Pharmacology

• Diuretics


  Drugs that increase the volume of urine excreted
• Most diuretic agents are inhibitors of renal ion transporters that decrease the reabsorption of Na+ at different sites in the nephron
• Kidney structure


  • Glomerular filtration
  • Tubular reabsorption
  • Tubular secretion
  • Water conservation
• Filtrate volume: women 150L/day, men 180L/day. Urine: 1%. Reabsorption: 99%
• Proximal convoluted tubule


  Active absorption of sodium chloride, sodium bicarbonate, glucose, amino acids, organic solutes. Followed by passive absorption of water
• Loop of Henle


  • Descending loop: Permeable to water, osmolarity increases along the descending portion due to countercurrent mechanism
  • Ascending loop: Impermeable to water but permeable to sodium by Na+-K+-2Cl- cotransporter. About 25% of filtered sodium is absorbed here
• Distal convoluted tubule


  Active transport of sodium by Na+/Cl- symport. Calcium excretion is regulated (Parathomone and Calcitriol)
• Collecting tubule and duct

  Aldosterone causes sodium reabsorption by Na+/H+/K+ exchange. ADH makes collecting tubular epithelium permeable to water. Sodium retention and potassium excretion
• Diuretic efficacy


  • High Efficacy (Loop or High-Ceiling Diuretics)
  • Moderate Efficacy (Thiazides and Related Agents)
  • Weak Efficacy (Carbonic Anhydrase Inhibitors, Osmotic Diuretics)
  • Weak Efficacy (Potassium Sparing Diuretics)
• Loop or High-Ceiling Diuretics

  1. Inhibit the cotransport of Na+/K+/2Cl− in the luminal membrane in the ascending limb of the loop of Henle

  2. Diuresis: Fast, powerful, short, mass loss of Na+, K+, Cl-, Ca2+, Mg2+

  3. Vasodilation: Dilating renal artery, ↑ renal blood flow, beneficial to acute renal failure
• Thiazides and Related Agents

  Affect the distal convoluted tubule, "low ceiling diuretics" as increasing dose does not promote further diuretic response
• Thiazide diuretics


  • Chlorothiazide
  • Hydrochlorothiazide
  • Benzthiazide
  • Hydroflumethiazide
  • Chlorthalidone
  • Metolazone
  • Xipamide
  • Clopamide
  • Indapamide
• Thiazide mechanism of action


  Act mainly in the cortical region of the ascending loop of Henle and the distal convoluted tubule to decrease the reabsorption of Na+, apparently by inhibition of a Na+/Cl− cotransporter on the luminal membrane of the tubules
• Thiazide actions


  • Increased excretion of Na+ and Cl−
  • Loss of K+
  • Loss of Mg2+
  • Decreased urinary calcium excretion
  • Reduced peripheral vascular resistance
• Potassium-Sparing Diuretics


  Act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion. Two mechanisms: Aldosterone antagonists (spironolactone) and Sodium channel blockers (amiloride)
• Spironolactone


  Antagonizes aldosterone, preventing translocation of the receptor complex into the nucleus and failure to produce proteins that stimulate Na+/K+-exchange in the collecting tubule
• Amiloride


  Blocks Na+ transport channels, decreasing Na+/K+ exchange. Not very efficacious as a diuretic but used in combination with other diuretics for potassium-sparing properties
• Carbonic Anhydrase Inhibitor (Acetazolamide)


  Inhibits carbonic anhydrase in the proximal tubule, leading to decreased reabsorption of Na+, HCO3-, and water
• Osmotic Diuretics


  Increase water excretion rather than Na+ excretion, used to maintain urine flow following acute toxic ingestion capable of producing acute renal failure