Week 17 Pharmacology - Diuretics Flashcards
What are the major classes of diuretics?
- Carbonic anhydrase inhibitors
- Loop diuretics
- Thiazide diuretics
- Potassium sparing diuretics
- Osmotic diuretics
How does carbonic anhydrase inhibitors exert a diuretic effect?
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.
At what location of the Loop of Henle do loop diuretics work?
Thick Ascending limb
What is the channel/transport that is the target of loop diuretics?
Na+/K+/2Cl- co-transporter on apical membrane
Why are loop diuretics the most powerful diuretic effect?
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
What channel is present in thick ascending limb basal membrane that allows sodium to be reabsorbed normally:
Na+/K+ ATPase
Chloride channel permits passive movement
What ions are secondarily affected by increased secretion due to loop diuretics?
Calcium
Magnesium
What is the target of thiazide diuretics?
Early part of distal tubule, inhibit Na/Cl co-transporter
How do thiazides cause hypercalcaemia?
- Decreased sodium reabsorption in distal tubule leads to compensatory increase in reabsorption in proximal tubule which causes electrical gradient that favours increased Ca2+ reabsorption
- 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
How do do loop diuretics and thiazides cause hypokalaemia?
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)
Where is the target of potassium sparing diuretics?
Collecting duct, principal cells.
These cells have separate Na+ and K+ channels on apical surface, and Na/K ATPase on basal membrane.
What are the two classes of potassium sparing diuretics?>
Na+ channel blockers in principal cells
Aldosterone antagonists
What are names of Na+ channel blocking potassium sparing diuretics?
Amiloride
Triamterene
What is the major electrolyte difference with loop vs thiazide diuretics?
Thiazides cause increased Calcium reabsorption and hypercalcaemia.
Loop diuretics leads to hypocalcaemia
Describe pharmacology of hydrochlorothiazide:
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
What is the toxicity of thiazides, think ‘HyperGLUC’
Hyperglycaemia
Hyperlipidaemia
Hyperuricaemia
Hypercalcaemia
Describe PK of frusemide?
A: Rapid absorption - 2hrs
D: low Vd, protein bound, 40-70% bioavailability
M: Renal
E: PCT excretion
How does frusemide increase renal blood flow?
Increased expression of COX-2, leading to increased PGE synthesis and therefore relaxation of afferent arteriole/kidney vasculature
What are clinical indications for frusemide?
APO
Hyper K and hyper Ca2+
Acute renal failure –> increased rate of urine flow
How does frusemide cause hypokalaemic metabolic alkalosis?
Increased delivery of Na+ to collecting duct, causing increased activity in principal cells of excreting H+ and K+ in return for Na+
How does spironolactone cause diuresis?
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+.
What is the PK of spironolactone?
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
What are the clinical indictions for spironolactone?
Primary hyperaldosteronism
Secondary hyperaldosteronism: CCF, cirrhosis, nephrotic syndrome
What is the toxicity of spironolactone?
Hyperkalaemia
Hyperchloraemic metabolic acidosis (inhibition of H+ in parallel with K+ excretion)
Gynaecomastia (blocks androgen receptors also)
What are the clinical indications for acetazolamide?
Glaucoma –>reduce aqueous humor formation
Urinary alkalisation
Meniere’s disease
Why are carbonic anhydrase inhibitors contraindicated in hepatic failure?
Urinary alkalisation can lead to decreased excretion of NH4+ and development of hyperammonaemia and encephalopathy in patients with cirrhosis
