Diuretics Flashcards
How do diuretics work?
TARGETS THE KIDNEYS
Kidney physiology: proximal convoluted tubule (PCT)
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Kidney physiology: Loop of Henle
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Countercurrent effect
- 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
Kidney physiology: distal convoluted tubule (DCT)
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Kidney physiology: collecting duct
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Diuretic functions
- Inhibit sodium ion and chloride ion reabsorption (increases excretion)
- Increase tubular fluid osmolarity (reduces osmotic gradient across epithelia so less water reabsorbed)
Diuretic classes
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)
Loop diuretics mechanism of action
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Loop diuretics on ionic composition
- 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
Thiazide diuretics mechanism of action
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Thiazides on ionic composition
- 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
Problem with thiazides and loop diuretics
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Potassium sparing diuretics mechanism of action
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Potassium sparing diuretic classes
- Aldosterone receptor antagonists (eg: Spironolactone)
- Aldosterone-sensitive sodium channel inhibitors (eg: Amiloride)
Potassium sparing diuretics on ionic composition
- 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
Common diuretic side effects
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)
Diuretics in the treatment of hypertension
-Thiazides are the first line treatment in most countries=especially useful in salt-sensitive hypertension
Diuretics in the treatment of heart failure and oedema
- 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)
Hyperuricaemia
-excess of uric acid in the blood
Thiazides vs other diuretics for hypertension treatment
- 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
