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Diuretics - Complete Exam-Oriented Notes

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OVERVIEW

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CLASSIFICATION - SITE OF ACTION (HIGH-YIELD MNEMONIC)

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1. LOOP DIURETICS ("HIGH-CEILING" DIURETICS)

Drugs

• Furosemide (Lasix) - most commonly used
• Bumetanide (Bumex) - 40x more potent than furosemide
• Torsemide (Demadex) - better oral bioavailability, fewer hospitalizations in HF
• Ethacrynic acid (Edecrin) - only non-sulfonamide; used in sulfa allergy

Mechanism

• Inhibit the Na+-K+-2Cl- symporter (NKCC2) on the luminal membrane of the thick ascending limb (TAL) of the loop of Henle
• Also block the same transporter (NKCC1) in the inner ear - basis of ototoxicity
• TAL is normally impermeable to water, so blocking NaCl reabsorption here reduces the medullary concentration gradient → prevents water reabsorption from the collecting duct → dilute, high-volume urine
• Inhibit urinary concentration AND dilution (compare with thiazides which only inhibit dilution)

Pharmacokinetics (Exam-Favorite Table)

Effects on Urine Composition

• ↑ Na+, K+, Cl-, Mg2+, Ca2+ excretion (hypercalciuria)
• ↑ H+ excretion → metabolic alkalosis
• ↑ uric acid reabsorption (chronic use) → hyperuricemia

Clinical Uses

1. Acute pulmonary edema - first-line (rapid venous dilation + diuresis)
2. Chronic CHF / volume overload - most commonly used diuretics
3. Hypertension - when GFR <30 mL/min or resistant hypertension (NOT first-line with normal renal function)
4. Edema of nephrotic syndrome, cirrhosis (with caution - avoid volume depletion in cirrhosis)
5. Hypercalcemia - combined with isotonic saline (loop diuretics increase Ca2+ excretion)
6. Life-threatening hyponatremia - combined with hypertonic saline
7. Forced diuresis in drug overdose
8. CKD-associated edema (require higher doses due to right-shifted dose-response curve)

Adverse Effects (EXAM HIGH-YIELD)

Drug Interactions

• NSAIDs - blunt diuretic response (prostaglandin inhibition)
• Aminoglycosides - additive ototoxicity and nephrotoxicity
• Digoxin - hypokalemia potentiates digoxin toxicity
• Lithium - reduced renal clearance → toxicity

Dose in Heart Failure (DOSE Trial)

• Initial IV dose = 2.5x the outpatient oral dose for volume-overloaded patients
• High-dose strategy: greater dyspnea relief and net fluid loss, but transient creatinine rise
• Steep dose-response curve: double the dose until effective response

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2. THIAZIDE AND THIAZIDE-LIKE DIURETICS

Drugs

• Thiazides: Hydrochlorothiazide (HCTZ), Chlorothiazide
• Thiazide-like: Chlorthalidone, Metolazone, Indapamide

Mechanism

• Inhibit the Na+-Cl- symporter (NCC) on the luminal membrane of the early distal convoluted tubule (DCT)
• Also inhibit carbonic anhydrase (proximal tubule) at higher doses
• Inhibit urinary dilution only (not concentration - because they act before the collecting duct's ADH-sensitive segment)

Effects on Electrolytes - CLASSIC EXAM QUESTION

Clinical Uses

1. Hypertension - first-line agent (especially in African Americans and elderly)
2. Heart failure - adjunct to loop diuretics
3. Nephrolithiasis (calcium oxalate stones / hypercalciuria) - thiazides reduce urinary calcium
4. Nephrogenic diabetes insipidus - paradoxical effect: reduces urine volume by volume depletion → ↑ proximal Na+ reabsorption → less water reaching collecting duct
5. Osteoporosis - calcium retention may be protective
6. Hypoparathyroidism - reduces hypercalciuria

Adverse Effects

Important Notes

• Metolazone is effective even with GFR <30 mL/min (unlike other thiazides) - useful in CKD
• Chlorthalidone has longer half-life, more potent antihypertensive than HCTZ
• Thiazide-induced hyponatremia: inhibit dilution in DCT → inability to dilute urine → free water retention

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3. POTASSIUM-SPARING DIURETICS

Two Subgroups

A. ENaC Channel Blockers (Na+ Channel Inhibitors)

• Amiloride (Midamor), Triamterene (Dyrenium)
• Site: Cortical collecting duct (CCD) / connecting tubule
• Mechanism: Directly block the epithelial Na+ channel (ENaC) on luminal membrane
  • Less Na+ entry → less negative lumen → less K+ and H+ secretion → K+ retention
• Independent of aldosterone
• Triamterene is metabolized by the liver; amiloride is renally excreted

B. Aldosterone/Mineralocorticoid Receptor Antagonists

• Spironolactone (Aldactone), Eplerenone (Inspra)
• Site: Cortical collecting duct (aldosterone-sensitive nephron)
• Mechanism: Competitive antagonists of the mineralocorticoid receptor
  • Block aldosterone's genomic effects → ↓ ENaC and Na+/K+ ATPase expression → ↓ Na+ reabsorption, ↓ K+ secretion
• Dependent on aldosterone being present (no effect in adrenal insufficiency)
• Eplerenone is more selective (fewer anti-androgenic side effects)
• Spironolactone has anti-androgenic and anti-androgenic-progesterone effects

Clinical Uses

Adverse Effects

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4. CARBONIC ANHYDRASE INHIBITORS (CAI)

Drugs

• Acetazolamide (Diamox) - prototype
• Dorzolamide, Brinzolamide (topical, for glaucoma)

Mechanism

• Inhibit carbonic anhydrase (enzyme that converts CO2 + H2O → H2CO3 → H+ + HCO3-)
• In proximal tubule: ↓ H+ available for Na+/H+ exchange → ↓ Na+ and HCO3- reabsorption
• Net effect: bicarbonate-rich, alkaline urine
• Causes hyperchloremic metabolic acidosis (self-limiting - as plasma HCO3- falls, less substrate available)
• Increased HCO3- delivery to distal tubule → increased K+ secretion

Clinical Uses

1. Glaucoma - most common use; reduces aqueous humor formation
2. Altitude sickness (acute mountain sickness) - metabolic acidosis stimulates ventilation, compensating for respiratory alkalosis of altitude
3. Urinary alkalinization - facilitates excretion of uric acid, cystine, weak acids (aspirin overdose)
4. Epilepsy (adjunct) - especially absence seizures
5. Idiopathic intracranial hypertension (pseudotumor cerebri)
6. Familial periodic paralysis
7. Metabolic alkalosis - to increase HCO3- excretion

Adverse Effects

• Metabolic (hyperchloremic) acidosis - self-limiting
• Hypokalemia
• Renal calculi - alkaline urine precipitates calcium phosphate; reduced citrate
• Drowsiness, paresthesias - with high doses
• Bone marrow depression - (sulfonamide derivative)
• Hepatic encephalopathy - contraindicated in cirrhosis (NH3 diversion to systemic circulation)
• Teratogenic - contraindicated in pregnancy
• Contraindicated in: hyperchloremic acidosis, severe COPD, cirrhosis

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5. OSMOTIC DIURETICS

Drugs

• Mannitol - most commonly used (IV only, not absorbed orally)
• Glycerin - oral; used in acute glaucoma
• Urea, Isosorbide - not available in the US

Mechanism

• Freely filtered at glomerulus, poorly reabsorbed
• Act as non-reabsorbable solutes → limit osmotic water reabsorption in proximal tubule and DTL of loop of Henle
• ↑ plasma osmolality → extract water from intracellular compartments → expand ECF volume
• ↓ medullary tonicity → ↓ water reabsorption from descending limb

Clinical Uses

1. ↑ Intracranial pressure (ICP) - e.g., cerebral edema, head trauma
2. ↑ Intraocular pressure (IOP) - acute glaucoma
3. Acute oliguric renal failure (maintain urine flow in early ATN)
4. Forced diuresis in drug overdose (to keep tubular fluid flowing)

Adverse Effects

• Pulmonary edema - due to ECF expansion; contraindicated in heart failure and pulmonary congestion
• Headache, nausea, vomiting - from hyponatremia (dilutional)
• Hypernatremia + dehydration - if water loss exceeds electrolyte loss
• Contraindicated in: anuria (severe renal disease), active intracranial bleeding, heart failure
• Urea - contraindicated in liver failure (↑ ammonia); can cause thrombosis if extravasation

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COMPARISON TABLE - CLASSIC EXAM QUESTIONS

Electrolyte Effects

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CLINICAL SCENARIOS - HIGH-YIELD EXAM PEARLS

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DIURETIC RESISTANCE

Causes

1. Non-compliance (diet - high Na+ intake)
2. Reduced oral bioavailability (furosemide only ~60%; use torsemide or bumetanide)
3. Reduced renal blood flow / GFR
4. Nephrotic syndrome - diuretics bind to protein in tubular lumen
5. Braking phenomenon - compensatory activation of RAS and distal tubule hypertrophy
6. NSAIDs - block prostaglandin-mediated increase in RBF

Management

• Switch from furosemide to torsemide (better bioavailability)
• IV administration
• Increase dose (steep dose-response curve)
• Add thiazide (sequential nephron blockade) - particularly metolazone
• Continuous IV infusion vs. bolus dosing

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SPIRONOLACTONE VS EPLERENONE

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THIAZIDE HYPONATREMIA - WHY IT'S UNIQUE

• Thiazides inhibit urinary dilution only (in DCT) - cannot dilute urine
• BUT concentrating ability (loop of Henle) is intact
• Free water is retained → hyponatremia
• Loop diuretics inhibit BOTH concentration AND dilution → less hyponatremia risk
• Thiazides are 12x more likely to cause hyponatremia than loop diuretics (Brenner & Rector's)
• This is why thiazides + SIADH + elderly patients are classic hyponatremia combination

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CARBONIC ANHYDRASE INHIBITORS - SPECIAL POINTS

• Effect is self-limiting - as plasma HCO3- falls (hyperchloremic acidosis), less HCO3- is filtered, so the drug "runs out of substrate"
• Unlike other diuretics, CAIs cause acidic blood (hyperchloremic metabolic acidosis) and alkaline urine
• The urinary alkalinization is useful to prevent calcium phosphate stones? No - actually calcium phosphate precipitates in alkaline urine, so CAIs can cause renal calculi
• Paradoxically, alkaline urine from CAIs is useful for uric acid and cystine stones (which precipitate in acidic urine)

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QUICK RECALL MNEMONICS

• Ototoxicity
• Thromboembolic episodes (volume depletion)
• Osmolality changes (hyponatremia)
• Tetany (hypocalcemia, rare)
• Overuse → hypovolemia
• Xcreted K+ ↑ (hypokalemia)
• Increase uric acid (hyperuricemia)
• C = hypochloremic alkalosis

• Spironolactone / eplerenone = aldosterone antagonists
• Amiloride, triamterene = ENaC blockers
• Female (gynecomastia from spironolactone)
• E = Eplerenone (more selective)
• K = Keeps potassium

• Glucose ↑ (hyperglycemia)
• Lipids ↑ (mild)
• Uric acid ↑ (hyperuricemia)
• Calcium ↑ retained (hypercalcemia / treat hypercalciuria)
• Hypokalemia, Hyponatremia, Hypomagnesemia
• Alkalosis (metabolic)
• Metolazone = works even in CKD

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