21: Diuretics Flashcards
What happens in the proximal convoluted tubule of the kidney?
60-70% of Water and Na reabsorbtion
- Apical membrane is permeable to water and Na+
- Basal Membrane: Na+/K+ ATP ase to transport Na+ out
- Water: transcellularly or paracellularly via oncotic pressure
- Also important: Bicarbonate reabsorbtion and H+ ecretion
- Active drug /exogenous agent excretion
What happens at the Loop of Henle?
- The Descending Limb is waterpermeable
- The Ascending Limb is waterimpermeable and actively reabsorbs Na+/Cl+/K+ (via an cotransporter) (with some K+ loss)
- This forms an extracellular osmogradient via the countercurrent mechanism
Explain the counter-current mechanism in the kidney
In the ascending limb ions are actively pumped out to the interstitium and therefore: interstitium has a higher osmolality and fluid in tubule have a lower osmolality
- In decending limb: water will diffuse out to interstitioum to counteract t the high osmolality –> fluid will get more conentrated in descending limb and less concentrated in ascending limb
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What happens in the distal convoluted tubule of the kidney?
Early:
- More Watera and Salt resorbtion (Na+/Cl- cotransporter)
Later: Site of control
- Still water and Salt resorbtion
- aldosterone sensitive
- VP sensitive
What happens in the collecting duct of the kidney?
Site of controll:
- aldosterone sensitive
- VP sensitive
(But Aldosterone Na+ resorbtion might cause K+ ecretion and Cl- reabsobtion due to NA+ K+ ATPase)
How do osmodiuretics work?
Work in the whole system of the kidney by increasing the osmolarity of the tubular fluid
How and where doe Carbonic anhydrase inhibitors work as a diuretic in the kidney?
Work in the proximal convoluted tubule
- by inhibiting Carbonic anhydrase
- Prevent reabsorbtion of Bicarbonate
- No H+/ Na+ exchanger on apical membrane
Explain the MOA of Loop diuretics
Inhibit the Na+/Cl+/K+ cotransporter in ascending limb of loop of henle
–> less Na+ and Cl- reabsorbtion and therefore
- increased tubular osmolarity
- decreased interstitial osmolarity
- less Water reabsorbtion
Explain the effects of Loop Diuretics on electrolytes
Decrease levels of
- Na+
- Cl-
- K+ –> loss of K+
- Ca2+
- Mg2+
Why do loop diuretics and thiazide diretics increase the risk of hypokalaemia?
Because less Na+ is reabosrbed in the loop of henle, tubular fluid will still be rich in Na+
- (late) Distal convoluted tubule will try to absorb as much Na+ as possible
- Is transported into interstitium at basal membrane via Na+/K+ exchangers
- K+ loss
Explain the MOA of Thiazide diuretics
Work in the early Distal Convoluted Tubule
- block the Na+/Cl+ cotransporter
- increase tubular fluid osmolarity = decreased H2O reabsorption in the collecting duct
What are the effects of Thiazide diuretics on Electrolytes
Decreases
- Na+
- K+
- Cl+
- Mg2+
But increases
- Ca2+
What are the effects of diuretics on renin secretion?
They increase renin secretion due to
- decrease in renal perfusion pressure
- decrase in blood Na+ levels
Name a loop diuretic
Frusemide (furosemide)
Name a Thiazide diuretic
bendrofluazide (bendroflumethiazide)
Explain the MOA of Potassium Sparing Diuretics
Aldosterone receptor antagonists
Inhibitors of aldosterone-sensitive Na+ channels
- Inhibit Na+ reabsorption (and concomitant K+secretion) in early distil tubule – 5%
- tubular fluid osmolarity = ¯ H2O reabsorption in the collecting duct.
What are the effects of Potassium Sparing diuretics on electrolyte balance?
Decrease
- Na+
Don’t change
- K+
Increase
- H+ (decreased Na+/H+ exchange)
Whar are the side effects of Loop and thiazide diuretics?
- Hypokalaemia
- Hyponatraemia
- Hypotension
- Metabolic alkalosis (due to Cl- loss)
- Hyperuricemia
What are the side effects of Potassium sparing diuretics?
Hyperkalaemia –> Less Na+/K+ exchange
How do loop diruretics/ K+ sparing diuretics cause hyeruricemia?
The diuretics need to reach the transporter on the apical membrane: first need to go through the cell and the basal membrane
- The Diuretics and Uric acid use the same transporter on the basal membrane and therefore compete for it –> less uric acid excretion
Explaint the use of diuretics in the treamtment of Hypertension
1st line treatment in “Salt Sensitive” populaiton
- over 55
- Affro-american/carribeal origin
Causing
- initially: a diuretic effect
- longterm:
- tolerance is likely to develop –> restoring of blood volume (via RAAS)
- induces vasodilation –> recution in TPR (Activation of eNOS (endothelium) , Ca2+ channel antagonism, opening of KCa channel (smooth muscle) )
Explain the use of Diuretics in Heart failure
To reduce
- congestion
- Na+ and Water retention to reduce blood volume
–> often together with ACE inhibitor to counteract activtion of RAAS
Otherwise: additional K+ sparing diuretic
What kind of K+ sparing diuretics are there?
Name example for each
- Aldosterone receptor antagonists
- e.g. spironolactone
- Inhibitors of aldosterone-sensitive Na+ channels
- e.g. amiloride
How does transport into the drug target differn in spironolactone compared to furosemide and/or bendrofluazide?
Spironolactone= lipid soluble, no need for transporter mechanism
REst= acidic, tranported by transporter mechanism
