Diuretics

Question 1

What are diuretics?

Answer 1

Drugs that act on the renal tubule to promote excretion of Na+, Cl- + H2O

Question 2

What percentage of filtered fluid is reabsorbed in the proximal tubule?

Answer 2

65-70%

Question 3

How does water move into the epithelial cells from the lumen in the proximal tubule?

Answer 3

Osmosis: follows the diffusion of Na+ into the cell

Question 4

What important protein is present on the basolateral membrane of epithelial cells along most of the tubule and is responsible for maintaining the concentration gradient that allows sodium reabsorption?

Answer 4

Na+/K+ ATPase

Question 5

What other force is present, within the interstitium, that helps draw water in from the tubule?

Answer 5

Oncotic pressure: proteins in the blood in the arterioles draws water towards blood

Question 6

Other than transcellularly, what other route is there for the movement of ions and water?

Answer 6

Paracellular pathway

Question 7

What is the paracellular pathway dependent on?

Answer 7

Gap junctions

Question 8

What 2 molecules in the filtrate are reabsorbed in the proximal tubule coupled with Na+ reabsorption? Which protein allows this movement?

Answer 8

Glucose
Amino acids
Sodium-Hydrogen exchanger protein

Question 9

Explain how sodium exchange is linked to carbonic anhydrase?

Answer 9

HCO3- + H+ are filtered in the glomerulus
Carbonic anhydrase converts them to H2O + CO2, which freely diffuse into the proximal tubule epithelial cell
Inside the epithelial cell, carbonic anhydrase converts them back to H+ + HCO3-
HCO3- is cotransported with Na+ into the interstitium
H+ is exchanged for Na+ at the apical membrane via the Na+/H+ exchanger

Question 10

How are exogenous agents removed in the kidneys?

Answer 10

Drugs are removed by transport proteins that pick up drugs as they pass through the kidneys + transport them into the lumen

Question 11

Describe the permeability of the loop of Henle to water.

Answer 11

Descending limb is freely permeable to water but not to ions
Ascending limb is impermeable to water but is permeable to ions

Question 12

What is the main channel present on the apical membrane of the epithelial cells of the ascending limb of the loop of Henle?

Answer 12

Na+/K+/2Cl- cotransporter

Question 13

What channels are present on the basolateral membrane of the epithelial cells of the ascending limb of the loop of Henle?

Answer 13

Na+/K+ ATPase

K+/Cl- cotransporter

Question 14

Describe how the counter-current system is established.

Answer 14

Filtrate travels down the LOH + as it goes up the ascending limb, Na+ moves from the tubule to the interstitium thus making the interstitium hypertonic + tubular fluid hypotonic.
Then, more fluid comes down the descending limb (permeable to water) + the hypertonic interstitium attracts water + increases reabsorption of water from the tubule into the interstitium
This increases the conc. of fluid reaching the ascending tubule where even more Na+ will be reabsorbed + move into the interstitium
This occurs repetitively, resulting in a hypertonic interstitium + hypotonic tubular fluid leaving the LOH
Hypertonic interstitium is also responsible for increasing water reabsorption in the CD (mediated by vasopressin)

Question 15

What are the main channels on the apical membrane of epithelial cells of the distal tubule?

Answer 15

Na+/Cl- cotransporter

Aldosterone dependent sodium channels

Question 16

Which channels are found on the basolateral membrane of the epithelial cells of the distal tubule?

Answer 16

Na+/K+ ATPase

K+/Cl- cotransporter

Question 17

Which aquaporin molecules are found in epithelial cells of the distal tubule?

Answer 17

AQP2: apical membrane

AQP3/AQP4: basolateral membrane

Question 18

Which vasopressin receptors are present on collecting duct cells?

Answer 18

V2 receptors

Question 19

Describe the effect of aldosterone on collecting duct cells.

Answer 19

Aldosterone stimulates production of Na+ channels + Na+/K+ ATPases

Question 20

Describe the effect of vasopressin on collecting duct cells.

Answer 20

Vasopressin stimulates production + assembly of AQP2 molecules thus increasing the ability of the CD to reabsorb water

Question 21

List the five groups of diuretics.

Answer 21

Osmotic Diuretics  
Carbonic Anhydrase Inhibitors  
Loop Diuretics  
Thiazide Diuretics  
Potassium Sparing Diuretics

Question 22

Give an example of an osmotic diuretic.

Answer 22

Mannitol

Question 23

Describe the mechanism of action of osmotic diuretics.

Answer 23

Increases plasma + urine osmolarity
Filtered by the glomerulus but not reabsorbed
Increasing osmolarity of filtrate means less water leaves the lumen + is reabsorbed

Question 24

What are osmotic diuretics used for?

Answer 24

Mainly used for their effect in increasing plasma osmolarity –they draw out fluid from cells + tissues (e.g. in oedema)

Question 25

Give an example of a carbonic anhydrase inhibitor

Answer 25

Acetazolamide

Question 26

Give an example of a loop diuretic.

Answer 26

Frusemide (furosemide)

Question 27

How much fluid loss can loop diuretics cause?

Answer 27

15-30%

Question 28

What is the target of loop diuretics?

Answer 28

Na+/K+/2Cl- cotransporter in ascending limb of LOH

Question 29

Explain how loop diuretics exert their diuretic effect.

Answer 29

Block the triple transporter thus reducing reabsorption of Na+ in the ascending limb This increases tubular fluid osmolarity thus reducing water reabsorption so urine fluid volume increases

Question 30

Explain why loop diuretics cause an increase in urinary excretion of Mg2+ and Ca2+.

Answer 30

K+ recycling, in normal conditions, means a certain amount of K+ in the tubular fluid maintains the positive lumen potential + drive other positively charged ions (Mg2+ + Ca2+) into the interstitium via the paracellular pathway Loop diuretics cause loss of K+ recycling meaning there is insufficient K+ in the lumen to drive the other positive ions through the paracellular pathway so you get increased urinary excretion of Mg2+ + Ca2+

Question 31

Why do loop diuretics cause an increase in K+ loss?

Answer 31

Loop diuretics increase the concentration of Na+ in the tubular fluid that is reaching the distal tubule So there is increased Na+/K+ exchange in distal tubule --> increased K+ loss

Question 32

What are the main uses of loop diuretics?

Answer 32

Oedema + Heart failure

Question 33

What are 6 unwanted effects of loop diuretics?

Answer 33

``` Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis Hyperuricemia Hyponatremia ```

Question 34

Give an example of a thiazide diuretic.

Answer 34

Bendrofluazide

Question 35

Where do thiazide diuretics act and what do they act on?

Answer 35

Act in the distal tubule | Bind to the Na+/Cl- cotransporter

Question 36

How much fluid loss can thiazide diuretics cause?

Answer 36

5-10% fluid loss

Question 37

What effect do thiazide diuretics have on Mg2+ and Ca2+?

Answer 37

Increase in Mg2+ + Ca2+ reabsorption | unknown mechanism

Question 38

What are the main uses of thiazide diuretics?

Answer 38

Hypertension | Heart failure

Question 39

What are 6 unwanted effects of thiazide diuretics?

Answer 39

``` Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis (increased Na+/K+ exchange causes increased K+ loss) Hyperuricemia Hyponatremia ```

Question 40

What effect do loop diuretics have on the macula densa cells?

Answer 40

Macula densa cells have the same Na+/K+/2Cl- cotransporter that is present in the ascending limb of the LOH + is targeted by loop diuretics This means loop diuretics prevent the entry of Na+ into macula densa cells, thus stimulating renin secretion

Question 41

Where are macula densa cells found?

Answer 41

At the top of the ascending limb of the LOH | where it comes very close to the afferent arteriole

Question 42

Explain the counter-productive effects of loop and thiazide diuretics on the renin-angiotensin system.

Answer 42

They cause loss of Na+ in the urine, so cause reduced Na+ in the blood meaning less Na+ is filtered in the glomerulus + hence less Na+ reaches the macula densa cells Also reduce blood volume + pressure Both reduction in Na+ reaching the macula densa + reduced renal perfusion pressure are stimuli for renin secretion This leads to aldosterone production, which promotes Na+ reabsorption (hence counterproductive to the desired diuretic effects)

Question 43

What measure can be taken to prevent the actions of unwanted activation of RAAS when using diuretics?

Answer 43

Give ACE inhibitors with the diuretics

Question 44

What are the two classes of potassium sparing diuretic? Give an example of a drug that falls into each class.

Answer 44

Aldosterone receptors antagonist: spironolactone | Inhibitors of aldosterone-sensitive sodium channels: amiloride

Question 45

How much fluid loss can potassium-sparing diuretics cause?

Answer 45

5%

Question 46

Describe the effects of potassium-sparing diuretics.

Answer 46

Reduce Na+ reabsorption in the late distal tubule, which leads to increased tubular osmolarity Results in reduced water reabsorption from the tubular fluid in the CD Also lead to increased H+ retention (because of reduced Na+/H+ exchange)

Question 47

What is the main use of amiloride?

Answer 47

Given with K+ losing diuretics

Question 48

What is the main use of spironolactone?

Answer 48

Hypertension/ heart failure (alongside loop diuretic)

Question 49

State an unwanted effect of K+ sparing diuretics.

Answer 49

Hyperkalaemia: metabolic acidosis (due to less Na+/K+ exchange)

Question 50

By what mechanisms of action can diuretics work?

Answer 50

Inhibit reabsorption of Na+ + Cl- (increase excretion) | Increase osmolarity of tubular fluid (decrease osmotic gradient across epithelia)

Question 51

How do thiazides exert their diuretic effect?

Answer 51

Inhibit Na+ + Cl- reabsorption in early distal tubule | Increase tubular fluid osmolarity, decreasing water reabsorption in the CD

Question 52

Why can diuretics cause hyperuricemia?

Answer 52

Diuretics + uric acid use the same transport protein to access tubular cells, thus presence of diuretics means there is competition for transporters