STEPTRACKERPHARMACOLOGY + RENAL PHYSIOLOGY | RENAL | HIGH-YIELD REVIEW

Diuretics

Each diuretic blocks one transporter at one nephron segment — the segment predicts how strong it is and what it does to potassium, calcium, magnesium and acid-base.

FOCUS ON

Carbonic anhydrase inhibitors (acetazolamide) — PCT: ↓ HCO₃⁻ reabsorption → metabolic acidosis; glaucoma, altitude sickness, idiopathic intracranial hypertension, metabolic alkalosis. Osmotic (mannitol) — PCT/descending limb: ↓ ICP and IOP; risk pulmonary edema in HF. Loop (furosemide, bumetanide, torsemide; ethacrynic acid = non-sulfa) — NKCC2 in thick ascending limb: most potent; ↑ Ca²⁺ excretion (hypercalcemia); ototoxicity, ↓ K⁺, ↓ Mg²⁺, contraction alkalosis, gout, sulfa allergy, NSAIDs blunt effect. Thiazides (HCTZ, chlorthalidone, metolazone) — NCC in DCT: ↓ Ca²⁺ excretion (stones, osteoporosis), nephrogenic DI; ↓ K⁺, ↓ Na⁺, ↑ glucose, lipids, uric acid, Ca²⁺. K⁺-sparing — collecting duct: spironolactone, eplerenone (aldosterone receptor), amiloride, triamterene (ENaC) → hyperkalemia, metabolic acidosis; amiloride for lithium-induced DI. Vaptans (V2 antagonists) → SIADH.

CLASS · SITE

MECHANISM

USES

ADVERSE · LYTES

Acetazolamide

PCT

Carbonic anhydrase inhibition → HCO₃⁻, Na⁺ lost in urine

Glaucoma, mountain sickness, pseudotumor cerebri, metabolic alkalosis

Hyperchloremic metabolic acidosis, ↓ K⁺, calcium phosphate stones, paresthesias, sulfa

Mannitol

PCT, thin descending limb

Filtered, not reabsorbed → holds water in tubule

↑ ICP, acute glaucoma

Pulmonary edema (expands ECF first), dehydration, hypernatremia; avoid anuria, HF

Loop diuretics

thick ascending limb

Block NKCC2 → loses medullary gradient; ↑ PGE2 dilates afferent

Edema (HF, cirrhosis, nephrotic), pulmonary edema, hypercalcemia, hyperkalemia

Ototoxicity, ↓ K⁺, ↓ Mg²⁺, ↓ Ca²⁺, alkalosis, gout, interstitial nephritis

Ethacrynic acid

Loop diuretic, not a sulfonamide

Sulfa-allergic patients

Most ototoxic; hyperuricemia

Thiazides

DCT

Block Na⁺/Cl⁻ cotransporter → ↑ Ca²⁺ reabsorption

HTN, mild HF, calcium nephrolithiasis, osteoporosis, nephrogenic DI

↓ K⁺, ↓ Na⁺, ↓ Mg²⁺, alkalosis, ↑ glucose, lipids, uric acid, Ca²⁺; sulfa; pancreatitis

Spironolactone · eplerenone

collecting duct

Aldosterone receptor antagonists

Hyperaldosteronism, HFrEF, cirrhotic ascites, resistant HTN, hirsutism (spironolactone)

↑ K⁺, acidosis; spironolactone antiandrogen → gynecomastia

Amiloride · triamterene

collecting duct

Block ENaC

K⁺-sparing add-on, Liddle syndrome, lithium nephrogenic DI (amiloride)

↑ K⁺; triamterene kidney stones

Tolvaptan · conivaptan

collecting duct

V2 receptor antagonist → aquaresis

SIADH, euvolemic/hypervolemic hyponatremia, ADPKD (tolvaptan)

Too-rapid Na⁺ rise → osmotic demyelination; hepatotoxicity

Urine Na⁺ / K⁺ pattern

Loop, thiazide: ↑ Na⁺, ↑ K⁺ loss · K⁺-sparing: ↑ Na⁺, ↓ K⁺ loss

—

Distal Na⁺ delivery drives K⁺ secretion

Calcium handling

Loops ↑ urinary Ca²⁺ · thiazides ↓ urinary Ca²⁺

—

Loops treat hypercalcemia; thiazides prevent stones

Acid-base

Acidosis: acetazolamide, K⁺-sparing · Alkalosis: loop, thiazide

—

Alkalosis from volume contraction + ↑ H⁺ secretion

Drug interactions

Loops + aminoglycosides → ototoxicity · thiazides/loops + lithium → ↑ lithium · NSAIDs blunt loops

—

Hypokalemia ↑ digoxin toxicity

Picture it — where each diuretic acts

Diuretic sites along the nephron1 Acetazolamide blocks carbonic anhydrase in the proximal tubule. 2 Mannitol holds water in the tubule where it is most permeable. 3 Loop diuretics block NKCC2 in the thick ascending limb (most potent). 4 Thiazides block NCC in the distal convoluted tubule. 5 Potassium-sparing drugs block ENaC or the aldosterone receptor in the collecting duct. 6 Vaptans block ADH (V2) receptors.

Schematic diagrams, not to scale.

Mechanism — why diuretics cause hypokalemic alkalosis

More Na⁺ reaches collecting duct

→

Volume loss → ↑ aldosterone

→

ENaC pulls Na⁺ inLumen more negative

→

K⁺ and H⁺ secreted↓ K⁺, metabolic alkalosis

Electrolyte summary

CLASS

K⁺

Ca²⁺ (urine)

Acetazolamide

↓

—

Acidosis

Loop

↓

↑

Alkalosis

Thiazide

↓

Alkalosis

K⁺-sparing

↑

—

Acidosis

How it's tested

COMMON CONFUSIONLoops "lose calcium" and are used for hypercalcemia; thiazides "keep calcium" and help recurrent calcium stones and osteoporosis.

THE TRAPThiazides paradoxically treat nephrogenic DI: mild volume contraction ↑ proximal reabsorption so less water reaches the collecting duct.

YOUR APPROACHName the segment → transporter → potency → K⁺, Ca²⁺, Mg²⁺, pH changes → special toxicity.

If you see… think…

Hearing loss on IV diuretic plus gentamicin → loop ototoxicity

Diuretic for a patient with sulfa allergy → ethacrynic acid

Diuretic for altitude sickness → acetazolamide

Raised ICP, need rapid osmotic effect → mannitol

Recurrent calcium stones with hypercalciuria → thiazide

Gynecomastia on a diuretic → spironolactone

Lithium-induced nephrogenic DI → amiloride

Hyperglycemia, gout, ↑ Ca²⁺ on BP drug → thiazide

Hyponatremia from SIADH, oral drug → tolvaptan

Hyperkalemia + metabolic acidosis on a diuretic → K⁺-sparing diuretic