S6) Diuretics

Question 1

What is diuresis?

Answer 1

Diuresis is the increased formation of urine by the kidney

Question 2

What is a diuretic?

Answer 2

A diuretic is a substance/drug that promotes a diuresis by increasing the renal excretion of Na⁺/H₂O, reducing ECF volume

Question 3

When are diuretics used clinically?

Answer 3

Clinical use is in conditions where Na⁺ and H₂O retention cause expansion of ECF volume and oedema eg. heart failure

Question 4

Briefly, describe how diuretics act on the nephron/kidney

Answer 4

Diuretics act by blocking reabsorption of Na⁺ and H₂O by the tubule and increase the fractional excretion (FE) of Na⁺

Question 5

Describe the 4 pathways in which diuretics can act on the nephron

Answer 5

• By blocking Na⁺ 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 the PCT

Question 6

Identify the 3 types of diuretics which act on cells to block Na⁺ transporters in the luminal membrane

Answer 6

• Thiazide diuretics
• Loop diuretics
• K⁺ sparing diuretics

Question 7

Describe the action of loop diuretics

Answer 7

• Drug is secreted into the lumen in the PCT
• Acts on Loop of Henle
• Blocks NaKCC co-transporter

Question 8

Describe the action of thiazide diuretics

Answer 8

• Drug is secreted into the lumen in the PCT
• Acts on the early Distal Tubule
• Blocks Na–Cl cotransporter

Question 9

Describe the action of K⁺ sparing diuretics

Answer 9

• Drug is secreted into the lumen in the PCT
• Acts on Late DT & CD
• Blocks Epithelial Na channels

Question 10

Describe how aldosterone acts on the kidney nephron

Answer 10

Aldosterone acts on principal cells of Late DT & CD to increase Na⁺ reabsorption via ENaC

Question 11

Identify and describe the mechanism of action of diuretics which antagonise the action of aldosterone

Answer 11

• Aldosterone antagonists act through competitive inhibition of the aldosterone receptor, decreasing Na⁺ reabsorption
• They also have a K⁺ sparing effect

Question 12

Osmotic diuretics act by modifying the filtrate content.

Describe this

Answer 12

Small molecules are freely filtered at glomerulus but not reabsorbed:

• Increased osmolarity of filtrate
• Reduced water & Na⁺ reabsorption throughout the tubule

Question 13

Describe the action of carbonic anhydrase inhibitors

Answer 13

Carbonic anhydrase has an inhibiting effect and interferes with Na⁺ & HCO₃^- reabsorption in PCT

Question 14

Loop diuretics block apical Na-K-2 Cl transporter.

In 5 steps, explain how this leads to diuresis

Answer 14

⇒ Na⁺ and Cl^- is not absorbed resulting in less H₂O absorption

⇒ Result is: Na⁺ and H₂O loss

⇒ K⁺ carried across apical membrane drifts back into lumen via K⁺ channels

⇒ Creates a (+) lumen potential

⇒ This decreases the absorption of Ca²⁺ and Mg²⁺

Question 15

Provide 2 examples of loop diuretics

Answer 15

• Furosemide
• Bumetanide

Question 16

Loop diuretics are very potent.

What is the impact of this?

Answer 16

• Affects 25 - 30% of filtered sodium reabsorption
• Segments beyond have limited capacity to reabsorb the resulting flood of Na⁺ & H₂O

Question 17

Describe the use of loop diuretics in heart failure

Answer 17

• Treats of symptoms of breathlessness & oedema
• Causes vaso and venodilatation (decreases after/preload)
• No effect on reducing mortality

Question 18

Describe the use of loop diuretics in treating acute pulmonary oedema

Answer 18

IV Furosemide given for rapid action

Question 19

Loop diuretics are used to treat fluid retention & oedema in a number of clinical conditions.

Identify 3

Answer 19

• Nephrotic syndrome
• Renal failure
• Cirrhosis of liver (spironolactone preferred)

Question 20

Loop diuretics are also used in treatment of hypercalcaemia.

Explain the benefit of this

Answer 20

• Impairs calcium absorption in the Loop of Henle
• Increases urinary excretion of calcium
• Furosemide given together with IV fluids

Question 21

Thiazide diuretics block Na–Cl transporter in DCT.

In 4 steps, explain how this leads to diuresis

Answer 21

⇒ Diuretic secreted into lumen in PCT and travels to act on DCT

⇒ Blocks Na⁺ absorption and increases Ca²⁺ absorption

⇒ Increases Na⁺ (and H₂O) loss in urine

⇒ Reduces Ca²⁺ loss in urine

Question 22

Provide an example of a thiazide diuretic

Answer 22

Bendroflumethiazide

Question 23

Thiazide diuretics are less potent diuretics than loop diuretics.

How does this manifest?

Answer 23

• Only 5% of sodium reabsorption inhibited
• Ineffective in renal failure

Question 24

Where are thiazide diuretics most commonly used?

Answer 24

Widely used in hypertension (vasodilatation)

Question 25

Two groups of drugs have potassium sparing diuretics. Identify these groups and provide examples

Answer 25

Act on late distal tubule and collecting duct: - **Inhibitors of ENaC** *e.g. Amiloride, triamterene* - **Aldosterone antagonist** *e.g. Spironolactone*

Question 26

Identify 4 similarities between aldosterone antagonist diuretics and inhibitors of ENaC

Answer 26

- Reduce ENaC activity (directly or indirectly) - Reduce the loss of K⁺ - Can produce life threatening hyperkalaemia - Are mild diuretics (affects only 2% of Na⁺ reabsorption)

Question 27

Hyperkalaemia may occur with both groups of K⁺ sparing diuretics. Illustrate this mechanism

Answer 27

Question 28

The 2 groups of drugs with potassium sparing effects are more likely to produce severe hyperkalaemia when used in certain circumstances. Identify 3 of these

Answer 28

- ACE Inhibitors - K⁺ supplements - Patients with renal impairment

Question 29

Describe 3 clinical uses of aldosterone antagonists

Answer 29

- Reduces mortality in heart failure - Preferred drug for cirrhosis (ascites & oedema) - Additional therapy in hypertension caused by primary hyperaldosteronism

Question 30

Describe the clinical use of ENaC blockers

Answer 30

Usually used in combination with K⁺ losing diuretics such as Loop or Thiazide diuretics to minimise K⁺ loss

Question 31

In 5 steps, explain how diuretics may also contribute to hypokalaemia

Answer 31

⇒ Diuretics may lead to reduced circulatory volume ⇒ Activation of RAAS ⇒ Increased aldosterone secretion ⇒ Increased Na⁺ absorption & K⁺ secretion ⇒ Hypokalaemia

Question 32

Loop & Thiazide diuretics both block Na⁺ & H₂O reabsorption in LoH or early DT. Ilustrate how this might lead to hypokalaemia

Answer 32

Question 33

What is Nephrotic syndrome?

Answer 33

**Nephrotic syndrome** is a glomerular disease caused by an increase in the permeability of the glomerular basement membrane to protein

Question 34

In 5 steps, explain the biochemical basis of Nephrotic Syndrome

Answer 34

⇒ Proteins are filtered and lost in urine (**proteinuria**) ⇒ Results in **low plasma albumin** and thus, **low plasma oncotic pressure** ⇒ **Peripheral oedema** occurs ⇒ The reduced circulatory volume activates **RAAS** ⇒ **Na & water retention** causes more oedema

Question 35

What is oedema?

Answer 35

**Oedema** is the abnormal accumulation of fluid in the interstial spaces

Question 36

In 4 steps, explain how oedema results from liver cirrhosis

Answer 36

⇒ Reduced **albumin synthesis** in liver ⇒ Results in low **plasma albumin** ⇒ Leads to low plasma **oncotic pressure** ⇒ **Peripheral oedema** occurs

Question 37

What is ascites?

Answer 37

**Ascites** is free fluid in the peritoneal cavity

Question 38

In 4 steps, explain how ascites results from liver cirrhosis

Answer 38

⇒ Low oncotic pressure occurs ⇒ **Portal hypertension** causes increased venous pressure in GI circulation ⇒ Fluid moves into peritoneal cavity (transudate) ⇒ Ascites occurs

Question 39

Describe the action of carbonic anhydrase inhibitors and a consequence of such

Answer 39

- Inhibits action of Carbonic anhydrase in brush border & PCT cell - Can cause metabolic acidosis due to loss of HCO₃^- in urine

Question 40

Identify an example of a carbonic anhydrase inhibitor

Answer 40

Acetazolamide

Question 41

Describe the clinical use of carbonic anhydrase inhibitors

Answer 41

Treatment of **glaucoma** – reduces formation of aqueous humor in eye by about 50%

Question 42

Osmotic diuretics act by increasing the osmolarity of the kidney filtrate. In 4 steps, explain how this leads to diuresis

Answer 42

⇒ Small inert molecules increase plasma osmolarity ⇒ Fluid drawn out from tissues and cells ⇒ Increased osmolarity of filtrate ⇒ Causes loss of H₂O, Na⁺ and K⁺ in the urine

Question 43

Identify an example of an osmotic diuretic

Answer 43

Mannitol

Question 44

Describe a clinical use of osmotic diuretics

Answer 44

IV mannitol used to treat cerebral oedema

Question 45

Identify 7 adverse effects of diuretic use

Answer 45

- Potassium abnormalities - Hypovolaemia (mainly loop) - Hyponatraemia - Increased uric acid → gout (thiazides & loop) - Glucose intolerance (thiazides & loop) - Gynaecomastia (spirinolactone) - Erectile dysfunction (thiazides)

Question 46

Identify 3 other substances which have diuretic action

Answer 46

- **Alcohol** which inhibits ADH release - **Coffee** which increases GFR and decreases tubular Na⁺ reabsorption - **Drugs** which inhibit action of ADH on CT *e.g. Lithium*

Question 47

Identify 4 conditions which cause diuresis and present as polyuria

Answer 47

- Diabetes Mellitus - Diabetes Insipidus (cranial – decreased ADH release) - Diabetes Insipidus (nephrogenic – poor response of CT to ADH) - Polydypsia