Diuretics

• Diuretics


  Drugs that increase the rate of urine flow and sodium excretion, used to adjust the volume and/or composition of body fluids
• Nephron


  • The basic urine-forming unit of the kidney, consisting of a filtering apparatus (glomerulus) connected to a long tubular portion that reabsorbs and conditions the glomerular ultrafiltrate
  • Each human kidney is composed of approximately one million nephrons
• Renal tubular transport


  1. Na+,K+–ATPase in basolateral membrane hydrolyzes ATP, transporting Na+ into intercellular/interstitial spaces and K+ into cell

  2. Na+ diffuses across luminal membrane via Na+ channels down electrochemical gradient

  3. Na+-linked symporters in luminal membrane cause concentration of substrates to rise in epithelial cell

  4. Accumulation of Na+ and other solutes in intercellular space creates osmotic pressure differential, driving water movement

  5. Water and solute movement into intercellular space increases hydrostatic pressure, driving bulk water flow and solute convection out of intercellular space
• Principles of diuretic action

  • Diuretics increase rate of urine flow and Na+ excretion, decreasing total-body NaCl content
  • Renal compensatory mechanisms (e.g. sympathetic activation, renin-angiotensin-aldosterone axis) bring Na+ excretion in line with intake, limiting sustained natriuresis
• Mechanism of action of carbonic anhydrase inhibitors

  1. Potently inhibit membrane-bound and cytoplasmic carbonic anhydrase, nearly abolishing NaHCO3 reabsorption in proximal tubule

  2. Also inhibit carbonic anhydrase involved in acid secretion in collecting duct
• Osmotic diuretics


  Agents that are freely filtered, undergo limited reabsorption, and increase plasma/tubular fluid osmolality
• Mechanism of action of osmotic diuretics

  1. Limit osmosis of water into interstitial space, reducing luminal Na+ concentration and net Na+ reabsorption

  2. Major site of action is the loop of Henle, where they reduce medullary hypertonicity and impair water reabsorption
• Acetazolamide


  May provide symptomatic relief in patients with altitude sickness, more appropriate to give as a prophylactic measure, useful in patients with familial periodic paralysis
• Mechanism of acetazolamide's beneficial effects in altitude sickness and familial periodic paralysis


  May be related to the induction of a metabolic acidosis
• Acetazolamide


  Causes vasodilation in human beings by opening vascular Ca2+-activated K+ channels, but clinical significance is unclear
• Osmotic diuretics


  Agents that are freely filtered at the glomerulus, undergo limited reabsorption by the renal tubule, and are relatively inert pharmacologically
• Mechanism and Site of Action of Osmotic Diuretics

  1. Osmotic diuretics limit the osmosis of water into the interstitial space and thereby reduce luminal Na+ concentration to the point that net Na+ reabsorption ceases

  2. Osmotic diuretics expand the extracellular fluid volume, decrease blood viscosity, and inhibit renin release

  3. Osmotic diuretics reduce medullary tonicity, which decreases the extraction of water from the DTL and limits the passive reabsorption of NaCl in the ATL

  4. Osmotic diuretics interfere with transport processes in the thick ascending limb, mechanism unknown
• Loop Diuretics, High-Ceiling Diuretics

  Drugs that inhibit the activity of the Na+–K+–2Cl– symporter in the thick ascending limb of the loop of Henle
• Inhibitors of Na+–K+–2Cl– symport in the thick ascending limb are highly efficacious, and for this reason, they sometimes are called high-ceiling diuretics
• Mechanism and Site of Action of Loop Diuretics

  • Inhibitors of Na+–K+–2Cl– symport bind to the Na+–K+–2Cl– symporter in the thick ascending limb and block its function, bringing salt transport in this segment of the nephron to a virtual standstill
  • Inhibitors of Na+–K+–2Cl– symport also inhibit Ca2+ and Mg2+ reabsorption in the thick ascending limb by abolishing the transepithelial potential difference
• Inhibitors of Na+–Cl– Symport (Thiazide and Thiazide-like Diuretics)

  Benzothiadiazides were synthesized to enhance the potency of inhibitors of carbonic anhydrase, but were found to predominantly increase NaCl excretion, an effect independent of carbonic anhydrase inhibition
• Mechanism and Site of Action of Thiazide Diuretics

  Thiazide diuretics inhibit the Na+–Cl– symporter, and Na+ or Cl– binding to the Na+–Cl– symporter modifies thiazide-induced inhibition of the symporter, suggesting the thiazide-binding site is shared or altered by both Na+ and Cl–