PharmacologyTier 1Medical Sciences concept

Diuretic classes - site and mechanism of action

Core concept

Site	% filtered Na	Transporter	Class
Proximal tubule	65%	Na/H exchanger, carbonic anhydrase	Acetazolamide (weak - distal segments compensate)
		SGLT2	SGLT2 inhibitors
Thick ascending limb	25%	NKCC2	Loop - frusemide, bumetanide, ethacrynic acid
Early DCT	5-7%	NCC	Thiazides - hydrochlorothiazide, indapamide, chlortalidone
Collecting duct	2-3%	ENaC / mineralocorticoid receptor	Amiloride, triamterene / spironolactone, eplerenone
Collecting duct	-	V2 receptor / aquaporin-2	Tolvaptan (aquaretic)

Loop diuretics also abolish the medullary concentration gradient (NKCC2 drives countercurrent multiplication) -> loss of both concentrating and diluting ability
Thiazides block the diluting segment only -> urine can still be concentrated -> free water retention -> hyponatraemia
Loops and thiazides are secreted into the lumen by OAT1/3 in the proximal tubule - they must reach the luminal side to work

Hypokalaemia mechanism (loops and thiazides) - inc distal Na delivery -> ENaC-mediated Na uptake -> lumen-negative potential -> inc K secretion via ROMK and inc H secretion
- Secondary hyperaldosteronism from volume depletion amplifies it -> hypokalaemic metabolic alkalosis

	Loop	Thiazide
Ca	inc excretion (hypocalcaemia)	dec excretion - hypercalcaemia
Mg	inc loss	inc loss
Urate	inc (both)	inc (both) -> gout
Na	Hyponatraemia less common	Hyponatraemia characteristic
Glucose/lipids	Minimal	inc glucose, inc lipids
Efficacy at low eGFR	Retained (dose up)	Lost below eGFR ~30 (except metolazone, indapamide)

Thiazides for hypercalciuric stones and idiopathic hypercalciuria; loops for hypercalcaemia
Diuretic braking/resistance - distal nephron hypertrophy on chronic loop therapy
- Overcome with a thiazide added to a loop (sequential nephron blockade) - potent, watch K and Na
Spironolactone is non-selective -> gynaecomastia, hyperkalaemia; eplerenone selective, less gynaecomastia
Acetazolamide -> normal anion gap metabolic acidosis (bicarbonate wasting)
Ethacrynic acid contains no sulfonamide group -> use in true sulfonamide allergy

Frusemide dosing in heart failure and CKD - dose is threshold-dependent, not linear; if a dose fails, double it rather than increase frequency
- Oral bioavailability ~50% and erratic -> IV in decompensation with gut oedema
Hyponatraemia on a thiazide - classic in an older woman within weeks of starting; stop the drug, it recurs on rechallenge
Spironolactone - HFrEF, resistant hypertension, primary hyperaldosteronism, ascites (with frusemide in a 100:40 ratio)
- Ascites is the one setting where the aldosterone antagonist is the primary agent
Amiloride is specific for Liddle syndrome and for lithium-induced nephrogenic DI
Check U&E 1-2 weeks after starting or up-titrating any diuretic, and with any RAAS inhibitor combination
Tolvaptan - SIADH and ADPKD; hepatotoxicity and rapid overcorrection risk

Renal tubule segment function - reabsorption/secretion site mapping
Inherited tubulopathies - Gitelman phenocopies a thiazide, Bartter a loop, Liddle is ENaC gain of function
Mechanism of hypokalaemia in vomiting-induced metabolic alkalosis
Hyponatraemia - diagnostic approach by volume status
Vasopressin receptor antagonists; SGLT2 inhibitors

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