Loop Diuretics and Thiazides
Mechanisms, Electrolyte Consequences, and Clinical Applications
Nephron Targets by Diuretic Class
| Segment |
% Na Reabsorbed |
Transporter |
Diuretic Class |
| Proximal convoluted tubule |
~65% |
Na-H exchanger isoform 3 + carbonic anhydrase |
Carbonic anhydrase inhibitors |
| Thick ascending limb |
~25% |
Na-K-2Cl cotransporter (NKCC2) |
Loop diuretics |
| Distal convoluted tubule |
~7% |
Na-Cl cotransporter (NCC) |
Thiazides |
| Collecting duct |
~2% |
Epithelial sodium channel (ENaC) |
Potassium-sparing diuretics |
Calcium Effects — Opposite Between Classes
| Feature |
Loop Diuretics |
Thiazides |
| Mechanism |
Abolish lumen-positive potential in thick ascending limb — impair paracellular Ca reabsorption |
Lower intracellular Na in distal convoluted tubule — enhance TRPV5-mediated Ca entry |
| Calcium effect |
Calciuresis (urinary Ca loss) |
Calcium retention (hypocalciuria) |
| Use |
Hypercalcemia management |
Calcium nephrolithiasis prevention |
| Contraindication |
Calcium nephrolithiasis |
Hypercalcemia |
Electrolyte Complications
Both Loop Diuretics and Thiazides
- Hypokalemia — increased collecting duct Na delivery drives K secretion; thiazides via secondary aldosteronism
- Hypomagnesemia — blocks paracellular Mg reabsorption (loop) or TRPM6 (thiazide)
- Metabolic alkalosis — NHE3 upregulation, hypokalemia, secondary aldosteronism
- Hyperuricemia — compete with urate at organic anion transporters in proximal tubule
- Hyponatremia — thiazide-specific; impairs dilution without impairing concentration
Clinical Applications
By Drug Class
- Loop diuretics — acute heart failure (IV furosemide), acute hypercalcemia (after IV saline)
- Chlorthalidone — preferred thiazide for hypertension (ALLHAT data)
- Thiazides — calcium nephrolithiasis prevention (reduce urinary Ca 30–50%)
- Metolazone — add-on to loop diuretics in diuretic resistance (works at low GFR)
- DOSE trial — high-dose IV furosemide (2.5x oral dose) superior in acute heart failure
Refractory Hypokalemia Rule
When potassium supplementation fails to correct hypokalemia, check and replete magnesium first. Magnesium depletion prevents suppression of collecting duct potassium secretion — the channel stays open regardless of potassium replacement. Correct the magnesium deficit, and potassium levels will respond.