Diuretics + renal pharmacology Flashcards
(39 cards)
What are the regulatory roles of the kidneys?
- Fluid balance
- Acid-base balance
- Electrolyte balance
Where in the nephron does most of the water and electrolyte reabsorption take place?
PCT
(thus is main site of action of diuretics)
What is reabsorbed in the ascending and descending limbs of the LoH?
Descending limb: water
Ascending limb: solutes (via NKCC2 transporter); impermeable to water as no aquaporin channels on luminal membrane
List the main types of drugs acting on the renal tubules
- Carbonic anhydrase inhibitors
- Osmotic diuretics (mannitol)
- SGLT2 inhibitors
- Loop diuretics
- Thiazides
- Potassium sparing diuretics
- Aldosterone antagonists
- ADH antagonists
Define the terms; diuretic, natiuretic, aquaretic
Diuretic:
Increased production of urine
Natiuretic:
Loss of sodium in urine
Aquaretic:
Loss of water without electrolytes
For each of the different types of diuretics, list their primary site of action in the nephron
- Carbonic anhydrase inhibitors: PCT
- Osmotic diuretics: PCT
- Loop diuretics: ascending limb of LoH
- Thiazides: DCT
- K+ sparing diuretics (aldosterone receptor antagonists eg spironolactone): late DCT + early CD
- ADH antagonists: CD
Explain the mechanism of action of carbonic anhydrase inhibitors
- Inhibition of CA thus reduced HCO3- and Na+ reabsorption at PCT
- Reduced HCO3- reabsorption thus less H+ ions to drive Na+/H+ exchanger- thus decreased Na+ reabsorption
- Enhances Na+ delivery results in K+ loss in the collecting duct; ENaC, due to acidosis as well
Carbonic anhydrase splits carbonic acid into CO2 + H2O
Describe the transport of ions through ENaC channels
Na+ reabsorbed into tubular cells via ENac
K+ goes other way and is secreted via ENaC into the tubular lumen
Describe and explain the side effects of carbonic anhydrase inhibitors
Loss of NaHCO3-
Hypokalaemic metabolic acidosis; hypokalaemia due to upregulation of ENaC + acidosis due to loss of HCO3-
Tolerance developed after 2/3 days
What are carbonic anhydrase inhibitors used for now?
- Glaucoma
- Mountain sickness
Why are diuretics that target transporters further upstream not ideal?
As the transporters downstream can become upregulated and try to compensate for the actions earlier on in the tubule
Give an example of an osmotic agent (diuretic) and describe its mechanism of action
Mannitol
Draws water to it thus draws water into the tubular lumen via osmosis
Causes an osmotic diuresis
Can have effects along entire tubule, but mostly occurs at PCT due to increased water reabsoption at PCT
Briefly describe the effects and risks of mannitol (osmotic diuretic)
- Loss of water
- Reduced intracellular volume
- Risk of HYPERNATRAEMIA
Are SGLT2 inhibitors a diuretic, natiuretic or aquaretic?
Natiuretic; loss of Na+ in urine
Describe the mechanism of action of SGLT2 inhibitors
- Inhibit reabsorption of Na+ and glucose in PCT
- Increased Na+ and glucose within tubular lumen leads to increased uric acid secretion into lumen
- Leads to GLUCOSURIA + NATIURESIS
(useful in metabolic syndrome as this is associated with hyperuricaemia)
Explain why SGLT2 inhibitors can be useful in diabetic patients
- Increased NaCl delivery to macula densa in DCT
- Macula densa thinks there is a high BP
- Thus causes afferent arteriole constriction
- Reducing glomerular pressure + hyperfiltration
- Protective against diabetic nephropathy
Give the main clinical effects of SGLT2 inhibitors
- Low plasma glucose levels
- Reduced body weight
- Reduced BP
- Reduced plasma uric acid (beneficial in metabolic syndrome)
- Reduced glomerular hyperfiltration (useful in DM)
Give an example of a loop diuretic
Furosemide
Describe the mechanism of action of loop diuretics
- Inhibit NKCC2 co-transporter on luminal membrane
- Normally, K+ back diffusion through ROMK is a driving force for cation reabsorption (Ca2+, Mg2+)- ROMK facilitates Ca2+ + Mg2+ reabsorption
- Thus, with LD, increased divalent Ca2+ + Mg2+ loss
- Loss of H+- metabolic alkalosis
- Enhanced Na+ delivery results in K+ loss in CD (increased stimulation of ENaC channes thus more open)
List the main clinical findings of loop diuretics and explain why they can be used to treat hypercalcaemia
- Loss of Na+ and water
- Hypokalaemic metabolic alkalosis
- Increased Ca2+ + Mg2+ loss (hypocalcaemia + hypomagnesaemia); thus LD’s can be used for Tx of hypercalcaemia
Describe the mechanism of action of thiazide diuretics
- Inhibit Na+/Cl- co-transporter in DCT
- Low intracellular Na+ facilitates Ca2+ reabsoprtion via NCX on basolateral membrane
- Enhanced Na+ delivery results in K+ loss in collecting duct (ENaC upregulation)
List the main clinical features of thiazide diuretics
- Loss of Na+ and water
- Hypokalaemic metabolic alkalosis (due to loss of H+ via NHX on luminal membrane)
- Increased Ca2+ reabsorption- hypercalaemia (opposite to LD’s)
Describe how aldosterone acts to increased BP via its action on the nephron
- Increases expression of ENaC on luminal membrane of collecting duct
- Increases expression of Na+/K+ ATP ase in principal cells of CD
- Increased Na+ thus water reabsorption
- Thus increased; effective circulating blood volume, SV, CO, BP
Describe the mechanisms of action of spironolactone and amiloride
- Spironolactone: mineralocorticoid/aldosterone receptor antagonist; blocks mineralocorticoid receptor, preventing effects of aldosterone
- Amiloride: inhibits ENaC channels in CD; counteracting effect of aldosterone
