What are the potential side effects of spironolactone (aldosterone antagonist)?

Spironolactone Side Effects

Most Critical Side Effect: Hyperkalemia

Hyperkalemia is the most dangerous side effect of spironolactone, with population-based data showing hospitalizations for hyperkalemia increased from 2.4 to 11 per thousand patients after widespread adoption, and associated mortality rising from 0.3 to 2 per thousand. 1

Hyperkalemia Risk Profile and Monitoring

• Hyperkalemia occurs in 24% of patients in routine practice, with half having potassium levels exceeding 6 mEq/L 1
• Check potassium and renal function within 3 days of initiating spironolactone, then repeat at 1 week 2
• When potassium reaches 5.5 mmol/L, reduce the spironolactone dose by half; when it reaches 6.0 mmol/L, discontinue immediately 2
• The incidence in real-world practice is substantially higher than in controlled trials 2

High-Risk Populations for Hyperkalemia

• Elderly patients, particularly those with low muscle mass, require intensive monitoring 1
• Diabetic patients have significantly increased hyperkalemia risk 1
• Patients with baseline creatinine >1.6 mg/dL develop hyperkalemia more rapidly 2
• Avoid spironolactone when creatinine exceeds 2.5 mg/dL in men or 2.0 mg/dL in women, or when eGFR <30 mL/min/1.73 m² 1

Dangerous Drug Combinations That Precipitate Hyperkalemia

• Avoid combining spironolactone with ACE inhibitors and ARBs due to excessive hyperkalemia risk 1
• Do not use with potassium supplements or other potassium-sparing diuretics 1
• Avoid potent CYP3A4 inhibitors 1
• NSAIDs and COX-2 inhibitors can precipitate worsening renal function and hyperkalemia 1
• High-dose ACE inhibitors (captopril ≥75 mg/day; enalapril or lisinopril ≥10 mg/day) accelerate hyperkalemia development 2

Acute Situations Requiring Immediate Action

• Hyperkalemia can develop suddenly during dehydration, volume depletion from other diuretics, or when ACE inhibitors/ARBs are added or increased 2
• In these situations, temporarily discontinue spironolactone 2

Hormonal and Sexual Side Effects

Decreased Libido and Sexual Dysfunction

• Decreased libido is a frequent side effect due to spironolactone's potent anti-androgenic activity, which inhibits testosterone and dihydrotestosterone binding to androgen receptors 3
• The medication decreases testosterone production and potentially inhibits 5-alpha-reductase activity 3
• In men with cirrhosis and ascites, decreased libido is one of the most frequent side effects, occurring alongside impotence 3
• Sexual side effects include inability to achieve or maintain erection in men 4

Gynecomastia

• Gynecomastia occurs in 10% of patients overall 1
• The incidence is highly dose-dependent: 52.2% at doses ≥150 mg/day compared to 6.9% at 50 mg/day 3
• Men should be counseled about feminization risks including gynecomastia, breast discomfort, and decreased libido 1
• Breast and nipple pain can occur 4

Menstrual Irregularities

• Irregular menses or amenorrhea occur in women 4
• Postmenopausal bleeding has been reported 4
• Menstrual irregularities are prominent in women treated for acne 3

Dose-Dependent Management Strategy

• Start with the lowest effective dose to minimize anti-androgenic effects: 75-100 mg daily is as effective as 150-300 mg daily but with substantially fewer sexual side effects 3
• Consider eplerenone as an alternative, which has reduced affinity for androgen and progesterone receptors, resulting in decreased sexual side effects 3
• Potassium canrenoate may also reduce gynecomastia and have fewer sexual side effects 3

Gastrointestinal Side Effects

• Gastric bleeding, ulceration, and gastritis 4
• Diarrhea and cramping 4
• Nausea and vomiting 4
• Abdominal pain 5

Neurological and Psychiatric Side Effects

• Lethargy, mental confusion, and ataxia 4
• Dizziness and headache 4
• Drowsiness 4
• In patients with hepatic disease, cirrhosis, and ascites, spironolactone can cause sudden alterations of fluid and electrolyte balance that precipitate impaired neurological function, worsening hepatic encephalopathy, and coma 4

Hematologic Side Effects

• Leukopenia (including agranulocytosis) 4
• Thrombocytopenia 4

Hypersensitivity Reactions

• Fever and urticaria 4
• Maculopapular or erythematous cutaneous eruptions 4
• Anaphylactic reactions 4
• Vasculitis 4
• Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) 4

Metabolic and Electrolyte Abnormalities

• Hyponatremia and hypovolemia 4
• Electrolyte disturbances beyond hyperkalemia 4
• Two patients developed hyponatremia in one clinical cohort 5

Renal Side Effects

• Renal dysfunction including renal failure 4
• Worsening renal function, particularly in combination with NSAIDs 1
• Mean creatinine may increase during treatment (1.12 to 1.21 mg/dL in one study) 5
• Spironolactone is substantially excreted by the kidney, and the risk of adverse reactions is greater in patients with impaired renal function 4

Hepatic Side Effects

• Very rare cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality 4

Other Side Effects

• Leg cramps 4
• Alopecia and pruritus 4
• Hypotension 4

Special Population Considerations

Pregnancy

• Spironolactone may adversely affect sex differentiation of male fetuses during embryogenesis due to its anti-androgenic activity 4
• At 200 mg/kg/day in rats, feminization of male fetuses was observed 4
• Offspring exposed during late pregnancy exhibited changes in reproductive tract that persisted into adulthood 4

Lactation

• Canrenone (active metabolite) is present in breast milk in low amounts expected to be clinically inconsequential 4
• Long-term effects on breastfed infants are unknown 4

Geriatric Patients

• Elderly patients are more likely to have decreased renal function and require close monitoring 4
• The risk of adverse reactions is greater due to substantial renal excretion 4

Hepatic Impairment

• Initiate spironolactone in the hospital for patients with cirrhosis and ascites 4
• Start with the lowest initial dose and titrate slowly due to reduced clearance 4