Major Diuretic Classes and Agents
Loop Diuretics
Loop diuretics are the most potent diuretics, acting on the thick ascending limb of the loop of Henle by inhibiting the Na⁺-K⁺-2Cl⁻ cotransporter, resulting in excretion of 20-25% of filtered sodium. 1, 2, 3
Major agents:
- Furosemide – 20-80 mg orally once to twice daily (maximum 600 mg/day outpatient; 200 mg/dose inpatient IV) 1, 2
- Bumetanide – 0.5-2 mg orally once to twice daily (maximum 10 mg/day outpatient; 5 mg/dose inpatient IV) 1, 2
- Torsemide – 10-40 mg orally once daily (maximum 200 mg/day outpatient; no IV formulation available in US) 1, 2
Key characteristics:
- Duration of action: Bumetanide 4-6 hours, Furosemide 6-8 hours, Torsemide 12-16 hours 1, 2, 4
- Bumetanide has more predictable oral bioavailability than furosemide, particularly useful when gut edema impairs absorption 4
- Standard conversion: 1 mg bumetanide ≈ 40 mg furosemide 4
Thiazide and Thiazide-Type Diuretics
Thiazide-type diuretics act on the early distal convoluted tubule by inhibiting the Na⁺-Cl⁻ cotransporter, producing moderate diuresis with excretion of 5-10% of filtered sodium. 5, 2, 3
Major agents:
- Hydrochlorothiazide (HCTZ) – 25-50 mg orally once daily (maximum 100 mg/day) 1, 2, 6
- Chlorthalidone – 12.5-25 mg orally once daily (maximum 100 mg/day) 1, 2, 6
- Metolazone – 2.5-5 mg orally once daily (maximum 20 mg/day) 1, 2
- Indapamide – 2.5 mg orally once daily (maximum 5 mg/day) 2, 6
- Chlorothiazide – 250-500 mg IV once to twice daily (maximum 2 g/day inpatient) 1, 2
Key characteristics:
- Duration of action: HCTZ 6-12 hours, Chlorthalidone 24-72 hours, Indapamide 36 hours, Metolazone 12-24 hours 2
- Chlorthalidone is preferred over HCTZ based on longer half-life and proven CVD reduction in trials 1, 6
- Lose effectiveness when GFR <30 mL/min, except when used synergistically with loop diuretics 5, 7
Potassium-Sparing Diuretics
Potassium-sparing diuretics act on the late distal tubule and collecting duct, producing mild diuresis with excretion of only 2-3% of filtered sodium while conserving potassium. 5, 3, 8
Aldosterone Antagonists (Mineralocorticoid Receptor Antagonists)
- Spironolactone – 25-100 mg orally once daily (maximum 100-200 mg/day) 5, 2, 6
- Eplerenone – 50-100 mg orally once to twice daily 6
Epithelial Sodium Channel Blockers
- Amiloride – 5-10 mg orally once to twice daily (maximum 20-40 mg/day) 5, 6
- Triamterene – 50-100 mg orally once to twice daily (maximum 100-200 mg/day) 5, 6
Key characteristics:
- Should only be used if hypokalemia persists despite ACE inhibitor therapy and loop/thiazide diuretics 5, 7
- Risk of hyperkalemia, especially when combined with ACE inhibitors, ARBs, or in patients with CKD 9, 2, 6
- Spironolactone causes gynecomastia more frequently than eplerenone 6
Carbonic Anhydrase Inhibitors
Carbonic anhydrase inhibitors act primarily on the proximal tubule by inhibiting carbonic anhydrase, producing weak diuresis with increased bicarbonate excretion. 3, 8
Major agent:
Key characteristics:
- May be helpful as adjunctive therapy for diuretic-resistant edema and metabolic alkalosis 9
- Causes metabolic acidosis due to bicarbonate loss 8
Common Adverse Effects by Class
Loop and thiazide diuretics: Hypokalemia, hypomagnesemia, hyponatremia, hyperuricemia, glucose intolerance, acid-base disturbances 1, 5, 2
Potassium-sparing diuretics: Hyperkalemia (especially with concurrent ACE inhibitor/ARB use or CKD), rash, gynecomastia (spironolactone) 5, 9, 6
All diuretics: Volume depletion, impaired GFR (transient creatinine elevation during effective decongestion is expected and not associated with worse outcomes) 1, 9, 2
Clinical Pearls for Combination Therapy
For refractory edema unresponsive to loop diuretics alone, add a thiazide-type diuretic (metolazone or chlorothiazide) for synergistic effect rather than increasing loop diuretic dose. 1, 5, 2
This combination should be reserved for patients not responding to moderate- or high-dose loop diuretics to minimize electrolyte abnormalities, with frequent monitoring of creatinine and electrolytes required. 5, 2