6. Diuretics

Question 1

describe the transporters involved in Na+ transport in different parts of the nephron

Answer 1

Basolateral Na/K ATPase used throughout nephron.

Apical Na+ transporters vary:

• PCT: Na/H antiporter and several symporters, eg SGLT2, Na/AA, etc.
• TAL: NKCC2
• Early DCT: Na/Cl symporter
• Late DCT and CD: ENaC

Question 2

what is a diuretic

Answer 2

drug that promotes diuresis (increased urine formation by kidneys) via increased renal excretion of Na+ and H2O, leading to decreased ECF volume

Question 3

which type of diuretic is the most potent? where and how do these act?

Answer 3

• loop diuretics (eg furosemide)

- act at TAL by inhibiting NKCC2

Question 4

which type of diuretics act in the early DCT? what is their MOA?

Answer 4

• thiazide diuretics

- inhibit Na/Cl symporter

Question 5

name the K+ sparing diuretics? where and how do these act

Answer 5

Act in late DCT and CD:

• amiloride: inhibits ENaC
• spironolactone: aldosterone antagonist (competes for binding at aldosterone Rs)

Question 6

why do K+ sparing diuretics decrease K+ secretion

Answer 6

In late DCT and CD, Na reabsorption via ENaC creates -ve potential in lumen - favours K+ secretion through ROMK.

• Amiloride inhibits ENaC - no Na reabsorption so no K+ secretion.
• Spironolactone antagonises aldosterone (normally increases expression of ENaC, ROMK and Na/K ATPase) - no Na reabsorption so no K+ secretion.

Question 7

why can loop diuretics cause hypocalcaemia and hypomagnesaemia

Answer 7

K+ carried across apical membrane in TAL by NKCC2 drifts back into lumen via K+ channels… creates +ve luminal potential… drives reabsorption of +ve charged Ca2+ and Mg2+.

So inhibition of NKCC2 by loop diuretics increases Ca2+ and Mg2+ secretion.

Question 8

which diuretic is used in the treatment of hypertension

Answer 8

thiazides - only inhibit 5% Na reabsorption but effective in causing vasodilation

Question 9

which diuretic is used in treatment of heart failure

Answer 9

1. loop diuretics: treatment of oedema (and associated symptoms, eg SOB due to pulmonary oedema) via diuretic effect and vaso/venodilation (decreased after/preload)
2. aldosterone-antagonists (spironolactone): decreased mortality in HF (due to negative impact of aldosterone on heart?)

Question 10

which diuretic is used in treatment of fluid retention and oedema in nephrotic syndrome, renal failure and liver cirrhosis

Answer 10

1. aldosterone-antagonists (spironolactone)

2. loop diuretics (add-on)

Question 11

which diuretic is used in treatment of hypercalcaemia

Answer 11

loop diuretics - inhibit Ca2+ reabsorption by inhibiting NKCC2

Question 12

which diuretic is used in treatment of Conn’s syndrome-associated hypertesion

Answer 12

Conn’s syndrome (1 hyperaldosteronism due to adrenal hyperplasia/tumour) causes increased aldosterone so treated via spironolactone - aldosterone antagonist

Question 13

why do loop and thiazide diuretics result in hypokalaemia

Answer 13

Loop and thiazide diuretics block Na and H2O reabsorption in TAL or early DCT…

1. increased Na and H2O delivery to late DCT and CD:
   - increased Na reabsorption by principal cells… favourable electrochemical gradient for K+ excretion
   - faster flow rate of filtrate in lumen… K+ secreted into lumen is washed away faster… decreased K+ conc. in lumen… favourable electrochemical gradient for K+ excretion
2. decreased circulatory volume… RAAS activation… increased aldosterone secretion… increased Na reabsorption and K+ secretion

So increased K+ loss in urine.