Week 15 Pharmacology

Overview of renal function.

  • PCT
    • NaHCO3, H2O, NaCl out of tubule
    • NaH counter transport, chloride/base counter transport
    • Acetazolamide acts at NaHCO3
    • Osmotic agents eg mannitol act at H2O
  • Thin descending Loop
    • H2O out
    • Osmotic agents
  • Thick ascending loop
    • NaK2Cl actively out, Ca2+, Mg2+ secondarily transported out(due to 2 neg charge coming with cl-)
    • Loop diuretics inhibit NaK2CL channel
    • PTH increase Ca absorption\
  • Distal convoluted tubule
    • NaCl co transporter, Ca2+ abs (due to PTH and also to balance CL- coming in)
    • Ca/Na countertransport, Ca/H active counter transport – both to pump Ca into interstitum. ????
    • Thiazides act on NaCl
  • Collecting duct
    • NaCl, H2O out of tubule
    • Principal cells – Na out via ENaC, K in via channel, Cl comes in between cells.
    • Aldosterone increase NaCl abs
    • Intercalated cell – apical H+ in ATPase, basal HCO3/Cl countertransport.
    • ADH increase H2O out
    • ADH antagonists act here, aldosterone antagonists act here
    • K+, H+ secreted into tubule

Throughout the whole tubule the NaK ATPase pumps Na into interstitum at the basolateral membrane to continue absorbtion at apical side

Classification & mechanism of action of diuretics as a group

  • Carbonic anhydrase inhibitors
    • Azetazolamide
    • Decrease HCO3 reabsorption–> hyperchloremic metabolic acidosis, decrease intra occ pressure
    • Use – glaucoma, mountain sickness, edema with alkalosis
    • Duration – 8-12hrs
    • Toxicity – metabolic acidosis, renal calculi, hyperammonemia in cirrhotics
  • Osmotic diuretics
    • Mannitol
    • Marked increase in urinary flow, reduced brain volume, decrease IOP, initial hypoNa then HyperNa
    • Use – renal failure due to increased solute load (eg rhabdo, chemotheraphy), increase ICP, glaucoma
    • IV admin
    • Toxicity – nausea, vomiting, headache
  • Loop diuretics
    • Frusemide
    • Inhibit NaK2Cl channel in ascending loop of henle
    • Marked increase in NaCL loss, K wasting, increase urine Ca and Mg –> hypokalaemic metabolic alkalosis
    • Uses – pulm oedema, peripheral oedema, HTN, anion overdose, acte hyperK or hyperCa
    • Duration of action 2-4hrs
    • Toxicity – ototoxicity, hypovolaemia, hypoK, hypoMg, hyperuricaemia
  • Thiazides
    • HCT
    • Inhibits Na/Cl channel in DCT
    • Modest increase in NaCL excretion, some K wasting –> hypokalaemic metabolic aklalosis, decreased Urine Ca
    • Uses: HTN, mild CCF, nephrolithiasis, nephrogenic diabetes insipidus
    • Duration 8-12hrs
    • Toxicity – hypokalaemic metabolic aklalosis, hyperuricaemia, hyperglycaemia, hyponatraemia
  • K sparing agents
    • Spironolactone
      • aldosterone antagonists, weak antagonism of androgen receptors
      • Reduce Na retention and K wasting
      • Uses – aldosteronism from any cause, hypokalaemia due to other diuretics, postMI
      • Slow onset/offset of action. Duration 24-48hrs
      • Toxicity – hyperkalaemia, gynaecomastia
    • Amiloride
      • Blocks epithelial Na channels in collecting tbules
      • Reduce Na retention and K wasting, increase lithium clearance
      • Toxicity – hyperK metabolic acidosis.

 

 

Viva questions:

  • What types of diuretics do you know ? lead-in to discussion of specific agent.
  • How do diuretics work ?
  • Tell me about Frusemide.
  • Tell me about Thiazides
  • Tell me about spironalactone/amiloride
  • Tell me about mannitol.