Diuretics

Question 1

What percentage of sodium is reabsorbed?

Answer 1

60-70% in the convoluted tubule

Question 2

What are the features of the PCT that allows reabsorption of sodium an water?

Answer 2

• lots of basal Na+/K+-ATPases to retain the sodium gradient
• Oncotic pressure is assisted by the movement of proteins and sodium
• Carbonic anhydrase on inside the lumen ensures that bicarbonate is broken down to allow CO2 and H2O to pass into the cell

Question 3

What happens in the descending loop of Henle?

Answer 3

only H2O reabsorption via AQA molecules

Question 4

What happens in the ascending loop of Henle?

Answer 4

Impermeable to water – for countercurrent flow

Triple transporter (Na, Cl, K) re-absorbs ions
- Na+ is also reabsorbed para-cellularly -> generates the hypertonic interstitium

Question 5

How is the countercurrent effect generated?

Answer 5

1. Loop is filled with isotonic fluid
2. Na+ is pumped out of the ascending limb into the interstitium. Fluid in ascending limb decreases in osmolarity
3. Concentrated interstitium pulls water into it from descending limb. Fluid in descending limb increases in osmolarity
4. More fluid flows into the tubule and shifts the descending limb fluid into the ascending limb
5. Na+ is pumped again out of the ascending limb into the interstitium. Ascending limb fluid decrease in osmolarity
6. Na+ is pumped again out of the ascending limb into the interstitium. Ascending limb fluid decrease in osmolarity

Question 6

What happens in the early DCT?

Answer 6

Draws more ions into the interstitium -mediated by the Na+/Cl—co-transporter

Impermeable to free water reabsorption
(no gap junctions), mediated mainly by selective AQA2 channels under VP control (much more common in late DCT than early though).

Question 7

What happens in the late DCT (collecting duct)?

Answer 7

Aldosterone induces Na+-channel production

VP induces AQA2 synthesis dependant on blood osmolarity
- AQA3/4 constitutively expressed on basal membrane

Impermeable to free water re-uptake – osmolarity increases as you pass deeper into the medulla so any free absorption would ruin the gradient as water would pass back into the tubular fluid

Question 8

How do diuretic work?

Answer 8

by:

• Inhibiting the reabsorption of Na+ and Cl- - raising excretion
• Increasing the osmolarity of the tubular fluid – decrease osmotic gradient (i.e. osmotic diuretics)

Question 9

What are the 5 main classes of diuretics? Give examples of each

Answer 9

1. Osmotic diuretic e.g mannitol
2. Carbonic anhydrase inhibitors e.g acetazolamide
3. Loop diuretics e.g furosemide (frusemide)
4. Thiazides e.g bendroflumethiazide (bendrofluazide)
5. Potassium-sparing diuretics e.g miloride, spironolactone

• only last three used clinically

Question 10

How do osmotic diuretics work?

Answer 10

Reduce water re-uptake at any part (PCT, LoH, CD) of the nephron that enables water re-absorption

Only action is to decrease the osmotic gradient by raising the osmolarity of the tubular fluid -> reduce water reabsorption

• Interferes with the countercurrent flow

Question 11

Are osmotic diuretics reabsorbed?

Answer 11

Pharmacologically inert and not reabsorbed after being filtered.

Question 12

How do carbonic anhydrase inhibitors work?

Answer 12

• Acts at the PCT.

By inhibiting the carbonic anhydrase, acetazolamide can:

• Increase bicarbonate in the tubular fluid
• Increase the pH of the cell as LESS H+ ions are made from CO2 and H2O -> Less Na+ is taken back up by the Na+/H+-anti-porter

Question 13

What is the effect of carbonic anhydrase inhibitors on sodium reabsorption?

Answer 13

inhibit Na+ and HCO3- reabsorption in PCT

Question 14

What is the effect of carbonic anhydrase inhibitors on water reabsorption?

Answer 14

increase tubular fluid osmolarity -> decrease water reabsorption

Question 15

What are other effects of carbonic anhydrase?

Answer 15

increase delivery of HCO3- to DCT and increase K+ loss

• This is bad for patients taking Digoxin!

Question 16

Why are carbonic anhydrase inhibitors not used clinically?

Answer 16

The kidney is good at compensating and as this drug acts early in the kidneys, they have a long time to compensate for it and thus it is not very effective and isn’t used much clinically

Question 17

How do loop diuretics work?

Answer 17

Acts on the ascending limb of the LoH

Inhibit the triple transporter -> Impacts the countercurrent effect -> Results in K+ and Na+ loss as well as loss of Ca2+ and Mg2+

There is a small leak of potassium into the tubule from the cell physiologically and furosemide inhibits this -> less positive luminal pressure -> less paracellular transport of ions

Mg2+ and Ca2+ ion loss due to loss of K+ recycling

Question 18

How do thiazides work?

Answer 18

Act on the early DCT

Inhibit the Na+/Cl—co-transporter -> Results in K+ and Mg2+ loss and Ca2+ re-absorption (via an unknown mechanism)

Question 19

What effect would diuretics have on renin secretion?

Answer 19

Decreased sodium load in the tubule will increase renin secretion to promote sodium reabsorption therefore diuretics would promote renin secretion

Question 20

What diuretic would have the greatest effect on renin secretion?

Answer 20

loop diuretics - retain more sodium in tubule

Question 21

What is a problem with thiazides and loop diuretics?

Answer 21

resistance to chronic use diuretics

Question 22

How do potassium sparing diuretics work?

Answer 22

Spironolactone – aldosterone receptor agonist

Amiloride – aldosterone-sensitive Na+ channel inhibitor

Inhibit sodium reabsorption in the early DCT

Also cause decreased reabsorption of Na+ in the DCT and increased H+ retention -Due to effects of decreased Na+/H+ exchange

Question 23

What are the side effects of diuretics?

Answer 23

Loop diuretics and thiazides: 
- Hypovolaemia 
- Hyponatraemia 
- Hypokalaemia 
- Metabolic alkalosis
 Hyperuricaemia 

• Loop diuretics have a more powerful effect of all

K+-sparing diuretics:
- Hyperkalaemia

carbonic anhydrase inhibitors:
- Metabolic acidosis

Question 24

How do diuretics cause hyperuricaemia?

Answer 24

Diuretic drugs use the OAT to transport into the tubule from the drug and thus can compete with uric acid in the blood -> can lead to a greater blood concentration of uric acid

Question 25

What are thiazides used for clinically?

Answer 25

1st line treatment in many countries for hypertension
- especially useful in salt-sensitive hypertension

Thiazides > calcium channel blockers > ACEi – for treating high SBP

Question 26

Describe the response to thiazides

Answer 26

• Initial (4-6 weeks) – reduction of BP due to reduction of blood volume
• After 4-6 weeks – plasma volume restored due to tolerance
• Chronic thiazides – reduction of TPR due to – activation of eNOS, Ca2+-channel antagonism and opening of KCa-channels. Leads to -> NO production, less calcium influx and hyperpolarisation

Question 27

What are loop diuretics used for clinically?

Answer 27

heart failure and oedema

acute reduction in congestion
- But will increase renin secretion -> cardiac remodelling

Question 28

What is chronic use of loop diuretics associated with? How is this accommodated for?

Answer 28

resistance and RAS activation

- Additional use of K+ sparing diuretics is used to try to stop the rebound activation of RAS