Diuretics Acting on the Distal Nephron
The diuretics that act on the distal nephron include thiazide and thiazide-like diuretics (acting in the distal convoluted tubule) and potassium-sparing diuretics (acting in the collecting duct). 1
Thiazide and Thiazide-Like Diuretics (Distal Convoluted Tubule)
These agents inhibit sodium reabsorption in the early distal convoluted tubule:
- Chlorothiazide (initial dose 250-500 mg once or twice daily, maximum 1000 mg daily, duration 6-12 hours) 1
- Chlorthalidone (initial dose 12.5-25 mg once daily, maximum 100 mg daily, duration 24-72 hours) 1
- Hydrochlorothiazide (initial dose 25 mg once or twice daily, maximum 200 mg daily, duration 6-12 hours) 1, 2
- Indapamide (initial dose 2.5 mg once daily, maximum 5 mg daily, duration 36 hours) 1
- Metolazone (initial dose 2.5 mg once daily, maximum 20 mg daily, duration 12-24 hours) 1
Mechanism and Clinical Considerations
- Thiazides block sodium and chloride reabsorption in the distal tubule, increasing fractional sodium excretion to 5-10% of filtered load 1
- These agents tend to decrease free water clearance and lose effectiveness when creatinine clearance falls below 40 mL/min 1
- Important exception: Metolazone maintains efficacy even with impaired renal function, making it useful for combination therapy with loop diuretics in refractory edema 1
- Hydrochlorothiazide blocks sodium and chloride ion reabsorption, increasing sodium delivery to the distal tubule where it exchanges for potassium and hydrogen ions 2
Potassium-Sparing Diuretics (Collecting Duct)
These agents act in the late distal tubule and collecting duct:
- Spironolactone (aldosterone antagonist) 1
- Amiloride (epithelial sodium channel blocker) 3, 4
- Triamterene (epithelial sodium channel blocker) 4, 5
Mechanism and Clinical Considerations
- Amiloride exerts its potassium-sparing effect through inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule, and collecting duct 3
- This decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion 3
- Amiloride is not an aldosterone antagonist and its effects occur even in the absence of aldosterone 3
- These agents cause excretion of only 2-3% of filtered sodium, making them mildly potent diuretics 5
- Potassium-sparing diuretics are primarily used in combination with thiazide or loop diuretics to minimize potassium losses 1, 4
Clinical Pitfalls and Caveats
- Electrolyte monitoring is essential: Thiazides can cause excessive potassium, hydrogen, and chloride losses with continued use 2
- Renal function matters: Thiazides (except metolazone) lose efficacy with creatinine clearance <40 mL/min, whereas loop diuretics maintain efficacy unless renal function is severely impaired 1
- Combination therapy caution: Adding thiazides (especially metolazone) to loop diuretics should be reserved for patients unresponsive to moderate- or high-dose loop diuretics to minimize electrolyte abnormalities 1
- Hyperkalemia risk: When using potassium-sparing diuretics, routine potassium supplementation may be unnecessary and potentially dangerous 1