:57(3):285-7 [PubMed PMID: 2357784]
Lainscak M, Pelliccia F, Rosano G, Vitale C, Schiariti M, Greco C, Speziale G, Gaudio C. Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone. International journal of cardiology. 2015 Dec 1:200():25-9. doi: 10.1016/j.ijcard.2015.05.127. Epub 2015 May 21 [PubMed PMID: 26404748]
Greenblatt DJ, Koch-Weser J. Adverse reactions to spironolactone. A report from the Boston Collaborative Drug Surveillance Program. JAMA. 1973 Jul 2:225(1):40-3 [PubMed PMID: 4740303]
. Spironolactone. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012:(): [PubMed PMID: 31643256]
Ko DT, Juurlink DN, Mamdani MM, You JJ, Wang JT, Donovan LR, Tu JV. Appropriateness of spironolactone prescribing in heart failure patients: a population-based study. Journal of cardiac failure. 2006 Apr:12(3):205-10 [PubMed PMID: 16624686]
Level 1 (high-level) evidenceWrenger E, Müller R, Moesenthin M, Welte T, Frölich JC, Neumann KH. Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases. BMJ (Clinical research ed.). 2003 Jul 19:327(7407):147-9 [PubMed PMID: 12869459]
Level 3 (low-level) evidence