Spironolactone (Aldactone)

Indications

Acne Vulgaris (see Acne Vulgaris)

Clinical Efficacy

Spironolactone is Efficacious in Acne Vulgaris (Dermatology, 2017) [MEDLINE]

Ascites (see Ascites)

Clinical Eficacy

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Congestive Heart Failure (CHF) (see Congestive Heart Failure)

Clinical Efficacy

Randomized Aldactone Evaluation Study (RALES) (NEJM, 1999) [MEDLINE]
- Spironolactone (25-50 mg qday) Decreased Mortality Rate in Severe CHF
TOPCAT Trial (NEJM, 2014) [MEDLINE]
- In Patients with CHF with Preserved Ejection Fraction (EF ≥45%), Spironolactone Did Not Decrease the Risk of Death from Cardiovascular Causes, Aborted Cardiac Arrest, or Hospitalization for CHF

Diuretic-Induced Hypokalemia (see Hypokalemia)

Spironolactone is Commonly Utilized in Conjunction with Other Diuretics (Such as Furosemide, etc), Due to its Potassium-Sparing Effect

Hirsutism (see Hirsutism)

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Hypertension (see Hypertension)

Clinical Efficacy

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Trial (Hypertension, 2007) [MEDLINE]
- Spironolactone Decreased Blood Pressure (21.9 mm Hg/9.5 mm Hg): blood pressure reduction was largely unaffected by smoking status, age, sex, and presence of diabetes mellitus
  - Median Dose of Spironolactone Used in the Trial: only 25 mg qday
Meta-Analysis Examining Spironolactone Addition in Resistant Hypertension (Clin Exp Hypertens, 2017) [MEDLINE]
- Spironolactone Addition Has Clinical Benefit in Resistant Hypertension, as Compared to Alternative Agents (β-Blockers, Candesartan, or α-Methyldopa)

Peripheral Edema (see Peripheral Edema)

Cirrhosis (see Cirrhosis)
Congestive Heart Failure (CHF) (see Congestive Heart Failure)
Nephrotic Syndrome (see Nephrotic Syndrome)

Primary Hyperaldosteronism (see Hyperaldosteronism)

Clinical Efficacy
- xxxx

Pharmacology

Aldosterone Receptor Antagonist

Spironolactone is a Competitive Antagonist for the Aldosterone Receptor on the Renal Collecting Tubule Cells
- Results in Aldosterone Resistance, Causing Drug-Induced Hypoaldosteronism (see Hypoaldosteronism)

Administration

PO (Congestive Heart Failure): 25-50 mg qday
PO (Edema): 25-200 mg qday (divided qday-BID)
PO (Hyperaldosteronism Maintenance Treatment): 100-200 mg qday (divided qday-BID)
PO (Hypertension): 25-50 mg qday (divided qday-BID)

Dose Adjustment

Hepatic
- Cautious Use
Renal
- CrCl <10 or Anuria: contraindicated

Use in Pregnancy (see Pregnancy)

Avoid Use in Pregnancy

Use During Breast Feeding

Probable Safe During Breast Feeding

Drug Interactions

Agents Which are Associated with Drug-Induced Hypoaldosteronism (see Hypoaldosteronism)

Aliskiren (Tekturna, Rasilez) (see Aliskiren): concomitant use of spironolactone and aliskiren (a renin inhibitor) increases the risk of hyperkalemia
- Aliskiren Causes Drug-Induced Hypoaldosteronism (see Hypoaldosteronism): decreased aldosterone synthesis results in decreased renal potassium excretion
Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors): concomitant use of spironolactone and ACE inhibitors increases the risk of hyperkalemia
- ACE Inhibitors Cause Drug-Induced Hypoaldosteronism (see Hypoaldosteronism): decreased aldosterone synthesis results in decreased renal potassium excretion
Angiotensin II Receptor Blockers (ARB’s) (see Angiotensin II Receptor Blockers): concomitant use of spironolactone and ARB’s increases the risk of hyperkalemia
- ARB’s Cause Drug-Induced Hypoaldosteronism (see Hypoaldosteronism): decreased aldosterone synthesis results in decreased renal potassium excretion

Adverse Effects

Cardiovascular Adverse Effects

Hypotension (see Hypotension)

Physiology
- Due to Hypovolemia

Endocrinologic Adverse Effects

Gynecomastia (see Gynecomastia)

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Hematologic/Oncologic Adverse Effects

Tumorigenic (in Chronic Use Studies in Rats)

FDA Black Box Warning

Renal Adverse Effects

Hyponatremia (see Hyponatremia)

Epidemiology
- Spironolactone-Induced Hyponatremia Has Been Reported Mainly in Two Treatment Scenarios
  - Treatment of Congestive Heart Failure
  - Treatment of Resistant Hypertension Which is Unrelated to Hyperaldosteronism
- Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Trial (Hypertension, 2007) [MEDLINE]
  - Spironolactone was Associated with Mild Hyponatremia (Pre-Spironolactone Serum Sodium 140 mEq/L -> Post-Spironolactone Serum Sodium 138 mEq/L): however, the median dose of spironolactone used in the trial was low (only 25 mg qday)
Physiologic Mechanisms
- Impairment of Aldosterone-Mediated Renal Sodium Resorption: with increased natriuresis

Hyperkalemia (see Hyperkalemia)

Epidemiology
- Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Trial (Hypertension, 2007) [MEDLINE]
  - Spironolactone was Associated with Hyperkalemia (Pre-Spironolactone Serum Potassium 4.13 mEq/L -> Post-Spironolactone Serum Potassium 4.54 mEq/L)
Physiology
- Decreased Renal Potassium Excretion
Clinical
- Caution Should Be Exercised When Using Spironolactone in Conjunction with Other Agents Which Also Impair Renal Potassium Excretion (Such as ACE Inhibitors, etc)

References

Spironolactone-associated hyponatremic coma. Nephron. 1994;67(4):503 [MEDLINE]
The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341: 709-17 [MEDLINE]
Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases. BMJ. 2003 Jul 19;327(7407):147-9 [MEDLINE]
ASCOT Trial. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007 Apr;49(4):839-45. Epub 2007 Feb 19 [MEDLINE]
Well tolerated spironolactone-related hyponatremia. J Clin Hypertens (Greenwich). 2008 Apr;10(4):317-21 [MEDLINE]
TOPCAT Trial. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92. doi: 10.1056/NEJMoa1313731 [MEDLINE]
Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure. Methodist Debakey Cardiovasc J. 2015 Oct-Dec;11(4):235-9. doi: 10.14797/mdcj-11-4-235 [MEDLINE]
Spironolactone for the Treatment of Acne: A 4-Year Retrospective Study. Dermatology. 2017 May 5. doi: 10.1159/000471799 [MEDLINE]
Heart failure. Lancet. 2017 Apr 28. pii: S0140-6736(17)31071-1. doi: 10.1016/S0140-6736(17)31071-1 [MEDLINE]
Addition of spironolactone in patients with resistant hypertension: A meta-analysis of randomized controlled trials. Clin Exp Hypertens. 2017;39(3):257-263. doi: 10.1080/10641963.2016.1246564 [MEDLINE]