Diuretics — Walk the Nephron

1️⃣

Proximal Convoluted Tubule

Carbonic Anhydrase Inhibitors

The PCT is where the nephron does its bulk work — 65-80% of filtered Na+, water, and bicarb get reabsorbed here. It's the Amazon warehouse of the kidney. Huge volume, not very selective.

The enzyme doing the heavy lifting is carbonic anhydraseCarbonic anhydrase converts CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-. In the PCT, this reaction lets the tubule reabsorb filtered bicarb by converting it to CO2 (which crosses membranes freely), then converting it back inside the cell. Block the enzyme → bicarb stays in the urine → metabolic acidosis.. Block it, and bicarb can't be reabsorbed. It stays in the tubule, drags Na+ and water with it.

The Drug
Acetazolamide — blocks carbonic anhydrase in the PCT. Causes a non-anion-gap metabolic acidosis (bicarb wasting) and alkaline urine. 🔑 Acetazolamide → Acidosis. The A's match. And alkaline urine (paradox: losing base makes you acidotic but the urine is basic because that's where the bicarb went).

Clinical uses: Glaucoma (decreases aqueous humor production), altitude sickness (forces bicarb diuresis → compensatory hyperventilation), pseudotumor cerebriIdiopathic intracranial hypertension. Acetazolamide decreases CSF production by the choroid plexus (which also uses carbonic anhydrase). Same enzyme, different address..

Side effects: Metabolic acidosis, hypokalemia (bicarb wasting drags K+ with it), calcium phosphate kidney stones (alkaline urine precipitates calcium phosphate instead of the usual calcium oxalate).

Board Trap
"Patient on acetazolamide develops kidney stones — what type?" The answer is calcium phosphate, NOT calcium oxalate. The alkaline urine shifts the stone composition. Boards love this because everyone defaults to oxalate.

Before we move on — what happens to urine pH when you give acetazolamide?

2️⃣

Thick Ascending Limb

Loop Diuretics

The TAL is the powerhouse of the nephron's concentrating ability. It reabsorbs ~25% of filtered Na+ via the Na-K-2Cl cotransporter (NKCC2)One Na+, one K+, two Cl- ions cross together from tubular lumen into the cell. This generates the medullary concentration gradient that lets the collecting duct concentrate urine with ADH. Block NKCC2 → lose the gradient → massive diuresis.. This is also where the kidney builds the medullary concentration gradient that lets you concentrate urine later.

Block NKCC2 and you lose the gradient entirely. That's why loop diuretics are the most powerful diuretics — they don't just block Na+ reabsorption, they destroy the kidney's ability to concentrate.

The Drugs
Furosemide (Lasix), bumetanide, torsemide, ethacrynic acid. All block NKCC2 in the TAL. 🔑 Loops lose Lots. They're the big guns. Also: Lasix = Lasts 6 hours. Bumetanide is 40x more potent dose-for-dose.

The electrolyte carnage:

Lost	Why
Na+	Direct — NKCC2 is blocked
K+	More Na+ in distal tubule → more Na/K exchange → K+ wasting
Ca2+	Paracellular Ca2+ reabsorption depends on the lumen-positive voltage from K+ recycling. Block NKCC2 → lose the voltage → Ca2+ stays in urine
Mg2+	Same paracellular mechanism as calcium

Clinical uses: Acute pulmonary edema (IV furosemide is first-line — works in minutes), CHF volume overload, hypercalcemia (loops waste calcium), acute kidney injury (maintain urine output).

Board Trap
Loops waste calcium. Thiazides save calcium. This is the #1 tested diuretic comparison on boards. Patient with hypercalcemia? Loop diuretic. Patient with osteoporosis + HTN? Thiazide. The TAL and DCT do opposite things to calcium. If you remember nothing else, remember this.

Ethacrynic acid is the oddball — it's the only loop diuretic that is not a sulfonamide. Use it when the patient has a sulfa allergyFurosemide, bumetanide, and torsemide are all sulfonamide derivatives. Ethacrynic acid is a phenoxyacetic acid — structurally unrelated. Safe in sulfa allergy, but more ototoxic than the others.. Tradeoff: higher risk of ototoxicity.

Ototoxicity
All loop diuretics can cause hearing loss (usually reversible). Risk increases with IV dosing, renal failure, and aminoglycosides (the combo is especially dangerous). Ethacrynic acid is the worst offender.

A patient has severe hypercalcemia. Which diuretic do you reach for?

3️⃣

Distal Convoluted Tubule

Thiazide Diuretics

The DCT reabsorbs only ~5% of filtered Na+ via the Na-Cl cotransporter (NCC)Simpler than NKCC2 — just Na+ and Cl-. No K+, no complex voltage games. Blocking NCC is a gentler diuresis than blocking NKCC2, which is why thiazides are maintenance drugs and loops are rescue drugs.. Less Na+ reabsorption means thiazides are weaker than loops. But they shine in chronic management.

The Drugs
Hydrochlorothiazide (HCTZ), chlorthalidone (longer-acting, preferred for HTN), metolazone (works even in low GFR — synergy with loops).

The calcium twist: Thiazides increase calcium reabsorption in the DCT. Opposite of loops. Mechanism: blocking NCC → less intracellular Na+ → Na/Ca exchanger on basolateral side works harder → more Ca2+ pulled from tubule into blood.

The Golden Comparison
Loops lose calcium. Thiazides save calcium.
Hypercalcemia → loop. Osteoporosis → thiazide. Kidney stones (calcium) → thiazide (less Ca2+ in urine = fewer stones).

Side effects (the HYPER-hypo pattern):

Effect	Direction	Why It Matters
Hypokalemia	↓	Same mechanism as loops — more distal Na → more K wasting
Hyponatremia	↓	Thiazides are the #1 drug cause of hyponatremia in the elderly
Hypercalcemia	↑	Ca2+ reabsorption increased (the whole point sometimes)
Hyperglycemia	↑	K+ depletion impairs insulin release from beta cells
Hyperuricemia	↑	Competes with uric acid for secretion in PCT → gout flares
Hyperlipidemia	↑	Mild — LDL and TGs go up

Board Trap
"Elderly patient on HCTZ presents with confusion and Na+ of 118." The answer is thiazide-induced hyponatremia. Boards love this vignette. Thiazides are the #1 drug cause of hyponatremia — not loops, even though loops are "stronger." Loops impair concentrating ability (dilute urine), while thiazides preserve it — meaning ADH can still concentrate urine and trap free water.

Patient with HTN and osteoporosis — which diuretic class gives you a two-for-one?

4️⃣

Collecting Duct

Potassium-Sparing Diuretics

The collecting duct is where aldosteroneAldosterone binds nuclear receptors in principal cells → upregulates ENaC (Na+ channels) on the luminal side and Na/K-ATPase on the basolateral side. Net effect: Na+ reabsorbed, K+ secreted. Block aldosterone → keep K+, lose Na+. does its final tuning — Na+ in, K+ out. This is where potassium-sparing diuretics live.

Two totally different mechanisms, same result:

Mechanism	Drugs	How
Aldosterone antagonists	Spironolactone, Eplerenone	Block the aldosterone receptor → no ENaC upregulation → Na+ stays in tubule, K+ stays in blood
ENaC blockers	Amiloride, Triamterene	Directly block the ENaC channelEpithelial sodium channel. The final gatekeeper for Na+ in the collecting duct. Even without aldosterone, some baseline ENaC activity exists. Amiloride plugs the channel directly. — don't need aldosterone to be involved

Spironolactone Bonus Effects
Heart failure: Reduces mortality in HFrEF (RALES trial). Not for its diuretic effect — for its anti-fibrotic, anti-remodeling effects on the heart.
Side effect: Gynecomastia (anti-androgen effect). Eplerenone is more selective → less gynecomastia but more expensive. 🔑 Spironolactone gives you spironol... man boobs. The "spiro" sounds like it's spinning your hormones. Eplerenone is the gentleman's version — same job, fewer side effects.

The danger: Hyperkalemia. These drugs SAVE potassium. Combine with an ACE inhibitor (which also raises K+) + renal insufficiency = cardiac arrest territory. Always check K+ levels.

Board Trap
"Patient on lisinopril + spironolactone presents with peaked T waves and K+ of 6.8." Both drugs raise potassium through different mechanisms. ACE inhibitor → less aldosterone → less K+ secretion. Spironolactone → blocks whatever aldosterone is left. Double whammy. The combo is used in HF but requires aggressive K+ monitoring.

Amiloride special use: Treats Liddle syndromeGain-of-function mutation in ENaC — the channel is always open, always reabsorbing Na+, always wasting K+. Looks like hyperaldosteronism but aldosterone is LOW. Amiloride plugs the overactive channel directly. Spironolactone won't work because the problem isn't aldosterone — it's the channel itself. (gain-of-function ENaC mutation). Also used to prevent lithium-induced nephrogenic DILithium enters principal cells through ENaC and downregulates aquaporin-2. Amiloride blocks ENaC → blocks lithium entry → protects the collecting duct's concentrating ability. — blocks lithium entry through ENaC.

📈

The Full Picture

Side-by-Side

Class	Site	K+	Ca2+	Acid-Base	Power
CA Inhibitors Acetazolamide	PCT	↓	—	Met. Acidosis	Weak
Loop Furosemide	TAL	↓	↓ (wastes)	Met. Alkalosis	Strongest
Thiazide HCTZ	DCT	↓	↑ (saves)	Met. Alkalosis	Moderate
K-Sparing Spironolactone	CD	↑ (saves)	—	Met. Acidosis	Weakest

The Pattern
Everything except K-sparing causes hypokalemia. Loops and thiazides both cause metabolic alkalosis (volume contraction + H+ wasting). CA inhibitors and K-sparing both cause metabolic acidosis (bicarb loss and reduced H+ secretion, respectively).

🛠

Which Diuretic? Decision Tree

A patient walks in. Pick the right diuretic.

Acute pulmonary edema — patient is drowning in fluid RIGHT NOW

Acute = loop. IV furosemide works in minutes. Thiazides are too slow. Spironolactone takes days to peak.

HTN maintenance in a 65-year-old with osteoporosis

Thiazide lowers BP AND saves calcium — two birds. Chlorthalidone > HCTZ for HTN (longer duration, better outcomes data).

HFrEF patient already on ACE inhibitor + beta blocker, still symptomatic

Spironolactone reduces mortality in HFrEF (RALES trial). It's not about diuresis here — it's about cardiac remodeling. But watch that K+ with the ACE inhibitor on board.

Patient on furosemide still volume-overloaded — "diuretic resistance"

Sequential nephron blockade. Loop blocks TAL, thiazide blocks DCT. The nephron can't compensate at one site if both are blocked. Metolazone works even in low GFR. This combo is powerful — monitor electrolytes closely.

Altitude sickness prophylaxis for a mountaineer

Acetazolamide causes metabolic acidosis → stimulates respiratory drive → compensatory hyperventilation → better oxygenation at altitude.

Patient with Liddle syndrome (ENaC gain-of-function)

Liddle = overactive ENaC. The problem is the channel, not aldosterone. Spironolactone blocks aldosterone receptors — useless if the channel ignores aldosterone. Amiloride plugs the channel directly.

🎯

Test Yourself

Board-Style Vignettes

Four patients just walked in. They all need a diuretic. Don't give them the wrong one.

Refresh to get different questions.