Week 17 Pharmacology - Diuretics

Question 1

What are the major classes of diuretics?

Answer 1

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

Question 2

How does carbonic anhydrase inhibitors exert a diuretic effect?

Answer 2

Reducing reabsorption of NaHCO3 in proximal convoluted tubule.

Occurs due to the fact that carbonic acid cannot lead to formation of CO2 in filtrate and therefore cannot diffuse into tubular cell, and therefore cannot form carbonic acid in luminal cell. This then reduces the amount of HCO3- that can be reabsorbed in exchange for K+. Also, because less H+ is being formed in tubular cells, there is less Na+ exchange via Na+/H+ exchange in PCT, which means less Na+ is reabsorbed from filtrate.

Question 3

At what location of the Loop of Henle do loop diuretics work?

Answer 3

Thick Ascending limb

Question 4

What is the channel/transport that is the target of loop diuretics?

Answer 4

Na+/K+/2Cl- co-transporter on apical membrane

Question 5

Why are loop diuretics the most powerful diuretic effect?

Answer 5

25% of Na+ reabsorbed normally in loop, and inhibiting its effect cannot be compensated for as it is distal in the nephron, so there is little back-up capacity for reabsorption

Question 6

What channel is present in thick ascending limb basal membrane that allows sodium to be reabsorbed normally:

Answer 6

Na+/K+ ATPase

Chloride channel permits passive movement

Question 7

What ions are secondarily affected by increased secretion due to loop diuretics?

Answer 7

Calcium
Magnesium

Question 8

What is the target of thiazide diuretics?

Answer 8

Early part of distal tubule, inhibit Na/Cl co-transporter

Question 9

How do thiazides cause hypercalcaemia?

Answer 9

1. Decreased sodium reabsorption in distal tubule leads to compensatory increase in reabsorption in proximal tubule which causes electrical gradient that favours increased Ca2+ reabsorption
2. Due to decreased sodium in DCT cells, there is increased activity of Na/Ca2+ exchanger, which leads to increased calcium reabsorption in distal tubule in exchange for Na+ from plasma

Question 10

How do do loop diuretics and thiazides cause hypokalaemia?

Answer 10

Because of increased Na+ reaching collecting duct, there is increased entry into principal cells.

This means the lumen is more negative, which leads to increased movement of potassium from luminal cells into the filtrate, leading to hypokalaemia (going down its electrical gradient)

Question 11

Where is the target of potassium sparing diuretics?

Answer 11

Collecting duct, principal cells.

These cells have separate Na+ and K+ channels on apical surface, and Na/K ATPase on basal membrane.

Question 12

What are the two classes of potassium sparing diuretics?>

Answer 12

Na+ channel blockers in principal cells

Aldosterone antagonists

Question 13

What are names of Na+ channel blocking potassium sparing diuretics?

Answer 13

Amiloride
Triamterene

Question 14

What is the major electrolyte difference with loop vs thiazide diuretics?

Answer 14

Thiazides cause increased Calcium reabsorption and hypercalcaemia.

Loop diuretics leads to hypocalcaemia

Question 15

Describe pharmacology of hydrochlorothiazide:

Answer 15

A: Poor absorption, but is administered orally, 70% bioavailability
D: Half life 5-15 hours
E: Secreted in proximal tubule via organic acid secretory system, competes with uric acid, can precipitate gout

Question 16

What is the toxicity of thiazides, think ‘HyperGLUC’

Answer 16

Hyperglycaemia
Hyperlipidaemia
Hyperuricaemia
Hypercalcaemia

Question 17

Describe PK of frusemide?

Answer 17

A: Rapid absorption - 2hrs
D: low Vd, protein bound, 40-70% bioavailability
M: Renal
E: PCT excretion

Question 18

How does frusemide increase renal blood flow?

Answer 18

Increased expression of COX-2, leading to increased PGE synthesis and therefore relaxation of afferent arteriole/kidney vasculature

Question 19

What are clinical indications for frusemide?

Answer 19

APO
Hyper K and hyper Ca2+
Acute renal failure –> increased rate of urine flow

Question 20

How does frusemide cause hypokalaemic metabolic alkalosis?

Answer 20

Increased delivery of Na+ to collecting duct, causing increased activity in principal cells of excreting H+ and K+ in return for Na+

Question 21

How does spironolactone cause diuresis?

Answer 21

Inhibition of mineralocorticoid receptors

Normal action of aldosterone is to increase expression of Na+/K+ exchange and Na+ channels on principal cells causing sodium reabsorption.

Reducing this causes increased sodium and water excretion, and spares K+.

Question 22

What is the PK of spironolactone?

Answer 22

A: 70% Bioavailability, long metabolite T/12 (drug t/12 only 1.8 hrs, metabolite 14 hours)
D: >90 % protein bound
M: Hepatic metabolism, to active metabolites
E: Renal excretion

Question 23

What are the clinical indictions for spironolactone?

Answer 23

Primary hyperaldosteronism
Secondary hyperaldosteronism: CCF, cirrhosis, nephrotic syndrome

Question 24

What is the toxicity of spironolactone?

Answer 24

Hyperkalaemia
Hyperchloraemic metabolic acidosis (inhibition of H+ in parallel with K+ excretion)
Gynaecomastia (blocks androgen receptors also)

Question 25

What are the clinical indications for acetazolamide?

Answer 25

Glaucoma –>reduce aqueous humor formation
Urinary alkalisation
Meniere’s disease

Question 26

Why are carbonic anhydrase inhibitors contraindicated in hepatic failure?

Answer 26

Urinary alkalisation can lead to decreased excretion of NH4+ and development of hyperammonaemia and encephalopathy in patients with cirrhosis