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PH4.5 | PH4.5 | Diuretics and Antidiuretic Drugs — SDL Guide (Part 2)

Loop Diuretics and Thiazides: PK, PD, Uses, ADRs

Loop diuretics — the most potent diuretics — act by inhibiting NKCC2 (the Na-K-2Cl cotransporter) on the apical membrane of the thick ascending limb. Because the TAL handles ~25% of the filtered sodium load, NKCC2 inhibition produces a large natriuresis and diuresis. Furosemide, the prototype, is given orally or IV. Oral bioavailability is variable (~50–70% for furosemide; ~80% for torsemide — better and more predictable; bumetanide ~80%). After IV administration, diuresis begins within 5 minutes and peaks at 30 minutes. The IV route bypasses gut bioavailability variability — this explains why IV furosemide works in cardiac failure when gut wall oedema impairs oral absorption.

Loop diuretics are effective even in significant renal impairment (unlike thiazides) because they reach the tubular lumen via tubular secretion (proximal tubule organic acid transporter). High doses may be needed in CKD to deliver adequate luminal concentration — this is the concept of loop diuretic resistance (also caused by: excessive sodium intake, NSAID use blocking prostaglandin-mediated afferent vasodilatation, hypoalbuminaemia reducing drug delivery).

Electrolyte ADRs of loop diuretics: hypokalaemia (K lost in TAL as a consequence of NKCC2 inhibition + secondary hyperaldosteronism), hyponatraemia, hypomagnesaemia (magnesium lost alongside K), hypocalcaemia (calcium excretion increased — the opposite of thiazides), metabolic alkalosis, and hyperuricaemia (loop diuretics compete with urate for proximal tubular secretion → reduced urate excretion → gout). Ototoxicity (tinnitus, hearing loss) is dose-related, particularly with rapid high-dose IV infusion; ethacrynic acid has the highest ototoxic risk.

Thiazide diuretics inhibit NCC (Na-Cl cotransporter) in the early DCT. They are moderate-potency diuretics with a ceiling effect at maximal dose. A critical pharmacological difference from loop diuretics: thiazides increase calcium reabsorption in the DCT by creating a sodium-poor intracellular environment that indirectly stimulates a basolateral Ca transporter, resulting in hypercalcaemia (or reduced urine calcium — useful in Ca-stone disease). Thiazides become ineffective as eGFR falls below 30 mL/min/1.73m² because adequate drug cannot reach the tubular lumen. Exceptions: metolazone and indapamide retain some efficacy even at lower GFR.

Electrolyte ADRs of thiazides: hypokalaemia (K lost in DCT), hyponatraemia (particularly in elderly women on high fluid intake), hypercalcaemia, hypomagnesaemia, metabolic alkalosis, hyperuricaemia. Metabolic effects: thiazides cause mild dyslipidaemia (raise LDL and TG at high doses, reduce HDL) and impair glucose tolerance (hypokalaemia reduces insulin secretion) — relevant in diabetic or pre-diabetic patients. Hydrochlorothiazide causes more metabolic effects than chlorthalidone or indapamide at equivalent antihypertensive doses.

Potassium-Sparing Diuretics, Carbonic Anhydrase Inhibitors, and Osmotic Diuretics

Potassium-sparing diuretics form a critical counterpart to loop diuretics and thiazides, which both waste potassium. They act at the cortical collecting duct to retain potassium by one of two mechanisms.

Aldosterone antagonists — spironolactone and eplerenone competitively block the mineralocorticoid receptor (MR), preventing aldosterone-driven ENaC expression and Na-K-ATPase upregulation. They are therefore most effective when aldosterone is elevated (heart failure, cirrhosis, primary hyperaldosteronism). In HFrEF, the RALES trial demonstrated that spironolactone 25 mg/day added to ACEi and loop diuretic in patients with severe HFrEF (LVEF <35%) reduced all-cause mortality by 30%. The EMPHASIS-HF trial confirmed eplerenone's benefit in mild–moderate HFrEF. Both are used in hepatic cirrhosis with ascites — spironolactone is first-line because ascites is aldosterone-driven, and the spironolactone:furosemide ratio of 100:40 mg is the standard combination. Spironolactone's key ADR (beyond hyperkalaemia) is gynaecomastia and sexual dysfunction — due to anti-androgenic action at androgen receptors. Eplerenone is more selective for MR and lacks the anti-androgenic ADRs — it is preferred when gynaecomastia is an issue.

Amiloride and triamterene are ENaC (epithelial Na channel) blockers at the collecting duct — they are NOT aldosterone antagonists (they do not bind MR; their effect is independent of aldosterone levels). Both retain potassium and are used in combination with thiazide or loop diuretics to prevent hypokalaemia. Triamterene may crystallise in urine (nephrotoxicity); amiloride is preferred clinically.

Key shared ADR of all potassium-sparing diuretics: hyperkalaemia — dangerous when combined with ACEi, ARBs, or NSAIDS, all of which also elevate potassium. Monitor K regularly.

Carbonic anhydrase inhibitors (CAIs) — acetazolamide: inhibit CA in the proximal tubule → bicarbonate and Na loss → metabolic acidosis (self-limiting diuresis). Used for: (1) glaucoma — reduces aqueous humour production; (2) altitude sickness (AMS) — accelerates metabolic acidosis that drives the hyperventilatory response; (3) idiopathic intracranial hypertension — reduces CSF production; (4) metabolic alkalosis (to correct).

Osmotic diuretics — mannitol: a six-carbon sugar alcohol, freely filtered at the glomerulus but not reabsorbed. Exerts an osmotic pressure in the tubular lumen, retaining water (and to a lesser extent Na) throughout the nephron. Used IV for: (1) cerebral oedema — reduces ICP by drawing water from brain (0.5–1 g/kg IV); (2) acute oliguric renal failure — to maintain tubular flow and prevent cast obstruction; (3) haemolysis/myoglobinuria — flushes myoglobin from tubules. The concept of sequential nephron blockade (combining a loop diuretic + a distal diuretic, e.g., furosemide + metolazone) is used in refractory oedema — acting at two different nephron sites achieves much greater natriuresis than either drug alone.

Antidiuretic Drugs: Vasopressin Analogues and Vaptans

The antidiuretic arm of this topic is obligate under PH4.5 and covers the pharmacology of vasopressin (antidiuretic hormone, ADH) and its therapeutic manipulation in both directions — supplementation (when ADH is deficient) and blockade (when ADH excess causes hyponatraemia).

Vasopressin (ADH) acts on two receptor subtypes: V1a receptors in vascular smooth muscle (→ vasoconstriction, used in shock and variceal bleeding) and V2 receptors in the renal collecting duct principal cells (→ adenylyl cyclase → cAMP → protein kinase A → aquaporin-2 vesicle fusion with apical membrane → water reabsorption).

Desmopressin (DDAVP) is a synthetic V2-selective vasopressin analogue (D-Arg substitution at position 8 + no V1a activity). Key uses: (1) central diabetes insipidus (CDI) — the primary indication, given intranasally or orally; (2) primary nocturnal enuresis in children — reduces nocturnal urine output; (3) haemophilia A and von Willebrand disease type 1 — IV desmopressin releases stored vWF and factor VIII from endothelium (V2 receptor on endothelial cells). ADR: dilutional hyponatraemia if excess water intake — educate patients to restrict fluids.

Terlipressin is a V1a-preferring long-acting vasopressin analogue. Key use: variceal haemorrhage — V1a-mediated splanchnic vasoconstriction reduces portal pressure, slowing bleeding while endoscopy is arranged. Also used in hepatorenal syndrome type 1.

Vasopressin antagonists (vaptans) — tolvaptan (selective V2) and conivaptan (V1a + V2 blocker) — block vasopressin's water-retention action at the collecting duct. The result is excretion of electrolyte-free water (aquaresis, not natriuresis) — raising serum sodium without worsening sodium depletion. Used for euvolaemic and hypervolaemic hyponatraemia due to SIADH, chronic heart failure hyponatraemia, and cirrhosis-associated hyponatraemia. Key limitation: overly rapid correction of hyponatraemia risks osmotic demyelination syndrome (ODS) — rise should not exceed 6–8 mEq/L in 24 hours. Tolvaptan is oral and now standard-of-care in SIADH. Conivaptan is IV only. Tolvaptan is also used in autosomal dominant polycystic kidney disease (ADPKD) to slow cyst growth.