27: Diuretics

Question 1

Na:K ATPase

Answer 1

Pumps sodium into the blood. Located in the basolateral membrane of renal tubular cells. Inhibited by digoxin, ouabain.

Question 2

Carbonic anhydrase inhibitors

Answer 2

• Acetazolamide
• PO, readily filtered
• Acts in the proximal tubule
• Inhibits membrane bound and cytoplasmic carbonic anhydrase
• Self-limited NaHCO3 diuresis, reduction in total-body HCO3 stores, inhibited H+ secretion –> metabolic acidosis

Question 3

Osmotic diuretics

Answer 3

• Mannitol, urea, glucose (in DM)
• IV, readily filtered
• Poorly reabsorbable
• Proximal tubule
• Cause obligatory water retention in the lumen, increasing delivery of NaCl and H2O out of all segments; rapid urine flow ↓reabsorption, ↑formation dilute urine

Question 4

Loop diuretics

Answer 4

• Furosemide, bumetanide
• PO, readily filtered
• Secreted in proximal tubule via organic acid transporter (OAT)
• Inhibits Na:K:2Cl co-transporter (NKCC)
  
  • ​Inhibits dilution, concentration of urine
  • Promotes Ca & Mg excretion
  • Vasodilation (stimulates PGE release)
• Toxicity = OH DANG
  
  • Ototoxicity (hearing loss/tinnitis)
    
    • Supporting cells fail to secrete K into endolymph
  • Hypokalemia
  • Dehydration (volume depletion)
  • Alkalosis
  • Nephritis (interstitial)
  • Gout (hyperuricemia)

Question 5

Bartter’s Syndrome

Answer 5

• Genetic dz resembling chronic furosemide use
• Mutation in: NKCC or ROMK or CLC-Kb

Question 6

Thiazide diuretics

Answer 6

• Hydrochlorthiazide, chlorthiazide
• PO, readily filtered
• Distal tubule
• Secreted by **organic anion transporter (OAT) **in proximal tubule
• Inhibits **NaCl cotransporter (TSC) **reabsorption
  
  • ​↑delivery NaCl out distal tubule
  • inhibits dilution but not concentration of urine
  • ↓Ca excretion
• Toxicity: volume depletion, hypokalemia, glucose intolerance, hypercholesterolemia, hyponatremia

Question 7

Gitelman’s syndrome

Answer 7

• Genetic dz resembling chronic thiazide use
• Via mutation in thiazide-sensitive co-transporter (TSC): Na:Cl co-transporter
• Mild volume depletion, hypocalciuria, hypomagnesiuria

Question 8

Sodium channel blockers

Answer 8

• Amiloride, triamterene
• “Potassium-sparing diuretics”
• PO, readily filtered
• Cortical collecting tubule
• Inhibits epithelial Na channel (ENaC), reducing lumen negative charge potential causing:
  
  • Inhibited H+ secretion
  • Inhibited K+ secretion
• Toxicity: hyperkalemia (if patient acidotic) can cause arrhythmias

Question 9

Aldosterone antagonists

Answer 9

• Spironolactone, eplerenone
• PO, readily filtered
• Cortical collecting tubule
• “Potassium-sparing diuretic”
• Compete with aldosterone for binding to its receptor, reducing activity of ENaC and H+ATPase, reducing lumen negative potential resulting in:
  
  • Inhibited H+ secretion
  • Inhibited K+ secretion
• Toxicity: hyperkalemia (if acidotic) may cause arrhythmias

Question 10

Resistance to diuretics

Answer 10

XS diuresis –> volume depletion –> ↑renin, AII, aldo

• Decreased delivery:
  
  • ↑AII –> ↑FF, ↑NaCl absorption in PT –> ↓Na delivery to site of action of diuretics
• Increased reabsorption:
  
  • ​↑aldo –> NaCl absorption in CT

Question 11

Vasopressin

Answer 11

Binds V2 receptor –> ↑cAMP –> fusion of vesicles containing aquaporin 2 with apical membrane –> ↑water reabsorption, ↑urine concentration

Question 12

Vasopressin V2 receptor antagonists

Answer 12

• Conivaptan
• “Aquaretics”
• Decrease production of cAMP –> inhibit fusion of aquaporin 2 vesicles
• Allow dilute urine to be excreted