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Diuretics - K. Sembulingam (Most Important Notes)

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Sites of Action Along the Nephron

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Definition

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Classification of Diuretics (Sembulingam - 7 Types)

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1. Osmotic Diuretics

• Freely filtered at glomerulus but NOT reabsorbed
• Acts as non-reabsorbable solute - retains water in tubular lumen
• Reduces medullary tonicity by washing out NaCl and urea
• Opposes ADH action in collecting tubule
• Increases urine volume >> increases NaCl excretion (water diuresis > natriuresis)

• Given IV only (poorly absorbed orally - causes osmotic diarrhea)
• Not metabolized; excreted by glomerular filtration in 30-60 min
• Oral: Glycerin, Isosorbide (for reducing intraocular pressure)

• Raised intracranial pressure (1-2 g/kg IV - reduces in 60-90 min)
• Raised intraocular pressure (before ophthalmologic procedures)
• Acute renal failure (maintain urine flow)
• Dialysis disequilibrium syndrome
• Forced diuresis in poisoning

• Extracellular volume expansion + pulmonary edema (in heart failure - CONTRAINDICATED)
• Hyponatremia (initial dilutional)
• Hypernatremia (after prolonged use - water loss exceeds Na loss)
• Contraindicated in: anuric renal failure, pulmonary edema, heart failure

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2. Carbonic Anhydrase Inhibitors (CAIs)

• Inhibits carbonic anhydrase (CA) enzyme
• CA normally: H2O + CO2 → H2CO3 → H+ + HCO3-
• Inhibition → less H+ available → less Na+/H+ exchange via NHE-3
• Result: Na+, HCO3- retained in urine → alkaline diuresis
• Self-limiting: once plasma HCO3- falls (metabolic acidosis), effect wanes

• Glaucoma (main use - reduces aqueous humor formation)
• Altitude sickness (mountain sickness prophylaxis)
• Alkalinizing urine (cystinuria, uric acid stones)
• Correcting metabolic alkalosis from thiazide/loop diuretics
• Epilepsy (petit mal seizures)

• Metabolic acidosis (hyperchloremic)
• Hypokalemia
• Renal stones (alkaline urine + reduced citrate)
• Drowsiness, paresthesia
• Sulfonamide allergy cross-reactivity

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3. Loop Diuretics (High-Ceiling Diuretics)

• Inhibits Na+/K+/2Cl- cotransporter (NKCC2) on luminal membrane of TAL
• Blocks reabsorption of NaCl, destroys medullary concentration gradient
• Also abolishes the positive luminal potential → reduces Ca2+ and Mg2+ reabsorption
• "High ceiling" = dose-response curve is steep; can produce very large diuresis

• ↑Na+, ↑Cl-, ↑K+ loss → hypokalemic metabolic alkalosis
• ↑Ca2+ excretion (calciuric) - useful in hypercalcemia
• ↑Mg2+ excretion

• Furosemide - sulfonamide; oral + IV; duration 2-4 hours
• Bumetanide - sulfonamide; 40x more potent than furosemide
• Torsemide - sulfonamide; longer duration
• Ethacrynic acid - NOT a sulfonamide (use in sulfa allergy); also uricosuric; most ototoxic

• Acute pulmonary edema (IV furosemide - drug of choice)
• Heart failure (edema management)
• Hypertension (especially with renal impairment)
• Acute hypercalcemia (with IV saline)
• Nephrotic syndrome, cirrhosis with ascites
• Anion overdose (forced diuresis)
• Hyperkalemia (acute management)

• A - Alkalosis (hypokalemic metabolic alkalosis)
• B - Blood disorders (rare)
• C - Ca2+ loss (hypocalcemia with long use), Cholesterol ↑
• D - Dehydration, Dizziness
• E - Electrolyte disturbances (↓K+, ↓Na+, ↓Mg2+)
• F - Furosemide Ototoxicity (tinnitus, deafness - dose-dependent, more with aminoglycosides)
• Also: Hyperuricemia (compete with uric acid for tubular secretion), Hyperglycemia

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4. Thiazide Diuretics

• Inhibits Na+/Cl- cotransporter (NCC) in DCT
• Modest increase in NaCl excretion (~3-5% of filtered load)
• Reduces plasma volume → activates RAAS → K+ loss

• ↑Na+, ↑Cl-, ↑K+ loss → hypokalemic metabolic alkalosis
• ↓Ca2+ excretion (hypocalciuric) - KEY DISTINCTION from loop diuretics
• Mechanism of hypocalciuria: volume depletion → ↑proximal Ca2+ reabsorption; also direct DCT Ca2+ channel upregulation

• HCTZ - standard; oral; 8-12 h duration
• Chlorthalidone - very long t1/2 (50-60 h) - binds RBCs; preferred for hypertension
• Metolazone - used with loop diuretics for synergy (sequential nephron blockade)
• Indapamide - loop of Henle component; used in hypertension
• Chlorothiazide - only IV thiazide available

• Hypertension (first-line, especially uncomplicated)
• Mild heart failure
• Nephrolithiasis due to hypercalciuria (reduces urinary Ca2+)
• Nephrogenic diabetes insipidus (paradoxical - reduces free water by volume contraction)
• Osteoporosis (reduces Ca2+ loss)

• G - Gout (hyperuricemia)
• H - Hyperglycemia (impairs insulin release, increases insulin resistance)
• I - Increased LDL/triglycerides
• K - K+ loss (hypokalemia)
• Also: Hyponatremia (SIADH-like), sexual dysfunction, sulfonamide allergy

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5. Potassium-Sparing Diuretics

A. Aldosterone Antagonists

• Competitively antagonize aldosterone at mineralocorticoid receptors
• Aldosterone normally → transcription of Na+ channels (ENaC) and Na+/K+ ATPase → Na+ retention + K+ secretion
• Blockade → less Na+ reabsorption, less K+ secretion → K+ sparing
• Slow onset (2-3 days) because must wait for existing aldosterone-stimulated proteins to degrade

• Spironolactone: also blocks androgen + progesterone receptors → gynecomastia, impotence, menstrual irregularity
• Eplerenone: selective for mineralocorticoid receptor only → no hormonal side effects; more expensive

• Primary aldosteronism (Conn's syndrome) - diagnostic + therapeutic
• Heart failure (reduces mortality in severe HF - RALES trial)
• Cirrhosis with ascites
• Hypokalemia from other diuretics (combination therapy)
• Post-MI (eplerenone)
• Hirsutism in women (spironolactone's antiandrogenic effect)

B. ENaC Blockers

• Directly block epithelial Na+ channels (ENaC) in collecting duct
• Act independent of aldosterone levels
• Weak diuretics; mainly used to prevent K+ loss with other diuretics

• Reduces lithium-induced polyuria (blocks Li+ entry via ENaC)
• Liddle syndrome (gain-of-function ENaC mutation)

• Hyperkalemia - can be fatal (especially in renal failure, diabetes, with ACE inhibitors/ARBs/NSAIDs)
• Triamterene: nephrolithiasis (triamterene stones), megalo-blastic anemia (folate antagonism)
• Spironolactone: gynecomastia, menstrual irregularities

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6. ADH Antagonists (Vaptans / Aquaretics)

• Block V2 vasopressin receptors → reduce aquaporin-2 insertion → free water diuresis WITHOUT significant Na+ loss ("aquaresis")

• SIADH (hyponatremia)
• Euvolemic/hypervolemic hyponatremia
• Heart failure, cirrhosis-related hyponatremia
• Polycystic kidney disease (tolvaptan - slows progression)

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7. Xanthine Diuretics

• Inhibit phosphodiesterase → ↑cAMP
• Increase renal blood flow and GFR (mild)
• Weak direct tubular effects
• Weakest class of diuretics - rarely used primarily as diuretics

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High-Yield Comparison Table

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Most Important Clinical Points (Exam Favorites)

"Paradoxical" effects (frequently asked):

• Thiazides in nephrogenic DI - cause volume contraction → proximal tubule reabsorbs more → less water to diluting segment → paradoxically reduces polyuria
• Furosemide in hypercalcemia - calciuric; given with IV saline
• Thiazides in hypercalciuria/calcium stones - reduce urinary calcium

Drug of choice scenarios:

Ototoxicity:

• Loop diuretics (especially ethacrynic acid > furosemide)
• Enhanced by concurrent aminoglycosides

Hyperuricemia:

• Loop diuretics and thiazides both cause hyperuricemia (compete with uric acid for OAT secretion)
• Ethacrynic acid is actually uricosuric (unique - promotes uric acid excretion)

K+ effects - rule of thumb:

• Loop + Thiazide = K+ wasting
• K+-sparing = K+ retention
• Combining loop/thiazide + K+-sparing = balanced K+ effect (e.g., furosemide + spironolactone in cirrhosis)

RAAS activation:

• Loop and thiazide → volume depletion → ↑renin → ↑angiotensin II → ↑aldosterone → exacerbates K+ loss
• K+-sparing diuretics blunt this secondary effect

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Side Effects Memory Aid

• Ototoxicity
• Hypokalemia
• Hyperuricemia
• Hypomagnesemia
• Hyponatremia

• Gynecomastia
• Anti-androgenic effects
• Menstrual irregularity
• Electrolyte: Hyperkalemia

• Gout
• Hyperglycemia
• Impotence
• Increased cholesterol
• Calcium (decreased in urine)
• K+ loss (hypokalemia)

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