H3i: List the classes of drugs that are useful in inducing diuresis & outline their mechanism of action

  • Diuresis = ↑Na+ & H2O loss from the kidneys
  • 1° aim of drug diuresis is to ↑Na+ excretion (KA NATRIURESIS) to ↓ECF volume

Factors Affecting Diuretics

  • To work, a diuretic must reach its SoA
  • Most work on nephron lumen
  • Aldosterone works intracellularly
  • CA Inhibitors work on lumen & intracellularly
  • Diuretics gain access via GF
  • Some have large PPB (i.e. frusemide)
  • ∴effect of diuretic will be blunted with ↓GFR, ↓PPB, or by other drugs competing for binding

Diuretics Grouped Based on SoA

  • PCT: osmotic diuretics, carbonic anhydrase inhibitors
  • Ascending LoH: loop diuretics
  • Distal tubule: thiazides
  • Collecting duct: K-sparing diuretics, aquaretics

Osmotic Diuretics

  • Small molecular weight substances
  • Freely filtered at glomerulus
  • Not/minimally reabsorbed
  • Do not act on a membrane protein
  • Simply exert an osmotic force
  • 65% Na+ & H2O reabsorbed @ PCT → ∴need to act here to score $$$
  • The osmotic force inhibits fluid reabsorption
  • Causes some Na+ loss
  • But the Na+ can be reabsorbed downstream @ thick asc. LoH
  • Natriuresis only 10% of filtered load (because acts so early)
  • In disease: glucose
  • Therapeutics: mannitol

Also

  • Impairs H2O reabsorption of Thin Desc. LoH because dissipates ISF osmotic gradient
  • ↑RBF

Carbonic Anhydrase Inhibitors

  • Enzyme CA present in PCT (heaps), Thick Asc. LoH & Intercalated cells of Collecting Duct
  • Present in tubule lumen & tubule cells

Drives equation: H+ + HCO3– ⮂ H2CO3 ⮂ H2O + CO2

  • Non-competitive inhibition of CA by acetazolamide blocks NaHCO3 reabsorption by:
    • ↓H+ supply in tubule cell
    • H/Na antiporter can’t work
    • Na+ is not reabsorbed, H2O follows
    • 1/3 Na+ reabsorbed by Na/H antiporter
    • Modest diuresis
    • NaHCO3 loss creates alkaline urine & metabolic acidosis in plasma
Carbonic Anhydrase Inhibitors

Loop Diuretics

  • Most efficacious diuretics
  • Inhibit Na/K/2Cl symporter on Thick Asc. LoH
  • ↓Na & H2O reabsorption
  • 25% Na+ reabsorbed at Thick Asc. LoH
  • & responsible for counter-current multiplication
  • ∴kidney loses huge Na+ load & ability to concentrate urine
  • Occurs late in nephron ∴limited ability to reabsorbed Na+ later

Also

  • ↑RBF
  • Loss of +ve potential from K+ recycling which aids Mg2+/Ca2+ reabsorption = Mg2+/Ca2+ loss

Thiazide Diuretics

  • Inhibits Na/Cl cotransporter on DCT → ↓Na+ reabsorption
  • DCT is impermeable to H2O
  • Acts in cortex, not medulla ∴no effect on counter-current multiplication
  • 10% of filtered Na+ is lost

Also

  • ↑Ca2+ reabsorption
    • By blocking Na/Cl transporter
    • ↓IntraC Na+
    • ∴↑activity of Ca2+/3Na+ exchanger
Thiazide Diuretics

K+ Sparing Diuretics

  • Act at late DCT & collecting duct (because this is where K+ secretion occurs)
  • 2 types:
    1. SPIRO → antagonises aldosterone
    2. AMILORIDE → blocks Na+ entry on Apical Na+ channel

Principle Cells

Spironolactone

  • Synthetic steroid
  • Competitive antagonist of aldosterone
  • Binds aldosterone receptor → inactivates
  • Prevents translocation of receptor & binding to DNA
  • ∴
    • 1) Failure to synthesise proteins which stimulate Na/K/ATPase pump
    • 2) Upregulate apical Na+ channel
  • ↓Na+ reabsorption & stops K/H+ secretion

Amiloride

  • Blocks apical Na+ channel
  • ↓Na+ reabsorption & ∴Na/K/ATPase activity on BL membrane
  • Inhibition of K+ secretion is due to loss of voltage ∆
  • NB: Trimethoprim causes ↑K+ by same mechanism as amiloride!

Aquaretics

  • Antagonist V2 receptors on BL membrane
  • Inhibit action of ADH
  • Stops H2O reabsorption at collecting duct

Helpful to treat patient with hypo-osmotic ECF due to failure to excrete solute free H2O because ↑ADH from non-osmotic/non-haemodynamic mechanism (i.e. SIADH)