Diuretics

Question 1

what are the main channels in the PCT on the basal side (into blood)?

Answer 1

basal Na+/K+ ATPases (into interstitum)

there are also Na+/HCO3- co-transporters on this side

Question 2

what is the function of the basal Na+/K+-ATPases?

Answer 2

maintain the sodium gradient across the cell so it can keep coming from the tubule

NB basal is closest to the interstitium

Question 3

what creates the oncotic pressure in the interstitum?

Answer 3

movement of protein and sodium

Question 4

how is bicarbonate taken in at the PCT from the tubule?

Answer 4

bicarbonate is converted to water and CO2 by carbonic anhydrase in the lumen.
These products can cross into the cell and are converted to bicarbonate (and H+) by intracellular carbonic anhydrase

Question 5

where are drugs exported out of?

Answer 5

the PCT

Question 6

how much sodium is reabsorbed at the PCT?

Answer 6

65-70% of Na+ reabsorbed.

Question 7

what occurs at the descending limb (DL) of the Loop of Henle (LoH)?

Answer 7

• only H2O reabsorption via AQP molecules
• impermeable to ions
  i. e. it is permeable to water

Question 8

what occurs the AL of LoH?

Answer 8

• ions like sodium can move out
• impermeable to water
• interstitial becomes hypertonic (more ions)

Question 9

what is the purpose of the AL of LoH being impermeable?

Answer 9

to establish the counter current flow so there is water reabsorption at the collecting ducts

Question 10

what is the main transporter in the AL of LoH?

Answer 10

Triple transporter (Na, Cl, K)
sodium and chloride are mainly reabsorbed 

sodium can move in paracellularly

Question 11

how is the countercurrent flow established?

Answer 11

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 (ion loss)
3. Concentrated interstitium (with more sodium) pulls water from descending limb. Fluid in descending limb increases in osmolarity (more ions left in it- becomes concentrated)
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.

Question 12

what is the main transporter in the early DCT?

Answer 12

Na+/Cl- co-transporter.

Draws more ions into the interstitium

Question 13

how does water reabsorption occur in the early DCT?

Answer 13

• Impermeable to free water reabsorption (no gap junctions available)
• mediated mainly by selective AQP2 channels under VP control
• much more common in late DCT than early

Question 14

what 2 things occur in the late DCT and collecting duct?

Answer 14

• Aldosterone induces Na+-channel production (amiloride target)
• VP induces AQP2 synthesis dependant on blood osmolarity

Question 15

what AQPs are expressed basally (towards blood) in the collecting duct?

Answer 15

AQP3/4 constitutively expressed on basal membrane

AQP2 from the tubule

Question 16

how does water reabsorption occur in the late DCT and collecting duct?

why is water not freely re-uptaken?

Answer 16

• Impermeable to free water re-uptake
• therefore mediated by channels
• osmolarity increases deeper into the medulla so any free absorption would ruin the gradient as water would pass back into the tubular fluid.

Question 17

what are the main effects of diuretics?

Answer 17

o Inhibiting the reabsorption of Na+ and Cl- (less water moves out of tubules)

o Increasing the osmolarity of the tubular fluid (more water enters tubules)
– decrease osmotic gradient (i.e. osmotic diuretics).

Question 18

what are the 5 main classes of diuretics? which 3 are used clinically usually?

Answer 18

o Osmotic diuretic
- Mannitol
o Carbonic anhydrase inhibitors
- Acetazolamide.
o Loop diuretics
- Furosemide (Frusemide)
o Thiazides
- Bendroflumethiazide (Bendrofluazide)
o Potassium-sparing diuretics
-Amiloride, Spironolactone.

loop diuretics, thiazides and potassium sparing diuretics are mainly used

Question 19

what is the effect of osmotic diuretics like mannitol?

Answer 19

increased tubule osmolarity:

Reduce water re-uptake at any part of the nephron that enables water re-absorption

Question 20

what properties of mannitol allow it to carry out its function?

Answer 20

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 (it contributes to it)

this interferes with the counter current flow

Question 21

where do carbonic anhydrase inhibitors like acetozolamide act?

Answer 21

PCT

Question 22

what is the action of acetozolamide?

Answer 22

by inhibiting the carbonic anhydrase, it can:
o Increase bicarbonate in the tubular fluid.
o Increase the pH of the cell as LESS H+ ions are made from CO2 and H2O
o Less Na+ is taken back up by the Na+/H+-anti-porter.

Question 23

what are the actions of carbonic anhydrase inhibitors?

Answer 23

• inhibition of carbonic anhydrase leads to a reduction of H+ in the PCT
  [remember CA: CO2+H2O–> H+ and HCO3-]
• pH increases in PCT as less H+ is produced
• therefore less Na+ exchanges with the little H+ produced in PCT

knock on effects:

• inhibit Na+ and HCO3- reabsorption in PCT to blood
• increase tubular fluid osmolarity (more Na+) –> decrease water reabsorption.
• Other effects increase delivery of HCO3- to DCT (CA is birectional) and increase K+ loss.

Question 24

where does furosemide act?

Answer 24

Loop diuretic :
Acts on the ascending limb of the LoH on the triple transporter (Na,Cl,K)

very powerful

Question 25

what does furosemide do?

Answer 25

loop diuretic: Inhibit the triple transporter. | Impacts the countercurrent effect.

Question 26

what is the effect of inhibiting the triple transporter (by furosemide)?

Answer 26

action of loop diuretic: - Results in K+ and Na+ loss - as well as loss of Ca2+ and Mg2+ (due to loss of K+ recycling as the positive lumen potential is lost) K+ is lost eventually later down the stream to Na+

Question 27

how does furosemide decrease paracellular transport of ions?

Answer 27

- small leak of potassium back into the tubule from the cell physiologically (called K+ recycling) - furosemide inhibits this so less positive luminal pressure - less paracellular transport of ions including Mg2+, Ca2+

Question 28

where do thiazides like bendroflumethiazide act?

Answer 28

Act on the early DCT not as powerful as loop diuretics

Question 29

what does bendroflumethiazide do?

Answer 29

it is a thiazide: inhibit Na+/Cl- co-transporter in the early DCT

Question 30

what is the effect of inhibition of the Na+/Cl- co-transporter?

Answer 30

done by thiazides: - Results in K+ and Mg2+ loss and Ca2+ re-absorption - Na+ may not be lost but exchanged in the late DCT with potassium so K is lost

Question 31

why do loop diuretics not prevent the loss in K+?

Answer 31

Na+ moves further down to the DCT where its needs to be reabsorbed at the expense of K+

Question 32

what does the macula densa cell detect?

Answer 32

detects the tubular concentration of Na+ in the late ascending thick limb of the LoH.

Question 33

what effect diuretics have on the renin system?

Answer 33

Loop diuretics and thiazides reduce the sodium reaching the macula densa so this will increase renin secretion to promote sodium reabsorption and fluid retention therefore diuretics would promote renin secretion

Question 34

what diuretics has the greatest effect on renin secretion?

Answer 34

Loop diuretics would have the greatest effect as they retain more sodium in the tubule Effects result in resistance to chronic use diuretics

Question 35

what are the potassium sparing diuretic drugs?

Answer 35

1) Spironolactone – aldosterone receptor antagonist and Na/K ATPase inhibitor 2) Amiloride – aldosterone-sensitive Na+ channel inhibitor (lumen channel) antagonise aldosterone actions not powerful

Question 36

what is the effect of potassium sparing diuretic?

Answer 36

- inhibition of aldosterone action means fewer sodium channels are made for the reabsorption of sodium in the early DCT - increased H+ retention due to the effects of decreased Na+/H+ exchange. - K+ is retained as it is not exchanged for Na+

Question 37

what are the side effects of diuretics?

Answer 37

```  Hypovolaemia – loop diuretics and thiazides.  Hyponatraemia – loop diuretics and thiazides.  Hypokalaemia – loop diuretics and thiazides.  Metabolic alkalosis – loop diuretics and thiazides.  Hyperuricaemia – loop diuretics and thiazides. Loop diuretics have a more powerful effect of all.  Hyperkalaemia – K+-sparing diuretics due to less Na/K exchange  Metabolic acidosis – carbonic anhydrase inhibitors. ```

Question 38

why do diuretics cause hyperuricaemia?

Answer 38

Hyperuricaemia is excess urea in the blood Diuretic drugs use the OAT (organic anion transporter) to get into the tubule and compete with uric acid in the blood so uric acid increases in the blood

Question 39

what drug is used as the first line of treatment for hypertension in many countries?

Answer 39

Thiazides

Question 40

in which particular demographic are thiazides particularly useful?

Answer 40

the salt sensitive group - those aged 55+ - those of Afro Caribbean origin at any age

Question 41

what are the two phases of response to thiazides?

Answer 41

- intially diuretic (4-6 weeks) | - then vasodilatory with chronic use (decreased TPR due to NO production)

Question 42

what are the initial and later diuretic responses to thiazides?

Answer 42

``` o Initial (4-6 weeks) – reduction of BP due to reduction of blood volume. o After 4-6 weeks – plasma volume restored due to tolerance. ```

Question 43

what effect does chronic use of thiazides have?

Answer 43

reduction of TPR: - due to activation of eNOS, Ca2+-channel antagonism and opening of K[Ca]-channels - this leads to NO production (vasodilator) ,less calcium influx and hyperpolarisation.

Question 44

which drug is useful in acute reduction of congestion in HF presenting with oedema due to fluid retention?

Answer 44

Loop diuretics | Spironolactone (worsening HF)

Question 45

what is the negative effect of using loop diuretics in HF?

Answer 45

will increase renin secretion (due to reduced sodium load into macula dense) leading to cardiac remodelling.

Question 46

what effect does chronic use of loop diuretics have in association with in HF and oedema treatment? how can this effect be reduced?

Answer 46

problem of resistance and RAS activation. effect reduced with the additional use of K+ sparing diuretics to stop the rebound activation of RAS to reduce water and sodium retention