Thiazide Diuretics (HCTZ, chlorthalidone, metolazone)

Question 1

MoA

Answer 1

1. Inhibit Na/Cl co-transporter in DCT –> decrease NaCl reabsorption
2. Increase Ca2+ reabsorption into blood via volume contraction mechanism
   
   • **volume contraction ONLY occurs with loop diuretics & thiazides, since these induce the greatest amount of blood volume loss through diuresis
   • less volume contraction with thiazides compared to diuretics because thiazides still maintain a corticomedullary gradient (nothing affects their L.O.H), allowing urine concentration to occur when necessary

Question 2

Clinical Uses

Answer 2

1. HTN
2. HF
3. **hypocalcemia & hypercalciuria/history of renal calculi
   
   • along with increased Ca2+ reabsorption at PCT from volume contraction mechanism, decreased Na+ within tubular epithelial cells induces the Na+/Ca2+ exchanger in the DCT to secrete Na+ INTO renal tubule cells in exchange for Ca2+ reabsorption back into blood
4. osteoporosis
5. **nephrogenic DI via volume contraction mechanism
   
   • ​loss of large amount of Na+ and H20 –> increased reabsorption of Na+ (and all solutes that follow) in PCT –> increased reabsorption of H20 –> balances out the hypernatremia from extensive fluid loss –> less electrolyte imbalance + decreased urine output

Question 3

Adverse Effects

Answer 3

1. **SULFA-BASED drug –> risk of allergic reaction!
2. hypokalemic metabolic alkalosis
3. hyponatremia
4. volume contraction causes the following secondary to enhanced Na+ reabsorption at the PCT:
   
   • dehydration
   • hypercalcemia
   • hyperuricemia –> gout risk
   • hyperglycemia
     
     • **also due to hypokalemia causing hyper-polarization of beta islet cells in pancreas, preventing them from being able to depolarize enough to release insulin
   • hyperlipidemia