Diuretics & Renal Pharmacology

Mapping diuretics to the nephron

The transporter predicts the toxicity. Each diuretic class is defined by the transporter it blocks, and that transporter predicts its potency and its electrolyte and acid-base side effects. The proximal tubule reclaims about two-thirds of filtered sodium, but downstream segments compensate, so proximal agents are weak diuretics. The thick ascending limb reclaims roughly a quarter with little downstream rescue, which makes loops the most potent. The collecting duct handles only a few percent, so potassium-sparing agents are valued for their potassium and hormonal effects more than for diuresis.

Proximal agents: acetazolamide and mannitol

Acetazolamide. Inhibits carbonic anhydrase in the proximal tubule, so filtered bicarbonate cannot be reclaimed and NaHCO₃ is lost in the urine. The diuresis is self-limited: as serum bicarbonate falls, less is filtered. The result is a hyperchloremic (normal-anion-gap) metabolic acidosis ("ACIDazolamide") with hypokalemia from increased distal sodium delivery.

• Uses: glaucoma (less aqueous humor), altitude sickness (the acidosis stimulates ventilation), idiopathic intracranial hypertension (less CSF), metabolic alkalosis, urinary alkalinization.
• Toxicity: paresthesias, sulfa allergy, calcium phosphate stones (alkaline urine), hypokalemia, and hyperammonemia in cirrhosis.

Mannitol. An osmotic diuretic that is freely filtered and not reabsorbed, so it raises tubular fluid osmolarity and holds water in the proximal tubule and thin descending limb. Uses: elevated intracranial pressure, acute glaucoma, and increasing urine flow. It first pulls water out of cells into the extracellular space, expanding plasma volume before any diuresis, so it is contraindicated in heart failure/pulmonary edema. In anuria it cannot be excreted, stays intravascular, and can precipitate pulmonary edema. Excess free-water loss can also cause hypernatremia.

Loops and thiazides

Loop diuretics. Furosemide, bumetanide, and torsemide inhibit the Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb and are the most efficacious ("high-ceiling") diuretics. K⁺ recycling through ROMK normally creates a lumen-positive potential that drives paracellular Ca²⁺ and Mg²⁺ reabsorption; loops abolish it, so calcium and magnesium excretion INCREASE. Blocking NKCC2 also dissipates the medullary gradient, impairing urine concentration. Loops work partly through renal prostaglandins, so NSAIDs blunt them. Uses: pulmonary edema, heart failure, edematous states, and hypercalcemia (after saline repletion). Ethacrynic acid is the non-sulfa loop.

Loop toxicity "OH DANG": Ototoxicity, Hypokalemia/Hypomagnesemia, Dehydration, Allergy (sulfa), Nephritis (interstitial), Gout.

Thiazides. Hydrochlorothiazide and chlorthalidone block the Na-Cl cotransporter (NCC) in the early distal convoluted tubule. Lower intracellular Na⁺ enhances basolateral Na⁺/Ca²⁺ exchange, so more calcium is reabsorbed and calcium excretion DECREASES, which helps prevent calcium stones and osteoporosis. Uses: hypertension (first-line), heart failure, idiopathic hypercalciuria, and nephrogenic DI (mild volume contraction boosts proximal reabsorption, so less water reaches the collecting duct). Toxicity "hyperGLUC": hyperGlycemia, hyperLipidemia, hyperUricemia, hyperCalcemia, plus hypokalemia and hyponatremia. Thiazides are the classic diuretic cause of hyponatremia because they impair urine dilution while leaving the concentrating gradient intact.

Collecting duct: potassium-sparing agents and ADH antagonists

Mineralocorticoid receptor antagonists. Spironolactone and eplerenone block aldosterone's receptor in principal cells of the cortical collecting duct. Uses: hyperaldosteronism (Conn syndrome), heart failure (both reduce mortality), and cirrhotic ascites, which is driven by secondary hyperaldosteronism. Spironolactone also blocks androgen receptors and causes gynecomastia; eplerenone is more selective and does not.

ENaC blockers. Amiloride and triamterene directly block the epithelial sodium channel (ENaC) in the cortical collecting duct. Amiloride also treats lithium-induced nephrogenic DI, because lithium enters principal cells through ENaC.

Shared toxicity. All potassium-sparing agents reduce K⁺ and H⁺ secretion, causing hyperkalemia and metabolic acidosis; the risk rises with ACE inhibitors, ARBs, CKD, or potassium supplements.

ADH antagonists. Conivaptan (IV) and tolvaptan (oral) block the V2 receptor in the collecting duct, preventing aquaporin-2 insertion and causing aquaresis, the excretion of free water. They treat SIADH and hyponatremia; sodium must be corrected slowly to avoid osmotic demyelination. Tolvaptan also slows cyst growth in ADPKD. Demeclocycline, a tetracycline, antagonizes ADH action at the tubule and is an older alternative.

RAAS blockers and SGLT2 inhibitors

ACE inhibitors and ARBs. ACE inhibitors (-pril) lower angiotensin II and aldosterone, and renin rises from lost feedback. ACE also degrades bradykinin, so bradykinin accumulates and causes dry cough and angioedema. ARBs (-sartan) block the AT₁ receptor downstream and spare bradykinin, so there is no cough.

Renal hemodynamics. Angiotensin II preferentially constricts the efferent arteriole. Both classes dilate the EFFERENT arteriole, lowering intraglomerular pressure and proteinuria, which makes them renoprotective in diabetic and proteinuric CKD. Expect hyperkalemia and a small creatinine rise. They are contraindicated in bilateral renal artery stenosis, where GFR depends on efferent tone and collapses, and in pregnancy (teratogenic).

SGLT2 inhibitors (-flozin). Empagliflozin and related drugs block sodium-glucose cotransport in the proximal tubule, producing glucosuria and natriuresis. The extra sodium reaching the macula densa triggers afferent vasoconstriction by tubuloglomerular feedback, which also lowers intraglomerular pressure. They benefit type 2 diabetes, heart failure, and CKD.

SGLT2 inhibitors can cause euglycemic diabetic ketoacidosis, which is easily missed because glucose is near normal. Sugar in the urine also feeds genital yeast and bacteria, hence genital and urinary infections.

Potassium, acid-base, and sulfa at a glance

The logic. Upstream bicarbonate loss (acetazolamide) produces metabolic acidosis with hypokalemia. Loops and thiazides produce hypokalemic contraction metabolic alkalosis: more sodium delivered to the collecting duct drives K⁺ and H⁺ secretion, while volume contraction raises angiotensin II and aldosterone. Blocking aldosterone or ENaC does the reverse and produces hyperkalemic acidosis.

Sulfa-containing diuretics (acetazolamide, loops, thiazides) can cross-react in sulfa allergy; ethacrynic acid replaces a loop in true sulfa allergy.