21: Diuretics

Question 1

What happens in the proximal convoluted tubule of the kidney?

Answer 1

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

Question 2

What happens at the Loop of Henle?

Answer 2

1. The Descending Limb is waterpermeable
2. The Ascending Limb is waterimpermeable and actively reabsorbs Na+/Cl+/K+ (via an cotransporter) (with some K+ loss)
3. This forms an extracellular osmogradient via the countercurrent mechanism

Question 3

Explain the counter-current mechanism in the kidney

Answer 3

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
  *

Question 4

What happens in the distal convoluted tubule of the kidney?

Answer 4

Early:

• More Watera and Salt resorbtion (Na+/Cl- cotransporter)

Later: Site of control

• Still water and Salt resorbtion
• aldosterone sensitive
• VP sensitive

Question 5

What happens in the collecting duct of the kidney?

Answer 5

Site of controll:

• aldosterone sensitive
• VP sensitive

(But Aldosterone Na+ resorbtion might cause K+ ecretion and Cl- reabsobtion due to NA+ K+ ATPase)

Question 6

How do osmodiuretics work?

Answer 6

Work in the whole system of the kidney by increasing the osmolarity of the tubular fluid

Question 7

How and where doe Carbonic anhydrase inhibitors work as a diuretic in the kidney?

Answer 7

Work in the proximal convoluted tubule

• by inhibiting Carbonic anhydrase
• Prevent reabsorbtion of Bicarbonate
• No H+/ Na+ exchanger on apical membrane

Question 8

Explain the MOA of Loop diuretics

Answer 8

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

Question 9

Explain the effects of Loop Diuretics on electrolytes

Answer 9

Decrease levels of

• Na+
• Cl-
• K+ –> loss of K+
• Ca2+
• Mg2+

Question 10

Why do loop diuretics and thiazide diretics increase the risk of hypokalaemia?

Answer 10

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

Question 11

Explain the MOA of Thiazide diuretics

Answer 11

Work in the early Distal Convoluted Tubule

• block the Na+/Cl+ cotransporter
• increase tubular fluid osmolarity = decreased H2O reabsorption in the collecting duct

Question 12

What are the effects of Thiazide diuretics on Electrolytes

Answer 12

Decreases

• Na+
• K+
• Cl+
• Mg2+

But increases

• Ca2+

Question 13

What are the effects of diuretics on renin secretion?

Answer 13

They increase renin secretion due to

• decrease in renal perfusion pressure
• decrase in blood Na+ levels

Question 14

Name a loop diuretic

Answer 14

Frusemide (furosemide)

Question 15

Name a Thiazide diuretic

Answer 15

bendrofluazide (bendroflumethiazide)

Question 16

Explain the MOA of Potassium Sparing Diuretics

Answer 16

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.

Question 17

What are the effects of Potassium Sparing diuretics on electrolyte balance?

Answer 17

Decrease

• Na+

Don’t change

• K+

Increase

• H+ (decreased Na+/H+ exchange)

Question 18

Whar are the side effects of Loop and thiazide diuretics?

Answer 18

1. Hypokalaemia
2. Hyponatraemia
3. Hypotension
4. Metabolic alkalosis (due to Cl- loss)
5. Hyperuricemia

Question 19

What are the side effects of Potassium sparing diuretics?

Answer 19

Hyperkalaemia –> Less Na+/K+ exchange

Question 20

How do loop diruretics/ K+ sparing diuretics cause hyeruricemia?

Answer 20

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

Question 21

Explaint the use of diuretics in the treamtment of Hypertension

Answer 21

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) )

Question 22

Explain the use of Diuretics in Heart failure

Answer 22

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

Question 23

What kind of K+ sparing diuretics are there?

Name example for each

Answer 23

1. Aldosterone receptor antagonists
   
   • e.g. spironolactone
2. Inhibitors of aldosterone-sensitive Na+ channels
   
   • e.g. amiloride

Question 24

How does transport into the drug target differn in spironolactone compared to furosemide and/or bendrofluazide?

Answer 24

Spironolactone= lipid soluble, no need for transporter mechanism

REst= acidic, tranported by transporter mechanism