Saidala 24: Spironolactone

Generic name: Spironolactone
Drug class: Aldosterone receptor antagonist (potassium-sparing diuretic)
Formulation: Oral tablets
Available strengths: 25 mg, 50 mg, 100 mg
Route of administration: Oral, once daily or divided dosing
Primary indications: Hypertension, heart failure, edema, primary hyperaldosteronism, resistant hypertension, certain dermatological and endocrine syndromes

Spironolactone is a potassium-sparing agent that antagonizes aldosterone receptors in the distal nephron, promoting natriuresis and retention of potassium. It reduces sodium and water reabsorption while conserving potassium and hydrogen ions. It also exerts anti‑androgenic effects by blocking androgen receptors and inhibiting 5α‑reductase.

2. Mechanism of Action

Spironolactone competitively binds to mineralocorticoid (aldosterone) receptors in renal collecting ducts, preventing aldosterone-induced transcription of sodium and water reabsorption channels. This results in increased sodium and water excretion and reduced potassium and hydrogen loss.

In addition, spironolactone exhibits anti‑androgenic activity by antagonizing androgen receptors and inhibiting the enzyme 5α‑reductase, reducing conversion of testosterone to dihydrotestosterone. These effects confer utility in hormonal conditions such as acne, hirsutism, and polycystic ovary syndrome (PCOS).

3. Pharmacokinetics

Absorption: Well absorbed orally; bioavailability ~60–75%.
Distribution: Widely distributed; begins active metabolites (canrenone, 7‑alpha‑thiomethylspirolactone) mediate much of therapeutic effect.
Metabolism: Extensively metabolized by the liver into active metabolites, primarily canrenone.
Half-life: Parent drug short (~1.4 hours); active metabolites have longer half-lives (~16 to 24 hours), supporting once-daily dosing in most indications.
Protein binding: High (88–96%).
Excretion: Excreted via urine and feces as metabolites; minimal unchanged drug in urine.

4. Therapeutic Indications

4.1 Heart Failure (NYHA Classes III–IV)

Used in combination with ACE inhibitors (or ARBs), beta-blockers, and loop diuretics in symptomatic patients to reduce morbidity and mortality from heart failure.

4.2 Hypertension

Adjunctive therapy in resistant hypertension, especially in patients with low-renin, volume-dependent hypertension, or primary aldosteronism.

4.3 Edematous States

Effective in edema associated with congestive heart failure, cirrhosis with ascites, nephrotic syndrome, and hypoproteinemic states such as hepatic cirrhosis.

4.4 Primary Hyperaldosteronism

Approved for treatment of bilateral adrenal hyperplasia in primary aldosteronism; optimizes potassium and blood pressure control.

4.5 Pharmacologic Uses in Endocrine/ Dermatologic Syndromes

Off-label: Hormone-sensitive acne, hirsutism, female pattern hair loss, polycystic ovary syndrome, in transgender hormone therapy—due to anti-androgen effects.

5. Dosage and Administration

5.1 Heart Failure

Typical dose: 25 mg once daily; may be increased to 50 mg once daily or 25 mg twice daily depending on response and renal function.

5.2 Hypertension / Resistant Hypertension

Initial dose: 25–50 mg once daily, often given at night; dose may increase up to 100 mg daily in divided doses for resistant cases.

5.3 Edema (Cirrhosis, Nephrotic Syndrome)

Dose range: 50–200 mg daily or split doses based on severity and renal status; combined with loop diuretics as needed.

5.4 Primary Hyperaldosteronism

Starting dose: 50 mg daily, titrated to achieve normokalemia and blood pressure control; may range between 100–200 mg daily depending on individual response.

5.5 Hormonal Indications (e.g. hirsutism/acne)

Common off-label doses: 50–100 mg once daily, typically initiated in the early follicular phase; combined with oral contraceptives in women of reproductive age.

Administration Notes

Administer with food to improve absorption.
Dose adjustment or monitoring is necessary in renal or hepatic impairment.
Monitor serum potassium, creatinine during initiation and at regular intervals.

6. Contraindications

Known hypersensitivity to spironolactone or its formulations.
Hyperkalemia or severe renal impairment (e.g., creatinine clearance <30 mL/min).
Addison’s disease or hypoaldosteronism.
Concurrent use with potassium-sparing drugs or supplements without monitoring.
In pregnancy: generally avoided due to anti-androgenic fetal effects—especially in male fetuses.

7. Warnings and Precautions

Hyperkalemia: Most significant risk; especially in renal impairment, diabetes, use of ACE inhibitors/ARBs, potassium supplementation, or NSAIDs.
Renal Dysfunction: Monitor closely; discontinuation may be required if creatinine rises or hyperkalemia develops.
Hypotension and volume depletion: Risk increases when combined with other diuretics or vasodilators.
Gynecomastia and sexual side effects: Occurs predominantly in males at higher doses; often reversible upon discontinuation.
Menstrual irregularities: May occur in women due to hormonal modulation.
Electrolyte disturbances: Hyponatremia or metabolic acidosis may occur in susceptible individuals.
Use during pregnancy/lactation: Avoid use in pregnancy due to risk of feminization of male fetus; minimal transfer into breast milk but typically avoided in breastfeeding.

8. Adverse Effects

Common

Elevated serum potassium (hyperkalemia)
Gastrointestinal upset: nausea, vomiting, diarrhea, abdominal cramps
Dizziness, headache
Breast tenderness or enlargement (especially in men)
Irregular menstruation or amenorrhea

Less Common

Gynecomastia (mostly reversible)
Impotence or decreased libido
Fatigue, lethargy
Rash or urticaria

Rare but Serious

Severe hyperkalemia potentially leading to cardiac arrhythmias
Metabolic acidosis in patients with cirrhosis or renal dysfunction
Acute kidney injury in volume‑depleted or hypotensive states
Interstitial nephritis or allergic reactions (rare)

9. Drug Interactions

ACE inhibitors or ARBs: Increase risk of hyperkalemia; concurrent use requires monitoring.
Direct renin inhibitors (e.g., aliskiren): Additive risk for hyperkalemia and renal insufficiency.
Potassium supplements or potassium-containing salt substitutes: Elevated risk of dangerous hyperkalemia.
NSAIDs: May reduce renal function and predispose to hyperkalemia.
Lithium: Risk of increased lithium levels due to reduced renal clearance; monitor levels and renal function.
Digoxin: Spironolactone may modestly increase digoxin concentrations; monitor clinical effects.
Other diuretics: Careful adjustment required to avoid electrolyte imbalance or hypotension.
Furosemide or thiazide co‑administration: May offset potassium retention but requires close monitoring to maintain electrolyte balance.

10. Use in Special Populations

Elderly

Increased risk of hyperkalemia and renal impairment; start at lower doses, monitor electrolytes and renal function more frequently.

Pediatrics

Used for conditions such as congenital adrenal hyperplasia or heart failure in children; dosing ~1–3 mg/kg/day divided as needed.

Pregnancy & Lactation

Pregnancy: generally avoided due to anti-androgenic effects on male fetus; consider other agents for heart failure or hypertension.
Lactation: minimal levels in breast milk; use only if benefits outweigh potential risks.

Renal Impairment

Contraindicated in severe renal dysfunction. Use with caution and lower dose in moderate impairment; frequent potassium and creatinine monitoring required.

Hepatic Impairment

Eliminated via hepatic metabolism; use in advanced liver disease (e.g. cirrhosis) elevates risk of metabolic acidosis, hyperkalemia, and renal dysfunction; dose reduction and close monitoring essential.

11. Monitoring Parameters

Serum potassium and creatinine: Baseline, within first week, then periodically (monthly initially, then every 3–6 months); more frequent in high-risk individuals.
Blood pressure and weight: Monitor for efficacy in heart failure or hypertension.
Electrolytes (sodium, bicarbonate): Particularly in cirrhosis with ascites or metabolic alkalosis.
Liver function tests: Periodically for high-dose or prolonged use in hepatic impairment.
Menstrual cycle and breast examination: In women and in male patients for signs of gynecomastia.
ECG monitoring: If hyperkalemia suspected or arrhythmogenic electrolyte disturbances present.

12. Overdose and Toxicity Management

Symptoms

Severe hypotension or dehydration
Profound hyperkalemia
Confusion, dizziness
Gastrointestinal upset

Management Strategies

Discontinue spironolactone and any potassium sources
Provide intravenous fluids and supportive care for hypotension
Treat hyperkalemia using standard protocols (e.g. calcium, insulin/glucose, sodium bicarbonate, oral potassium binders)
Monitor ECG for arrhythmias
In severe hyperkalemia, consider dialysis

13. Clinical Considerations

Spironolactone is unique among diuretics for its combined diuretic and endocrine effects, offering substantial benefit in heart failure, resistant hypertension, cirrhotic ascites, and primary hyperaldosteronism.
Its anti‑androgenic activity confers benefit in certain endocrine and dermatologic syndromes, though at the cost of hormonal side effects.
Long-term use requires vigilance regarding serum potassium, renal and hepatic function, and endocrine alterations.
Combining spironolactone with other renin–angiotensin system blockers offers additive benefits in select cardiovascular conditions—but requires close electrolyte and renal monitoring.
Patient education is critical: avoid potassium-rich substitutes or supplements, report symptoms of weakness or irregular heartbeat, and attend regular lab checks for safety and dose adjustment.

Saidala 24

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Monday, July 28, 2025

Spironolactone