Diuretics

Question 1

Explain the main points about the PCT in the kidneys

Answer 1

Sodium is taken up and co-transports the H2O
• 65-70% of Na+ reabsorbed.

There are lots of basal Na+/K+-ATPases to retain the sodium gradient

Oncotic pressure is assisted by the movement of:
• proteins & sodium

Carbonic anhydrase on inside the lumen ensures that bicarbonate is broken down
• to allow CO2 and H2O to pass into the cell
• HCO3- can be reabsorbed
• H+ can be used to drive the Na+/H+ exchanger (at apical membrane)
• (onenote!!)

Many drugs are exported OUT of the PCT into the lumen

Question 2

Explain the main points about the LoH in the kindeys

Answer 2

Descending limb
– only H2O reabsorption via AQA molecules

Ascending limb:
– Impermeable to water for countercurrent flow
– Triple transporter (Na, Cl, K) re-absorbs ions
 Na+ is also reabsorbed para-cellularly
 This generates the hypertonic interstitium

Question 3

Explain the Countercurrent Effect of the Kidneys

Answer 3

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 IN to 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 4

Explain the main points about the EARLY DCT in the kidneys

Answer 4

Mediated by the Na+/Cl—co-transporter
• draws more ions into the interstitium

Impermeable to free water reabsorption
• mediated mainly by selective AQA2 channels under VP control (much more common in late DCT than early though)

NO gap junctions so not permeable to free re-uptake.

Question 5

Explain the main points about the LATE DCT & Collecting Duct in the kidneys

Answer 5

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 6

What are the 2 ways diuretics can work?

Answer 6

1. INHIBITING the reabsorption of Na+ & Cl-
   • raising excretion
2. Increasing the osmolarity of the tubular fluid
   • decrease osmotic gradient (i.e. osmotic diuretics)

Question 7

What are the 5 main classes of diuretics?

Answer 7

1. Osmotic diuretics
2. Carbonic anhydrase inhibitors
3. Loop diuretics
4. Thiazides
5. Potassium-sparing diuretics

Question 8

Which diuretics are used clinically used?

Answer 8

ONLY
• loop diuretics
• thiazides
• K+-sparing

Question 9

How do Osmotic Diuretics work?

Answer 9

Reduce water re-uptake at any part of the nephron that enables water re-absorption
• i.e. PCT, LoH & CD

Pharmacologically inert and is NOT reabsorbed after being filtered

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 10

What are osmotic diuretics normally used?

Answer 10

NOT as a diuretic

Used to raise PLASMA OSMOLARITY to fraw out fluid from cells & tissues
• e.g. in oedema

Question 11

Example of a osmotic diuretic drug?

Answer 11

Mannitol

Question 12

How do Carbonic Anhydrase diuretics work?

Answer 12

Acts at the PCT

By inhibiting the carbonic anhydrase, acetazolamide can:
• Increase HCO3- in the tubular fluid
• Increase the pH of the cell as LESS H+ ions are made from CO2 and H2O and so…
• Less Na+ is taken back up by the Na+/H+-anti-porter

Question 13

What effect does Carbonic Anhydrase therefore have on the reabsorption of Na+ and H20

Answer 13

Action on Na+ reabsorption
• inhibit Na+ and HCO3- reabsorption in PCT

Action on H2O reabsorption
• increase tubular fluid osmolarity –> decrease water reabsorption

Question 14

What other effect can carbonic anhydrase inhibitors have and when can this cause an issue?

Answer 14

Increase delivery of HCO3- to DCT
AND
increase K+ loss

• This is bad for patients taking Digoxin
• 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 15

Example of a Carbonic Anhydrase Inhibitor drug?

Answer 15

Acetazolamide

Question 16

How do Loop Diuretics work?

Answer 16

Acts on the ascending limb of the LoH

Loop diuretics are strong diuretics
– 15-30%

Inhibit the triple transporter:
• impacts the countercurrent effect (less H20 reabsorption in CD)

Results in:
• K+ and Na+ loss
as well as
• loss of Ca2+ and Mg2+

Question 17

How does Loop Diuretics cause the loss of Ca2+ & Mg2+

Answer 17

There is a small leak of K+ into the tubule from the cell physiologically
• 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

Example of a Loop Diuretic Drug?

Answer 18

Frusemide

Question 19

How do Thiazides work?

Answer 19

Act on the early DCT

Inhibit the Na+/Cl- co-transporter.
• not as strong as loop diuretics – 5-10%

Results in:
• K+ and Mg2+ loss and
• Ca2+ re-absorption (via an unknown mechanism)

Na+ may not be lost but exchanged in the late DCT with potassium so K is lost but not Na?

Question 20

What other effect do Thiazides have?

Answer 20

Increase Na+ delivery to DT

• increase K+ loss (as increase in Na+/k+ exchange)

Question 21

Example of a thiazide drug?

Answer 21

Bendroflumethiazide

Question 22

What is an problem that BOTH thiazides & loop diuretics have?

Answer 22

Release of RENIN from macula densa cells

Question 23

Explain the problem with BOTH thiazides & loop diuretics

Answer 23

Macula densa cell that detects the tubular [Na+] in the late ascending thick limb of the LoH

What effect would diuretics have on renin secretion?
• decreased Na+ load in the tubule will INCREASE renin secretion
• to promote Na+ reabsorption

Therefore diuretics would promote renin secretion

These effects result in resistance to chronic use diuretics!

Question 24

What diuretic would have the greatest effect on renin secretion?

Answer 24

LOOP DIURETICS

as they retain MORE Na+ in the tubule

Question 25

What is the final issue that BOTH thiazides and loop diuretics lead to and how is it tackled?

Answer 25

These effects result in resistance to chronic use diuretics! So very common to administer ACE Inhibitors with diuretics

Question 26

How do K+-sparing diuretics work?

Answer 26

Spironolactone – aldosterone receptor agonist Amiloride – aldosterone-sensitive Na+ channel inhibitor These are not very powerful diuretics – 5% • 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 27

Classes of K+ sparing drugs?

Answer 27

Spironolactone – aldosterone receptor agonist Amiloride – aldosterone-sensitive Na+ channel inhibitor

Question 28

Common SEs seen with the use of diuretics?

Answer 28

Hypovolaemia – loop diuretics – thiazides Hyponatraemia – loop diuretics – thiazides Hypokalaemia – loop diuretics – thiazides Metabolic alkalosis – loop diuretics – thiazides Hyperuricaemia – loop diuretics – thiazides – Loop diuretics have a more powerful effect of all Hyperkalaemia – K+-sparing diuretics Metabolic acidosis – carbonic anhydrase inhibitors

Question 29

Exampl the Hyperuricaemia SE seen with the use of diruetics

Answer 29

Diuretic drugs use the OAT to transport into the tubule from the drug and thus can compete with uric acid in the blood This can lead to a greater blood concentration of uric acid OAT = Organic Anion Transporter

Question 30

Why are other diuretics NOT K+-sparing?

Answer 30

Other diuretics cause an INCREASE in [Na+] reaching the CD • leads to increased Na+/K+ exchange in the CD • results in lots of K+ being LOST in the urine

Question 31

Explain the clinical use of diuretics in hypertension

Answer 31

Thiazides are the 1st line treatment in many countries • Thiazides are especially useful in salt-sensitive hypertension Thiazides > calcium channel blockers > ACEi – for treating high SBP

Question 32

Explain the response seen in patients with hypertension when given thiazides

Answer 32

Due to DECREASE in BV 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 33

Explain the clinical effects of diuretics use in HF and oedema?

Answer 33

Loop diuretics Acute reduction in congestion o but will increase renin secretion --> cardiac remodelling Chronic use is associated with resistance & RAS activation o additional use of K+ sparing diuretics is used to try to stop the rebound activation of RAS