Diuretics: A Comprehensive Educational Reference

Sites of Diuretic Action Along the Nephron

Nephron diagram showing sites of action for carbonic anhydrase inhibitors, SGLT2 inhibitors, osmotic agents, loop diuretics, thiazides, ENaC blockers, mineralocorticoid receptor antagonists, and vaptans.

Proximal tubule: about 65% of filtered sodium reabsorbed.

Thick ascending limb: about 25% of filtered sodium reabsorbed.

Distal tubule: about 5-8% of filtered sodium reabsorbed.

Collecting duct: about 2-3% of filtered sodium reabsorbed.

Descending limb: water permeable; minimal sodium reabsorption.

Class	Drug examples	Site of action	Mechanism	Potency	Primary clinical indications	Key adverse effects
Carbonic anhydrase inhibitors	Acetazolamide	Proximal convoluted tubule	Inhibits carbonic anhydrase, decreasing bicarbonate reabsorption and increasing sodium, potassium, and bicarbonate excretion; alkalinizes urine.	Weak, about 5% filtered sodium	Glaucoma Acute mountain sickness Metabolic alkalosis Idiopathic intracranial hypertension Adjunctive epilepsy therapy	Non-anion-gap metabolic acidosis Hypokalemia Hyponatremia Paresthesias
Osmotic diuretics	Mannitol	Proximal tubule and descending limb of loop of Henle	Increases intratubular osmotic pressure, decreasing water and sodium reabsorption and enhancing free water excretion.	Variable	Cerebral edema or increased intracranial pressure Acute glaucoma Selected AKI prevention contexts Rhabdomyolysis protocols	Initial volume expansion Hyponatremia or hypernatremia Pulmonary edema in heart failure Rebound intracranial pressure
Loop diuretics	Furosemide, bumetanide, torsemide, ethacrynic acid	Thick ascending limb of loop of Henle	Inhibits luminal NKCC2 sodium-potassium-2 chloride cotransporter, reducing sodium, potassium, and chloride reabsorption; impairs urinary concentrating ability and increases calcium and magnesium excretion.	High, about 20-25% filtered sodium	Heart failure with volume overload Pulmonary edema Nephrotic syndrome edema Acute hypercalcemia CKD-associated edema	Hypokalemia Hypomagnesemia Hypocalcemia Metabolic alkalosis Ototoxicity Hyperuricemia
Thiazide and thiazide-like diuretics	Hydrochlorothiazide, chlorthalidone, metolazone, indapamide	Early distal convoluted tubule	Inhibits NCC sodium-chloride cotransporter, reducing sodium and chloride reabsorption and decreasing urinary calcium excretion.	Moderate, about 5-8% filtered sodium	Hypertension Mild heart failure edema Calcium stone prevention Nephrogenic diabetes insipidus Sequential nephron blockade	Hyponatremia Hypokalemia Hypomagnesemia Hypercalcemia Hyperuricemia Glucose intolerance
Potassium-sparing ENaC inhibitors	Amiloride, triamterene	Collecting tubule principal cells	Blocks epithelial sodium channel ENaC, decreasing sodium reabsorption and reducing potassium and hydrogen secretion.	Weak, about 2-3% filtered sodium	Adjunct to prevent potassium loss Liddle syndrome, especially amiloride Lithium-induced nephrogenic diabetes insipidus	Hyperkalemia Metabolic acidosis
Potassium-sparing mineralocorticoid receptor antagonists	Spironolactone, eplerenone, finerenone	Collecting tubule principal cells	Blocks the mineralocorticoid receptor, decreasing ENaC and sodium-potassium ATPase expression; reduces sodium reabsorption and potassium secretion.	Weak, about 2-3% filtered sodium	HFrEF mortality benefit Resistant hypertension Primary hyperaldosteronism Cirrhosis with ascites CKD with type 2 diabetes, especially finerenone	Hyperkalemia Gynecomastia with spironolactone Menstrual irregularities
Vasopressin receptor antagonists	Tolvaptan, conivaptan	Collecting duct	Blocks V2 receptor signaling, decreasing aquaporin-2 insertion and reducing water reabsorption; causes aquaresis without natriuresis.	Not a natriuretic potency class	Euvolemic or hypervolemic hyponatremia SIADH in selected patients Autosomal dominant polycystic kidney disease, tolvaptan	Overly rapid sodium correction risk Thirst and polyuria Hepatotoxicity risk with tolvaptan
SGLT2 inhibitors	Empagliflozin, dapagliflozin, canagliflozin	Proximal convoluted tubule	Inhibits SGLT2, reducing glucose and sodium reabsorption; produces osmotic diuresis with mild, often transient natriuresis.	Mild to moderate, often transient	Heart failure with reduced or preserved ejection fraction Chronic kidney disease Type 2 diabetes with cardiovascular disease May augment loop diuresis	Genital mycotic infections Urinary tract infections Rare euglycemic ketoacidosis Volume depletion

Key Teaching Points

Potency correlates with site of action

The thick ascending limb reabsorbs about 25% of filtered sodium, making loop diuretics the most potent class. Thiazides act later at the distal convoluted tubule, and potassium-sparing agents act still later in the collecting duct.

Sequential nephron blockade

Combining a loop diuretic with a thiazide-type agent blocks sodium reabsorption at multiple nephron segments and can overcome compensatory downstream sodium uptake in diuretic resistance.

Electrolyte effects are predictable

Loop and thiazide diuretics can cause hypokalemia and metabolic alkalosis through enhanced distal sodium delivery. Thiazides are a classic cause of hyponatremia because they impair urinary dilution.

SGLT2 inhibitors are not classical diuretics

SGLT2 inhibitors cause glycosuria-associated osmotic diuresis and mild natriuresis, but their kidney and heart benefits extend beyond simple volume removal.

Calcium handling is high-yield

Thiazides decrease urinary calcium excretion and can help prevent calcium stones. Loop diuretics increase calcium excretion and can be useful in acute hypercalcemia.

Quick Comparison: Loop vs. Thiazide Diuretics

Feature	Loop diuretics	Thiazide diuretics
Potency	High, about 20-25% filtered sodium	Moderate, about 5-8% filtered sodium
Target	NKCC2 in thick ascending limb	NCC in distal convoluted tubule
Calcium effect	Increases calcium excretion	Decreases calcium excretion
Urine dilution/concentration	Impairs concentration and dilution	Impairs dilution more than concentration
Hyponatremia risk	Lower than thiazides in many settings	Higher; common drug cause of hyponatremia
Primary hypertension use	Usually for edema or reduced GFR contexts	Common first-line antihypertensive class
Edema management	First-line for significant edema	Mild edema or adjunctive sequential blockade

Selected References

Ernst ME, Moser M. Use of diuretics in patients with hypertension. New England Journal of Medicine. 2009;361(22):2153-2164.
Brater DC. Diuretic therapy. New England Journal of Medicine. 1998;339(6):387-395.