Diuretics

Question 0

Are most diuretics more dependent on glomerular filtration or on tubular secretion?

Answer 0

More dependent on tubular secretion.

Question 1

4 main sites of sodium reabsorption in the nephron?

Answer 1

Proximal tubule (PT) - 50-70% .
Thick ascending loop of Henle (tALH) - 25%.
Distal convoluted tubule (DCT) - 5%.
Collecting duct (CD) - 3%.

Question 2

Which class of diuretics targets proximal tubule?

Answer 2

Carbonic anhydrase inhibitor.

Question 3

How do carbonic anhydrase inhibitors produce a diuretic effect?
How do they affect HCO3-, Na+, and K+ excretion?

Answer 3

Reabsorption of HCO3- is blocked, and it doesn’t have a chance to be absorbed in the distal nephron, since usually bicarb is really low by then. (Osmotic diuresis from increased HCO3-?)
Increased HCO3- excretion.
Not much affect on Na+.
Increased K+ secretion in distal tubule (probs due to increased neg. charge in lumen).

Question 4

Clinical utility of carbonic anhydrase inhibitors?

Answer 4

Correction of alkalosis. (this… makes a lot of sense)
Last-ditch correction of hyperkalemia.

(Altitude sickness and glaucoma too… but I wouldn’t worry about that.)

Question 5

4 examples of loop diuretics? (probably the first one, which you already know, is most important to know)

Answer 5

Furosemide (Lasix)
Bumetanide
Torsemide
Ethacrynic acid

Question 6

Target of loop diuretics?

Answer 6

NKCC2 in the tALH.

Question 7

3 conditions for which loop diuretics are used?

Answer 7

Hypervolemia / Na+ retention (“edematous disorders”).
Hyperkalemia.
Hypercalcemia. (rarely.. for bone-lysing tumors.)

Question 8

4 potentially deleterious solute perturbations that can result from loop diuretics?

Answer 8

Hypokalemia.
Hypocalcemia / hypercalciuria.
Hypomagnesemia.
Hyperuricemia (-> gout).

Question 9

2 non-renal adverse effects of loop diuretics?

Answer 9

Ototoxicity (worse with ethacrynic acid).
Sulfa allergy (doesn't apply to ethacrynic acid).

Question 10

Given ethacrynic acid has a worse side effect profile than other loop diuretics, why would one ever use it?

Answer 10

All the other loop diuretics have a sulfa moeity.

If you have a sulfa allergy, and need a loop diuretic, you have to use ethacrynic acid.

Question 11

What is the “braking phenomenon” for loop diuretics?

Answer 11

After a few days, nephron will increase Na+ absorption at other sites, returning total body Na+ to a new, lower steady state.
This is good… you don’t want to lose all your volume.

Question 12

What drugs inhibit Na+ reabsorption in the distal tubule?

What’s the molecular target?

Answer 12

Thiazide diuretics inhibit the Na/Cl cotransporter.

Question 13

How do thiazide diuretics affect Ca++?

Answer 13

Reabsorption of Ca++ is increased.
In the DCT Ca++ is reabsorbed via the Ca++/Na+ antiporter on the basolateral membrane. Apparently the activity of the Ca++/Na+ antiporter (Na+ into cell, Ca++ out to blood) is increased due to decreased intracellular Na+ (which is a bit counterintuitive, but I guess the cell wants to maintain Na+ levels).

Question 14

4 clinical uses of thiazide diuretics?

Answer 14

First line Tx for HTN.
Edematous states (with a loop diuretic).
Idiopathic hypocalciuria.
Hyperkalemia.

Question 15

Effect of thiazide diuretics on K+ handling?

Answer 15

K+ secretion is increased.
(Why? There will be increased Na+ in the collecting duct, and Na+ reabsorption there is coupled to K+ secretion. Wasn’t mentioned in lecture… but this didn’t make sense to me.)

Question 16

4 solute-related side effects of thiazide diuretics?

Answer 16

Hypokalemia.
Hyponatremia.
Hyperuricemia.
Increased Ca++ reabsorption.

Question 17

1 non-renal side effects of thiazide diuretics?

Answer 17

Impaired insulin release / diminished use of glucose.

Question 18

Loop diuretics and thiazide diuretics have a lot of similar effects. What are two ways that they’re different?

Answer 18

Loop diuretics increase Ca++ excretion, thiazides increase Ca++ reabsorption.
Loop diuretics decrease ability to concentrate urine, by destroying the medullary tonicity gradient; thiazides don’t inhibit the ability to concentrate urine.

Question 19

Which is more likely to cause hyponatremia: a thiazide or a loop diuretic? Why?

Answer 19

Thiazide.
Because the ability to concentrate urine is preserved when taking thiazides, if ADH is present, free water can be reabsorbed in the collecting duct.
Not so with loop diuretics - even if ADH is present, water can’t be reabsorbed well in the collecting duct.

Question 20

What type of diuretic is “potassium sparing”? What is the molecular target, where in the nephron does it act, and why does it spare K+?

Answer 20

Inhibitors of aldosterone or of ENaC in the collecting duct spare potassium.
If Na+ is not absorbed in the collecting duct, the electrochemical gradient does not favor K+ secretion into the lumen.

Question 21

Review: Which cells in the collecting duct express ENaC?

Answer 21

Principal cells.

Question 22

2 examples of ENaC blockers?

Answer 22

Amelioride and triamterene.

Question 23

2 examples of aldosterone antagonists?

Answer 23

Spironolactone and eplerenone.

Question 24

Clinical utility of K+ sparing diuretics?

Answer 24

They’re not very potent natriuretics (recall only 3-5% of filtered Na+ is reabsorbed in the collecting duct), but they can be used in combo with other diuretics to help prevent hypokalemia.

Question 25

Advantage of spironolactone vs. other K+ diuretics?

Answer 25

There are several… but notably it doesn’t require tubular secretion, and works at low EABV.
(making it quite good for CHF)

Question 26

Side effects of K+ sparing diuretics?

Answer 26

Intuitively, hyperkalemia in those predisposed to it.

Spironolactone can cause gynecomastia.

Question 27

2 major sites where osmotic diuretics cause a different in water absorption?

Answer 27

Proximal tubule, loop of Henle.

Question 28

Do osmotic diuretics cause more Na+ or water diuresis?

Answer 28

They cause loss of both, but more water than Na+, potentially leading to hypernatremia.
(but it’s complicated. Remember HHNK.)

Question 29

Review: How do you inhibit ADH?

Answer 29

With a “-vaptan”. But these haven’t yet been shown to improve mortality.