Diuretics

Diuretics - regulate ECW - via diuresis and natriuresis

Site I = proximal tubule

• acetazolamine (Diamox)
• blocks CA
• decreases H+ secretion
• decreases Na+ reabsorption
• increases Na+ load at distal tubule (stimulates Na-K antiporter = K loss
• increases HCO3- excretion (corrects respiratory alkalosis from hypoxia-induced hyperventilation by causing metabolic acidosis; useful in high altitude) 

Sites 1-5

• Osmotic diuretics; e.g., mannitol - held in tubule
• expand ECF
• increase diuresis and natriuresis
• used to reduce intraocular pressure 
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Site 2 (loop of Henle)

• Furosemide (lasix)
• increased Na, Cl delivery to macula densa: tubuloglomerular feedback = senses increased GFR. macula densa (epithelial cells) release substance (maybe adenosine) that causes afferent vasconstriction. also MD inhibit granular cells release of renin (less AT2) efferent vasodilation.  result = decreased GFR.
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• used in CHF, cirrhosis - reduce edema
• side effects
• hypotension
• hyponatremia
• hypokalemia

Site 3 (distal tubule)

• Thiazides
• increase Na, Cl excretion
• inhibits Na Cl cotransporter in luminal membrane
• increases Na delivery to late distal tubule = Na reabsorption & K loss 
•  side effects
• hypotension
• hyponatremia
• hypokalemia
• decrease insulin sensitivity

 Site 4 (late distal tubule and CD)

• Na channel inhibitors; e.g., amilioride
• inhibit luminal Na channels - prevents Na reabsorption and K loss
• reduce H excretion (block Na - H antiporter)
• side effects
• hyperkalemia
• metabolic acidosis
• Aldosterone antagonists; e.g., spironolactone; eplerenone (more selective)
• block luminal Na channel
• decrease Na-K ATPase
• side effects
• hyponatremia
• hyperkalemia
• metabolic acidosis
• antiandrogenic effects (menstrual irreg.  gynecomastia)

Site 5 (collecting duct)

• Vasopressin antagonists; e.g., conivaptin (iv) tolvaptin (oral)
• block AVP binding to V2 receptors
• side effects
• dry mouth, thirst
• nephrogenic diabetes insipidus (excess water loss)