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 
• 
  

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.
• 
  
• 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)

James Cole Case wrap up

 Upr/Cr = "spot" protein instead of 24 hour protein.


James had pitting edema


Non-pitting edema indicates hypothyroidism (myxedema) or lymphedema

oval fat bodies are proximal tubular cells filled with lipids

ultrasound normal size 11cm; not chronic condition; increased echogenicity increased density.

negative serologies rule out systemic diseases causing nephrotic syndrome.

foot process effacement in EM specific for minimal change disease.

Treatment

• furosemide
• lisinopril - to decrease proteinuria.  High Pcap causes increased GFR and increased protein loss.  protein in tubule lumen triggers inflammation.  lisinopril blocks AT2 and dilates efferent arteriole = decreased Pcap and decreased proteinuria.  risk-benefit analysis = decreased GFR vs. protein inflammation.
• prednisone - decreased IL-1,3; decreased TH2 cells
• simvastatin - low albumin = increased liver synthesis of lipoproteins.
• heparin - risk of thrombosis due to loss of plasminogen, antithrombin, plus liver produces more fibrinogen. 

Glomerular filtration barrier

Mechanism of Edema in Nephrotic Syndrome

• Underfill hypothesis
• low protein in plasma = fluid shift to interstitial space = underfill = stimulation of RAS = Na retention and H2O 

 

• Overfill hypothesis
• low albumin doesn't always cause edema
• animals with no adrenal glands develop edema
• new theory = filtration of plasminogen.  converted to plasmin by urokinase.  Plasmin activates Na channels causing Na and H2O retention.