Renal Pharmacology

Diuretics — Classification (by nephron site)

PCT: carbonic anhydrase inhibitors(acetazolamide). Thick ascending limb(loop/high-ceiling): furosemide, bumetanide, torsemide, ethacrynic acid. DCT(thiazides): HCTZ, chlorthalidone, indapamide. Collecting duct(K+-sparing): aldosterone antagonists(spironolactone, eplerenone) + ENaC blockers(amiloride, triamterene). Osmotic: mannitol. Vasopressin-related: V2 antagonists(tolvaptan).

Organizing principle: potency tracks % filtered Na+ normally handled at that segment — loop(20-25%) >> thiazide(~5%) >> K+-sparing(~2-3%).

Diuretics — Mechanism

Acetazolamide: ↓carbonic anhydrase(PCT)→↓H+ for Na+/H+ exchange→↓HCO3- reabsorption. SELF-LIMITING(distal compensation)→weak diuretic. Main uses: glaucoma(↓aqueous humour), ↓CSF production(IIH, altitude sickness prophylaxis via resulting metabolic acidosis→↑ventilation).

Loop diuretics: block NKCC2(Na+-K+-2Cl- symporter, thick ascending limb) → BOTH ↓direct Na+/Cl- reabsorption AND collapses medullary hypertonicity(counter-current mechanism) → MOST POWERFUL diuretics (“high-ceiling”).

Thiazides: block NCC(Na+-Cl- symporter, DCT). Weaker(only ~5% filtered Na+ handled here) BUT same segment has ENHANCED Ca2+ reabsorption(intracellular Na+ depletion→↑basolateral Na+/Ca2+ exchange→↑luminal Ca2+ entry) = HYPOCALCIURIC (opposite of loop diuretics) → useful in idiopathic hypercalciuria/stone prevention.

K+-sparing: spironolactone/eplerenone = competitive MR(aldosterone receptor) blockade in collecting duct→↓ENaC+Na/K-ATPase expression. Amiloride/triamterene = DIRECT ENaC block, aldosterone-INDEPENDENT — same net effect, different mechanism. Both weak alone → used as K+-sparing add-ons.

Mannitol: freely filtered, poorly reabsorbed→↑tubular osmolality→osmotically retains water in lumen. Transporter-INDEPENDENT mechanism. Uses: acute ↓ICP/IOP(osmotic water pull across intact BBB/blood-aqueous barrier), maintain urine flow(major surgery, some poisoning protocols).

Tolvaptan(V2 antagonist): blocks ADH V2 receptor→↓aquaporin-2 insertion→WATER diuresis specifically(“aquaretic”), not Na+. Hypervolaemic/euvolaemic hyponatraemia(SIADH, HF) where problem = excess free water not excess Na+.

Diuretics — Adverse Effects

Loop: hypokalaemia(↑distal Na+ delivery→↑K+ secretion) · hypoMg2+/hypoCa2+(NKCC2 block also ↓lumen-positive potential driving paracellular Ca2+/Mg2+ reabsorption — OPPOSITE of thiazide Ca2+ effect) · ototoxicity(dose-related, worse+aminoglycosides/renal failure) · hyperuricaemia(competes for proximal organic anion secretion) · metabolic alkalosis · sulfonamide-allergy cross-reactivity(except ethacrynic acid).

Thiazides: hypokalaemia(milder than loop) · hyponatraemia(pronounced esp. elderly — distinctive thiazide liability) · hyperglycaemia/hyperlipidaemia/hyperuricaemia · HYPERCALCAEMIA(opposite of loop) · sulfonamide cross-reactivity.

K+-sparing: HYPERKALAEMIA(class-defining, esp +ACE-I/ARB or renal impairment) · spironolactone: gynaecomastia/menstrual irregularity(anti-androgenic cross-reactivity — eplerenone more MR-selective, avoids this).

Mannitol: transient volume expansion BEFORE diuresis(can precipitate pulmonary oedema in ↓cardiac reserve — CI in anuria/severe HF) · dehydration/hypernatraemia with excess use.

Tolvaptan: overly rapid hyponatraemia correction→osmotic demyelination syndrome(central pontine myelinolysis) risk.

Urinary pH / Uric Acid Handling

Alkalinizers(NaHCO3, K citrate): ↑urinary pH → prevents uric acid/cystine stones(more soluble alkaline) + enhances excretion of acidic drugs in OD(salicylates — “ion trapping,” ionized form trapped in alkaline tubular fluid).

Uricosurics(probenecid): inhibits proximal organic anion transporter reabsorbing filtered urate→↑urate excretion. Chronic gout(underexcretors), NOT acute attacks. CI: history of uric acid stones(↑urinary urate load) unless urine also alkalinized.

Clinical Relevance

Nephron-site principle explains almost everything without separate memorization: potency tracks % Na+ handled at that segment; Ca2+ handling runs OPPOSITE directions at loop vs DCT because of genuinely different local mechanisms(lost paracellular reabsorption vs enhanced basolateral exchange); K+-wasting happens because blocking upstream Na+ reabsorption ↑Na+ delivery to the K+-secreting collecting duct — K+-sparing diuretics counteract this precisely because they act AT that segment, not upstream of it.

Diuretics

Classification (by Site and Mechanism of Action Along the Nephron)

Proximal convoluted tubule: carbonic anhydrase inhibitors — acetazolamide
Thick ascending limb of loop of Henle (high-ceiling/loop diuretics): furosemide, bumetanide, torsemide, ethacrynic acid
Distal convoluted tubule (thiazides): hydrochlorothiazide, chlorthalidone, indapamide
Collecting duct (potassium-sparing): aldosterone antagonists (spironolactone, eplerenone) and epithelial Na⁺ channel (ENaC) blockers (amiloride, triamterene)
Osmotic diuretics: mannitol
ADH/vasopressin-related: vasopressin V2-receptor antagonists (tolvaptan) and ADH itself/desmopressin (antidiuretic, not diuretic — used for the opposite purpose, covered here for contrast)

This site-based classification is the organizing structure for the whole topic — each class’s efficacy, adverse effects, and drug interactions all trace back to which specific transporter, at which specific nephron segment, it blocks.

Mechanism of Action

Carbonic anhydrase inhibitors (acetazolamide): inhibit carbonic anhydrase in the proximal tubule, reducing H⁺ availability for the Na⁺/H⁺ exchanger and reducing HCO3⁻ reabsorption — leads to mild natriuresis but the effect is self-limiting (more distal Na⁺ reabsorption compensates), so acetazolamide is a weak diuretic in practice, used mainly for its other properties: reducing aqueous humour formation (glaucoma), reducing CSF production (idiopathic intracranial hypertension, altitude sickness prophylaxis via the resulting metabolic acidosis stimulating ventilation).

Loop diuretics: inhibit the Na⁺-K⁺-2Cl⁻ (NKCC2) symporter on the luminal membrane of the thick ascending limb — this is the single nephron segment responsible for generating the medullary hypertonicity that the counter-current mechanism depends on for concentrating urine, which is why loop diuretics are the most powerful (“high-ceiling”) diuretics available: blocking NKCC2 both prevents Na⁺/Cl⁻ reabsorption directly (roughly 20–25% of filtered Na⁺ normally reabsorbed here) and collapses the medullary concentration gradient the kidney would otherwise use to reabsorb water passively downstream.

Thiazides: inhibit the Na⁺-Cl⁻ (NCC) symporter in the distal convoluted tubule — a segment normally reabsorbing only ~5% of filtered Na⁺, so thiazides are inherently less potent diuretics than loop agents, but this same segment is where Ca²⁺ reabsorption is enhanced (thiazide-induced intracellular Na⁺ depletion drives basolateral Na⁺/Ca²⁺ exchange harder, pulling more Ca²⁺ out of the cell and favouring more luminal Ca²⁺ entry) — the mechanistic basis for thiazides’ distinctive hypocalciuric effect, useful in idiopathic hypercalciuria/calcium stone prevention and the opposite of loop diuretics’ hypercalciuric effect.

Potassium-sparing diuretics: spironolactone/eplerenone competitively block the mineralocorticoid (aldosterone) receptor in the collecting duct principal cells, preventing aldosterone-driven ENaC and Na⁺/K⁺-ATPase expression — reduces Na⁺ reabsorption and, critically, the K⁺ secretion that normally accompanies it. Amiloride/triamterene block ENaC directly, independent of aldosterone, producing the same net effect (Na⁺ retention in the lumen, less driving force for K⁺ secretion) through a different mechanism. Both are weak diuretics alone, used chiefly as K⁺-sparing add-ons to loop/thiazide therapy.

Osmotic diuretics (mannitol): freely filtered but poorly reabsorbed, raising tubular fluid osmolality throughout the nephron (especially the proximal tubule and descending limb, which are water-permeable) and osmotically obligating water to remain in the lumen — a mechanism independent of any specific transporter, which is why mannitol works even when tubular transport is otherwise impaired. Used for acute reduction of raised intracranial/intraocular pressure (draws water out of the brain/eye across an intact blood-brain/blood-aqueous barrier, an osmotic effect exploited outside the kidney) and to maintain urine flow in specific settings (e.g. during major surgery, some poisoning protocols).

Vasopressin V2-receptor antagonists (tolvaptan): block ADH’s V2 receptor on collecting duct principal cells, preventing aquaporin-2 insertion into the luminal membrane and thereby causing water (not Na⁺) diuresis specifically — an “aquaretic,” used for hypervolaemic/euvolaemic hyponatraemia (SIADH, heart failure) where the problem is excess free water relative to Na⁺, not excess total Na⁺.

Adverse Effects

Loop diuretics: hypokalaemia (increased distal Na⁺ delivery drives K⁺ secretion via the same mechanism aldosterone normally uses) · hypomagnesaemia, hypocalcaemia (NKCC2 blockade also reduces the lumen-positive potential that normally drives paracellular Ca²⁺/Mg²⁺ reabsorption in this segment — the opposite of thiazides’ effect on calcium) · ototoxicity (dose-related, worse with concurrent aminoglycosides or in renal failure, thought related to disruption of a similar NKCC isoform in the inner ear) · hyperuricaemia (competes with urate for proximal tubular organic anion secretion) · metabolic alkalosis (volume contraction plus increased distal H⁺ secretion) · allergic reactions in sulfonamide-allergic patients (most loop diuretics, other than ethacrynic acid, are sulfonamide derivatives).

Thiazides: hypokalaemia (same distal K⁺-secretion mechanism as loop diuretics, though generally milder given the weaker overall natriuretic effect) · hyponatraemia (can be pronounced, particularly in elderly patients — a distinctive thiazide liability more than a loop-diuretic one) · hyperglycaemia, hyperlipidaemia, hyperuricaemia (metabolic effects that made thiazides fall from pure first-line-antihypertensive-monotherapy favour in some more recent guidelines, though they remain a mainstay) · hypercalcaemia (opposite of loop diuretics, from the mechanism above) · sulfonamide-allergy cross-reactivity (thiazides are also sulfonamide derivatives).

Potassium-sparing diuretics: hyperkalaemia (the class-defining risk, especially when combined with ACE-I/ARB or in renal impairment) · spironolactone specifically: gynaecomastia, menstrual irregularity (anti-androgenic/progestogenic cross-reactivity at other steroid receptors — eplerenone, being more selective for the mineralocorticoid receptor, avoids this).

Osmotic diuretics: transient volume expansion before diuresis begins (can precipitate acute pulmonary oedema in a patient with reduced cardiac reserve — mannitol is contraindicated in anuria/severe heart failure for exactly this reason) · dehydration/hypernatraemia with excessive use.

Vasopressin antagonists: overly rapid correction of hyponatraemia risks osmotic demyelination syndrome (central pontine myelinolysis) — the same correction-rate caution that applies to any rapid Na⁺ correction, specifically flagged for tolvaptan given how effectively it drives free water excretion.

Drugs Affecting Urinary pH and Uric Acid Handling

Urinary alkalinizers (sodium bicarbonate, potassium citrate): raise urinary pH, used to prevent uric acid and cystine stone formation (both more soluble in alkaline urine) and to enhance renal excretion of certain acidic drugs in overdose (e.g. salicylates — “ion trapping,” where the ionized drug form is trapped in alkaline tubular fluid and cannot be passively reabsorbed).
Uricosuric agents (probenecid): inhibit the proximal tubular organic anion transporter that normally reabsorbs filtered urate, increasing urate excretion — used in chronic gout management (not acute attacks) in patients who are underexcretors of uric acid; contraindicated with a history of uric acid stones (increases urinary urate load, unless urine is also alkalinized).

Clinical Relevance

The nephron-site organizing principle explains nearly every clinically important fact about diuretics without needing separate memorization: potency tracks how much filtered Na⁺ a segment normally handles (loop >> thiazide >> potassium-sparing), calcium handling runs in opposite directions at the loop versus the distal tubule because of genuinely different local mechanisms (paracellular reabsorption lost with loop diuretics versus enhanced basolateral exchange with thiazides), and potassium-wasting occurs specifically because blocking upstream Na⁺ reabsorption increases the Na⁺ delivered to the K⁺-secreting collecting duct, which potassium-sparing diuretics counteract precisely because they act at that segment instead of upstream of it.

Nephron schematic marking each diuretic class’s site and specific transporter blocked (PCT/CAI, thick ascending limb/NKCC2, DCT/NCC, collecting duct/ENaC-aldosterone).
Opposite calcium-handling effects of loop vs thiazide diuretics traced to their distinct local mechanisms.