Diuretics

Question 1

How do diuretics work?

Answer 1

TARGETS THE KIDNEYS

Question 2

Kidney physiology: proximal convoluted tubule (PCT)

Answer 2

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Question 3

Kidney physiology: Loop of Henle

Answer 3

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Question 4

Countercurrent effect

Answer 4

• Descending limb is permeable to water but not ions
• Ascending limb is impermeable to water but permeable to ions
• sodium ions leave ascending limb into medullary interstitium=fluid in ascending limb decreases in osmolarity
• the more concentrated medullary interstitium draws water into it from the permeable descending limb=fluid in descending limb increases in osmolarity
• more fluid enteres tubule and forces fluid from descending to ascending limb=fluid increases in osmolarity due to increased sodium concentration in the medulla
• sodium ions then leave the ascending limb again to enter the medullary interstitium=decreases osmolarity of ascending limb fluid

Question 5

Kidney physiology: distal convoluted tubule (DCT)

Answer 5

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Question 6

Kidney physiology: collecting duct

Answer 6

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Question 7

Diuretic functions

Answer 7

• Inhibit sodium ion and chloride ion reabsorption (increases excretion)
• Increase tubular fluid osmolarity (reduces osmotic gradient across epithelia so less water reabsorbed)

Question 8

Diuretic classes

Answer 8

1) Osmotic diuretics (eg: mannitol)
2) Carbonic anhydrase inhibitors (eg: acetazolamide)
3) Loop diuretics (eg: furosemide)
4) Thiazides (eg: bendroflumethiazide)
5) Potassium sparing diuretics (eg: amiloride, spironolactone)

Question 9

Loop diuretics mechanism of action

Answer 9

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Question 10

Loop diuretics on ionic composition

Answer 10

• Inhibits sodium and chloride reabsorption in ascending limb (30%)
• Increases tubular fluid osmolarity (reduces osmolarity of medullary interstitium-> reduces water reabsorption in collecting duct)
• Increases sodium delivery to distal tubule which increases potassium loss (increased sodium potassium exchange)=common property with thiazides
• magnesium and calcium loss due to loss of potassium recycling

Question 11

Thiazide diuretics mechanism of action

Answer 11

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Question 12

Thiazides on ionic composition

Answer 12

• Inhibits sodium and chloride reabsorption in early distal tubule (5-10%)
• Increases tubular fluid osmolarity->reduces water reabsorption in collecting duct
• Increases sodium delivery to distal tubule and increased potassium loss (increased sodium potassium exchange)
• Increases magnesium loss and increases calcium reabsorption=unknown mechanism

Question 13

Problem with thiazides and loop diuretics

Answer 13

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Question 14

Potassium sparing diuretics mechanism of action

Answer 14

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Question 15

Potassium sparing diuretic classes

Answer 15

• Aldosterone receptor antagonists (eg: Spironolactone)

- Aldosterone-sensitive sodium channel inhibitors (eg: Amiloride)

Question 16

Potassium sparing diuretics on ionic composition

Answer 16

• Inhibits sodium reabsorpion and associated potassium secretion in early distal tubule=5%
• Increases tubular fluid osmolarity->reduced water reabsorption in the collecting duct
• Decreases sodium reabsorption to distal convoluted tubule and increases proton retention=decreased sodium/proton exchange

Question 17

Common diuretic side effects

Answer 17

Loop diuretics and thiazides
-Hypokalaemia (increased sodium potassium exchange)
-Hyponatremia
-Hypovolemia (increased fluid loss in tubules=30% loss for loop and 10% loss for thiazides)
-Metabolic alkalosis (increased chloride ion loss)
-Hyperuricaemia (diuretics compete with uric acid at basolateral organic anion transporter->less uric acid transported from interstitium to lumen)
-hypovolaemia=loss of extracellular fluid (30% loss in loop and 10% loss in thiazides)
Potassium sparing diuretics
-Hyperkalaemia (less sodium potassium exchange)
-Metabolic acidosis
-Gynaecomastia, menstrual disorders and testicular atrophy from Spironolactone (progesterone and androgen receptor inhibition)

Question 18

Diuretics in the treatment of hypertension

Answer 18

-Thiazides are the first line treatment in most countries=especially useful in salt-sensitive hypertension

Question 19

Diuretics in the treatment of heart failure and oedema

Answer 19

• intravenous furosemide admin typically results in prompt diuretic effect (within 30 minutes) peaking at 1.5 hours=decreases ventricular filling pressures and improves heart failure symptoms in majority of patients
• admin results in acute congestion reduction
• chronic use associated with resistance and RAS activation
• additional use of potassium sparing diuretics to stop rebound RAS activation (sodium and water retention)

Question 20

Hyperuricaemia

Answer 20

-excess of uric acid in the blood

Question 21

Thiazides vs other diuretics for hypertension treatment

Answer 21

• loop diuretics not used as do not lower blood pressure to the degree thiazides do
• initial thiazide response (4-6 weeks)=reduction of blood pressure due to plasma volume reduction
• after 4-6 weeks=plasma volume restored due to tolerance
• chronic thiazides=reduce total peripheral resistance due to activation of eNOS (endothelium), calcium channel antagonism and opening of Kca channels (smooth muscle=calcium activated so potassium leaves cell)=NO production, less calcium influx and hyperpolarisation
• chronic thiazide effect not exclusively due to blood volume loss