Diuretics

Question 1

What is a diuretic

Answer 1

Substance or drug that promotes a diuresis by increasing renal excretion of water and sodium

Question 2

State the sites of action of diuretics

Answer 2

• By direct action on cells to block sodium transporters in the luminal membrane
• By antagonising the action of aldosterone
• By modification of filtrate content - osmotic diuretics
• By inhibiting activity of enzyme carbonic anhydrase in PCT

Question 3

Explain the mechanism of how diuretics block sodium transporters

Answer 3

• By direct action on cells to block sodium transporters in the luminal membrane
• Drug is secreted into the lumen in the PCT and act from within the lumen on transporters
• Loop diuretics - act on loop of Henle and block NKCC cotransporter
• Thiazide diuretics - act on early distal tubule to block Na-Cl cotransporter
• K+ sparing diuretics - act on late distal tubule and collecting duct to block ENaC
  - Increasing sodium reabsorption increases potassium secretion

Question 4

How do diuretics affect aldosterone

Answer 4

• Aldosterone acts on principal cells of late distal tubule and collecting duct to increase sodium reabsorption via ENaC
• Aldosterone antagonists - competitive inhibition of aldosterone receptor to decrease Na reabsorption
• Also have K sparing effect

Question 5

How do osmotic diuretics work

Answer 5

• Modification of filtrate content
• Small molecules freely filtered at glomerulus but not reabsorbed
• Increases osmolarity of filtrate
• Reduces water and sodium reabsorption throughout the tubule

Question 6

Outline how loop diuretics work

Answer 6

• Act on the ascending limb of loop of Henle
• Block NaKCC transporter on the apical membrane
  
  • Na and Cl not absorbed causing medullary tonicity to decrease
  • Less water is reabsorbed further down the tubule so more Na and water excreted
• The K carried across apical membrane drifts back into lumen via K channels
  
  • Creates a lumen positive potential
  • Loop diuretic prevents K reabsorption and thus decreases K back-leak into the lumen
  • Leads to a decrease in calcium and magnesium reabsorption back into the bloodstream
• Very potent diuretics
  
  • 25-30% of filtered sodium reabsorbed in loop of Henle
    
    • Segments beyond have limited capacity to reabsorb the resulting Na and water

Question 7

When are loop diuretics used

Answer 7

• Used in heart failure for treatment of symptoms (breathlessness, oedema)
  
  • Diuretic effect
  • Vaso and venodilation (decrease afterload and preload)
  • Reduces symptoms but no effect on reducing mortality
  • In acute pulmonary oedema, furosemide given IV for rapid action
• Used to treat fluid retention and oedema in nephrotic syndrome, renal failure, cirrhosis of liver
• Useful in treatment of hypercalcaemia
  
  • Impairs calcium absorption and increases urinary excretion of calcium
    
    • Furosemide given together with IV fluids

Question 8

Outline how thiazide diuretics work

Answer 8

• Act on early distal tubule to block Na-Cl transporter
• Secreted into lumen in PCT and travels downstream to DCT
• Increases sodium loss in urine by blocking sodium reabsorption
• Increases calcium reabsorption as potassium leaking into lumen alongside sodium not being reabsorbed
  - Creates a large lumen positive potential

Question 9

When are thiazide diuretics work

Answer 9

• Less potent diuretics than loop diuretics
  
  • Only 5% of sodium reabsorption inhibited
  • Ineffective in renal failure
• Widely used in hypertension (vasodilation)
• Higher incidence of hypokalaemia

Question 10

Outline how potassium sparing diuretics work

Answer 10

• Act on late distal tubule and collecting duct
• Either inhibitors of epithelial Na channels (ENaC)
  
  • Eg. Amiloride
• Or aldosterone antagonists
  - Eg. Spironolactone
• Both groups of drugs reduce ENaC activity
• Reduce the loss of K
  
  • Decrease in Na reabsorption decreases K secretion
  • Both can produce life threatening hyperkalaemia
    
    • Especially if used with ACE inhibitors, K supplements or in patients with renal impairment
• Both are mild diuretics - affecting only 2% of Na reabsorption

Question 11

When are potassium-sparing diuretics used

Answer 11

• Aldosterone antagonists
  
  • Reduce mortality in heart failure - used in long term treatment of heart failure
  • Preferred drug for ascites and oedema in cirrhosis
  • Used as additional therapy if hypertension not controlled ACEI + CCB + Thiazide
    
    • ACT - ACE inhibitors + calcium channel blockers + thiazide
  • Treatment of hypertension due to hyperaldosteronism (Conn’s syndrome)
• ENaC blockers
  
  • Mild diuretics with K sparing effect
    
    • Usually used in combination with K losing diuretics such as loop or thiazide diuretics to minimise K loss

Question 12

Outline the use of carbonic anhydrase inhibitors

Answer 12

• Act on proximal tubule
• Inhibits action of carbonic anhydrase in brush border and PCT cell
• Can cause metabolic acidosis due to loss of HCO3 in urine
• Useful in the treatment of glaucoma
• Reduces formation of aqueous humour in eye by about 50%

Question 13

How does congestive heart failure lead to ECF volume expansion

Answer 13

• Drop in cardiac output with reduced renal perfusion
• Increase in systemic venous pressure leading to oedema as fluid moves from intravascular to interstitial compartment
• Both lead to activation of RAAS system
  - Na and water retention causes expansion of ECF

Question 14

How does nephrotic syndrome lead to ECF volume expansion

Answer 14

• Glomerular disease increases glomerular basement membrane permeability to protein
  
  • Charged proteins in the glomerulus fails to repel proteins
• Causes proteins to be filtered and lost in urine - proteinuria
• Causes low plasma albumin
  
  • Results in low plasma oncotic pressure - peripheral oedema
  • Reduced circulatory system - RAAS activated
    
    • Na and water retention leads to expansion of ECF and more oedema

Question 15

How does cirrhosis of the liver lead to ECF volume expansion

Answer 15

• Loss of liver function
• Reduced albumin synthesis in liver
  
  • Causes low plasma albumin
  • Leads to low plasma oncotic pressure - peripheral oedema
• Portal hypertension
  
  • Cause increased venous pressure in splanchnic circulation - obstruction in vessels
  • High venous pressure and low oncotic pressure
  • Movement of fluid in peritoneal capillaries to peritoneal cavity (transudate)
  • Leads to ascites (free fluid in peritoneal cavity)
• Both lead to reduced circulatory volume - RAAS activated
  - Na and water retention leads to further expansion of ECF

Question 16

What does K secretion in distal tubule depend on

Answer 16

• Concentration gradient across apical membrane
• Rate of sodium absorption
  - Inward movement of Na ion creates a favourable lumen negative potential for K secretion

Question 17

Describe how hypokalaemia can occur from diuretics

Answer 17

• Loop and thiazide diuretics block Na and water reabsorption
• Increases Na and water delivery to late DT and CD
  
  • Increased Na absorption by principal cells
    
    • Favourable electrical gradient for K excretion
  • Faster flow rate of filtrate in tubule lumen
    
    • K secreted into lumen is washed away faster
    • Lower K concentration in lumen - favourable chemical gradient for K secretion
• Both leads to more K loss in urine leading to hypokalaemia
• Diuretics also cause hypokalaemia as they lead to reduced circulatory volume
  
  • Activates RAAS system and increases aldosterone secretion
  • Increases Na absorption and K secretion

Question 18

Explain how hyperkalaemia can occur from diuretics

Answer 18

• Epithelial sodium channel inhibitors block ENaC
• Aldosterone antagonists block action of aldosterone and thus reduce activity of Na/K ATPase and ENaC
• Both reduce sodium reabsorption and reduces potassium loss in urine, leading to hyperkalaemia

Question 19

How can hyperkalaemia/ hypokalaemia be avoided when giving diuretics

Answer 19

• Monitoring K levels is vital as diuretics cause K abnormalities
• Combination of loop/thiazide diuretic with a K sparing diuretic can be used to minimise changes in potassium
• Or loop/thiazide diuretics can be used with potassium supplements if necessary
• Do not used K sparing diuretics alongside:
  
  • Potassium supplements
  • Renal function impairment
• K sparing diuretics often used alongside ACEI - regular K monitoring required
  
  • Eg. Use of ACEI and spironolactone in heart failure

Question 20

Explain the important adverse effects of diuretics

Answer 20

• Potassium abnormalities (above)
• Hypovolaemia - especially loop diuretics
  
  • Decrease ECF volume due to excessive loss of Na and water
  • Monitor weight, BP (postural drop), signs of dehydration
• Hyponatraemia
• Increased uric acid levels in blood (with thiazides, loop diuretics) can precipitate attack of gout
• Metabolic effects (thiazides, loop diuretics)
  
  • Glucose intolerance
  • Increased LDL levels
• Thiazides - erectile dysfunction (reversible when drug stopped)
• Spironolactone - gynaecomastia (oestrogen like effect)

Question 21

Give examples of substances with diuretic action

Answer 21

• Alcohol - inhibits ADH release
• Coffee - increases GFR and decreases tubular Na reabsorption
• Drugs which inhibit action of ADH on collecting ducts
  - Eg. Lithium

Question 22

What are diseases which cause diuresis

Answer 22

• Symptom - polyuria
• Diabetes mellitus - glucose in filtrate - osmotic diuresis
• Diabetes insipidus (cranial)
  
  • Increase pure water loss
  • Decrease ADH release from posterior pituitary
  • Reduced absorption of water in collecting ducts - diuresis
• Diabetes insipidus (nephrogenic)
  
  • Increase pure water loss
  • Poor response of collecting ducts to ADH - diuresis
• Psychogenic polydipsia
  
  • Increased in take of fluid