Diuretics

Diuretics are drugs that increase urine output by reducing sodium and water reabsorption in the nephron. They are classified by their site of action and mechanism. All diuretics except osmotic diuretics reach the tubular lumen via organic anion transporters (OAT1) at the proximal tubule basolateral membrane — they are not freely filtered because they are highly protein bound.

Osmotic diuretics (mannitol) are freely filtered at the glomerulus but poorly reabsorbed. Their osmotic force limits water reabsorption across water-permeable segments (proximal tubule, thin descending loop, collecting duct). They cause diuresis and natriuresis by osmosis. Mannitol is pharmacologically inert but osmotically active. It is used for emergency reduction of intracranial pressure by reducing cerebral intravascular volume. Because it expands extracellular fluid volume while it circulates, it can cause pulmonary congestion with rapid infusion or in renal injury.

Loop diuretics (frusemide, torsemide) inhibit the luminal NKCC2 (Na+/K+/2Cl-) co-transporter in the thick ascending limb of the loop of Henle by competing with Cl- for binding. NKCC2 normally drives the lumen-positive transepithelial potential (~10 mV) that drives paracellular reabsorption of Ca2+, Mg2+, and other cations. Loop diuretics can inhibit up to 25% of filtered Na+ reabsorption — the most potent diuretics. The large Na+ load delivered distally is exchanged for K+ and H+ at distal exchangers, causing hypokalaemia and metabolic alkalosis. ADRs: hypovolaemia, hyponatraemia, hypokalaemia (predisposes to digoxin toxicity), Mg2+ and Ca2+ depletion, metabolic alkalosis, hyperuricaemia (gout), ototoxicity (prolonged use).

Thiazide diuretics (bendroflumethiazide, chlorothiazide) inhibit the electroneutral NCC1 (Na+/Cl-) co-transporter in the cortical diluting segment of the distal tubule. They are secreted into the proximal tubule via OAT transporters. NCC1 is upregulated by aldosterone. Thiazides cause a milder diuresis (~5% filtered Na+). They are first-line agents for hypertension (often combined with ACE-I or CCB). Haemodynamic effects: initial decrease in CO and plasma volume; secondary decrease in TPR. ADRs: dehydration, postural hypotension (especially elderly), hyponatraemia, hypokalaemia, metabolic alkalosis, hyperuricaemia, prolonged QT (from hypokalaemia — watch for torsades de pointes with other QT-extending drugs), hyperglycaemia.

Potassium-sparing diuretics work at the collecting duct. Spironolactone is an aldosterone antagonist: it competitively binds the mineralocorticoid receptor (MR) and prevents nuclear translocation, thus preventing synthesis of aldosterone-inducible proteins (AIPs) including ENaC subunits and Na+/K+-ATPase. It binds the basolateral receptor and does not require luminal access. Its efficacy depends on aldosterone levels. ADRs: hyperkalaemia, gynaecomastia (androgen modulating effects due to steroid structure), GI disturbance.

Amiloride blocks ENaC (aldosterone-sensitive luminal Na+ channels) directly. It is transported via OAT into the proximal tubule lumen. It has complementary action to thiazides: augments Na+ loss but limits K+ loss. Very weak diuretic; typically combined with a thiazide (e.g. Amizide = amiloride + hydrochlorothiazide) to prevent hypokalaemia.

Clinical uses: loop diuretics — hypertension, oedema (cardiac/renal/hepatic), acute pulmonary oedema, hyperkalaemia, symptomatic hypercalcaemia. Thiazides — hypertension (1st line), acute pulmonary hypertension. Spironolactone — hyperaldosteronism, CHF oedema, hepatic failure oedema (used with ACE-I/ARB for hypertension in selected patients). Amiloride — with thiazide or frusemide when hypokalaemia is a concern.