Introduction
Spironolactone is a potassium-sparing diuretic that acts as a competitive antagonist of aldosterone at mineralocorticoid receptors. First approved by the FDA in 1960, it has evolved from primarily a diuretic agent to having multiple therapeutic applications across various medical specialties including cardiology, endocrinology, and dermatology.
Mechanism of Action
Spironolactone competitively inhibits aldosterone binding at mineralocorticoid receptors in the distal convoluted tubule and collecting ducts of the nephron. This inhibition prevents the aldosterone-mediated reabsorption of sodium and water while simultaneously reducing potassium and hydrogen ion excretion. Additionally, spironolactone demonstrates antiandrogenic properties through multiple mechanisms: competitive inhibition of androgen receptors, reduction of 17α-hydroxylase activity, and decreased testosterone production.
Indications
FDA-approved indications:- Essential hypertension (as monotherapy or combination therapy)
- Edema associated with congestive heart failure, cirrhosis, or nephrotic syndrome
- Primary hyperaldosteronism (diagnosis and treatment)
- Hypokalemia
- Heart failure with reduced ejection fraction (NYHA class II-IV)
- Acne vulgaris in women
- Hirsutism
- Polycystic ovary syndrome (PCOS)
- Ascites due to hepatic cirrhosis
Dosage and Administration
Hypertension:- Initial: 25-100 mg daily in single or divided doses
- Maintenance: 25-200 mg daily
- Initial: 25-200 mg daily in single or divided doses
- Maintenance: Adjust to lowest effective dose
- Initial: 12.5-25 mg once daily
- Target: 25-50 mg once daily
- Renal impairment: Use with caution; contraindicated in anuria, acute renal insufficiency
- Hepatic impairment: Initiate with lower doses; monitor closely
- Elderly: Consider starting with lower doses
- Pediatrics: Safety and efficacy not established for hypertension in children
Pharmacokinetics
Absorption: Well absorbed orally (≈90% bioavailability); food increases absorption Distribution: Vd ≈ 0.05 L/kg; highly protein bound (91-98%) Metabolism: Extensive hepatic metabolism via CYP3A4 to active metabolites (including canrenone) Elimination: Primarily renal (≈50%) and biliary excretion; terminal half-life 1.3-2 hours (parent drug), 14-17 hours (active metabolites) Onset of action: Diuresis within 2-4 hours; peak effect at 6-10 hours Duration: 24-48 hoursContraindications
- Anuria
- Acute renal insufficiency
- Significant impairment of renal function (CrCl <30 mL/min)
- Hyperkalemia
- Addison's disease
- Concomitant use with eplerenone in patients with diabetes mellitus with proteinuria
- Hypersensitivity to spironolactone or any component of the formulation
Warnings and Precautions
Hyperkalemia: Risk increased with renal impairment, diabetes, elderly patients, and concomitant use of ACE inhibitors, ARBs, NSAIDs, potassium supplements, or salt substitutes Renal impairment: May cause or worsen renal dysfunction; monitor renal function Electrolyte imbalances: Monitor sodium, potassium, magnesium, and calcium levels Hepatic impairment: May precipitate hepatic encephalopathy in cirrhotic patients Carcinogenicity: Benign adenomas reported in chronic rodent studies Gynecomastia: Dose-related incidence (reversible upon discontinuation) Tumorigenicity: Long-term safety in premenopausal women not establishedDrug Interactions
Major interactions:- ACE inhibitors/ARBs: Increased risk of hyperkalemia
- NSAIDs: Reduced diuretic effect and increased hyperkalemia risk
- Potassium supplements/salt substitutes: Increased hyperkalemia risk
- Digoxin: Spironolactone may increase digoxin half-life
- Lithium: Increased lithium toxicity risk
- CYP3A4 inhibitors/inducers: May alter spironolactone concentrations
- Other antihypertensives: Additive hypotensive effects
- Cholestyramine: Reduced spironolactone absorption
- Norepinephrine: Reduced pressor response
Adverse Effects
Common (≥10%):- Hyperkalemia
- Gynecomastia (dose-related)
- Gastrointestinal disturbances (nausea, vomiting, diarrhea)
- Dizziness
- Headache
- Menstrual irregularities
- Impotence
- Dehydration
- Hyponatremia
- Rash
- Fatigue
- Stevens-Johnson syndrome
- Agranulocytosis
- Hepatotoxicity
- Acute kidney injury
Monitoring Parameters
Baseline:- Complete metabolic panel (including potassium, sodium, creatinine)
- Renal function (BUN, creatinine, eGFR)
- Blood pressure
- Weight (for edema indications)
- Serum potassium: Within 1 week of initiation/dose change, then periodically
- Renal function: Regularly, especially in at-risk populations
- Electrolytes: Periodically
- Blood pressure: Regular monitoring
- Signs of hyperkalemia (muscle weakness, arrhythmias)
- For long-term use: monitor for gynecomastia, breast tenderness
Patient Education
- Take with food to enhance absorption
- Do not use potassium supplements or salt substitutes unless directed by healthcare provider
- Report signs of hyperkalemia (muscle weakness, irregular heartbeat)
- Report dizziness, especially when standing up
- Women should report menstrual irregularities or breast changes
- Regular blood tests are necessary during treatment
- Avoid excessive consumption of high-potassium foods
- Inform all healthcare providers about spironolactone use
- Do not stop medication abruptly without medical advice
References
1. FDA Prescribing Information: Aldactone (spironolactone) 2. Williams B, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104 3. Zannad F, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21 4. Yancy CW, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2017;70(6):776-803 5. Barbieri RL. Clinical practice. Gynecomastia. N Engl J Med. 2018;378(13):1249-1257 6. Lexicomp Online, Spironolactone monograph. Wolters Kluwer Clinical Drug Information, Inc 7. Micromedex Solutions. Spironolactone. Truven Health Analytics, Inc