Diuretics

Question 1

What is a diuretic?

Answer 1

Diuresis is an increased formation of urine in the kidney so a diuretic is a substance/drug which promotes diuresis by increasing renal excretion of sodium and water and thus reducing the ECF volume.

Question 2

What is the overall clinical use of a diuretic?

Answer 2

Conditions where Na+ and water retention causes an increase of ECF volume which needs to be reduced, e.g. in heart failure.

Question 3

What is the general principle of how a diuretic works?

Answer 3

Block the reabsorption of sodium and water by the tubule. If you block sodium reabsorption water cannot follow.
The fraction excretion of sodium is usually less than 1% but. diuretics increase the fraction excretion of sodium.

Question 4

Describe tubular reabsorption of sodium.

Answer 4

Sodium ions are pumped across the basolateral membrane by Na-K-ATPase.
This allows Na to move across the apical membrane down the concentration gradient. (utilising a membrane transporter or channel on the apical membrane).
Water moves down the osmotic gradient created by the sodium reabsorption.

Question 5

Which channel is found on all basolateral membranes in the segments of the tubule?

Answer 5

Na-K-ATPase.

BUT each segment has unique sodium transporters/channels in the apical membrane.

Question 6

What sodium transporters are found on the apical membrane of the proximal tubule?

Answer 6

1. Sodium-Hydrogen Antiporter.
2. Na-Glucose Symporter.
3. Na-AA Symporter.

Question 7

What sodium transporter is found on the apical membrane of the Loop of Henle?

Answer 7

1. Na-K-2Cl Symporter.

Question 8

What sodium transporter is found on the apical membrane of the Early Distal Convoluted Tubule?

Answer 8

1. Na-Cl Symporter.

Question 9

What sodium transporter is found on the apical membrane of the Later Distal Convoluted Tubule and the Collecting Duct?

Answer 9

1. ENaC (epithelial Na Channel).

Question 10

Describe Tubular Reabsorption of Sodium and Secretion of potassium by the principal cells in the late DT and the Collecting Duct.

Answer 10

1. Na-K-ATPase in the basolateral membrane creates a concentration gradient for Na to move in in the apical membrane by moving 3Na+ out of the cell and 2K+ into the cell.
2. Na+enters the apical membrane via ENaC.
3. Na+ reabsorption creates a negative potential in the lumen which favours the K+ secretion via K+ channels

Question 11

Describe clinical relevance of diuretics working on the ENaC.

Answer 11

Diuretics that reduce ENaC activity stop the negative potential of the Na+ which means K+ is less likely to be driven into the lumen. This reduces K+ secretion.

Question 12

How do diuretics work (Overview)?

Answer 12

1. Direct action on cells that block Na+ transporters in the luminal membrane. Drug is secreted into the lumen in the PCT and act within the lumen on apical transporters.
2. Block the action of aldosterone.
3. Modification of filtrate content.
4. Inhibition of Carbonic Anhydrase in the PCT.

Question 13

How can diuretics that block Na+ transporters work?

Answer 13

1. Loop diuretics: act on the loop of Henle, blocking the Na-K-2Cl Transporter.
2. Thiazide diuretics: act on the early distal convoluted tubule, blocking the Na-Cl transporter.
3. K+ sparing diuretics act on the late DT and CD to block the ENaC.

Question 14

How can diuretics that block the action of aldosterone work?

Answer 14

Aldosterone acts on the principal cells of the late DT and CD to increase Na+ absorption via ENaC so by blocking them it prevents ENaC expression and thus absorption of Na. K+ sparing effect.

Question 15

How can diuretics that modify the filtrate content work?

Answer 15

Small molecules are freely filtered at the glomerulus but are not reabsorbed, which creates an increased osmolarity of filtrate. This reduces water and sodium reabsorption throughout the tubule.

Question 16

How can diuretics that inhibit carbonic anhydrase in the PCT work?

Answer 16

They interfere with Na and HCO3- reabsorption in the PCT.

Question 17

Describe how Na+ and Cl- is absorbed in the Loop of Henle.

Answer 17

25% of filtered Na+ is reabsorbed via the Na-K-2Cl Transporter on the apical membrane.
The thick ascending limb in impermeable to water. The reabsorbed Na and Cl are responsible for the hypertonicity of the medulla.
The water gets reabsorbed in the water soluble descending limb (requires a hypertonic medulla and ADH to be present for AQP).
Water moves from hypotonic tubular fluid into hypertonic medulla.

Question 18

How do Loop Diuretics work?

Answer 18

Loop diuretics work by blocking Na-K-2Cl transporters in the Loop of Henle. This means:

1. Na and Cl are not absorbed so the medullary tonicity is less.
2. This affects water reabsorption further down the tubule (CD) so less water is reabsorbed and Na+ and water is lost more.
3. K+ is usually carried across the apical membrane (by Na-K-2Cl channel) moves back into the lumen via K+channels, which creates a lumen positive potential. This helps to drive absorption of the positively charged ion Ca2+ and Mg2+. Without this Mg2+ and Ca2+ aren’t going to be absorbed.

Question 19

Give examples of Loop Diuretics.

Answer 19

Furosemide and Bumetanide.

Question 20

Describe the characteristics of Loop Diuretics.

Answer 20

Very potent diuretics as 25-30% of filtered sodium is reabsorbed in the LoH, and it means. that segments beyond have a limited capacity to reabsorb the resulting flood. of Na and water.

Question 21

When are Loop Diuretics used?

Answer 21

1. Used in heart failure for treatment of symptoms (breathlessness, oedema). They have a diuretic effect and thus can vaso and venodilation which reduces pre/afterload. This reduces symptoms but has no effect on reducing mortality.
2. Nephrotic syndrome.
3. Renal failure.
4. Cirrhosis of the liver (spironolactone preferred but Loop diuretic can be added if needed).
5. Used to treat hypercalcaemia: impairs absorption, increases excretion. Furosemide given with IV fluids.

Question 22

What is given in acute pulmonary oedema?

Answer 22

Furosemide given IV for rapid action.

Question 23

How does Thiazide Diuretics work?

Answer 23

Block Na-Cl transporter in the early DCT. It is secreted in the lumen at the PCT and travels downstream to act at the DCT. Thus it increases Na+ and H20 loss in urine but unlike. in the LoH, blocking Na absorption increases Ca2+ absorption,soreduces Ca2+ loss in the urine.

Question 24

Give an example of Thiazide Diuretics.

Answer 24

Bendroflumethiazide.

Question 25

Describe characteristics of Thiazide Diuretics.

Answer 25

Less potent diuretics than loop diuretics: only 5% of sodium reabsorption is inhibited so is ineffective in renal failure. Commonly used in hypertension (vasodilation). Higher incidence of hypokalaemia.

Question 26

When is thiazide diuretics commonly used?

Answer 26

Hypetension.

Question 27

What are 2 types of diuretics that are K+ sparing?

Answer 27

1. Inhibitors of ENaC, like amiloride. | 2. Aldosterone antagonists, e.g. spironolactone.

Question 28

What do K+sparing diuretics do?

Answer 28

Reduce ENaC activity. Both can produce life threatening hyperkalaemia, especially used with ACE inhibitors, K+ supplements or if the patient. has renal impairment. Both mild diuretics, effect 2% of Na reabsorption.

Question 29

What can aldosterone antagonists be used to treat?

Answer 29

1. Reduces mortality in heart failure so is used in long term treatment. 2. Preferred drug for ascites and oedema in cirrhosis. 3. Additional therapy in hypertension not controlled by ACEI, CCB and Thiazide. 4. Treatment of hypertension due to primary hyperaldosteroinism (Conn's disease) as there is adrenal hyperplasia or an adrenal tumour which increases secretion of aldosterone and causes hypertension.

Question 30

Give an example of an aldosterone antagonist.

Answer 30

Spironolactone.

Question 31

Give an example of a ENaC blocker.

Answer 31

Amiloride.

Question 32

What can ENaC blockers be used for?

Answer 32

In combination with K+ losing diuretics to minimise K+ loss, as. blocking Na+ channels reduces K+ secretion.

Question 33

How is K+ secreted in the late distal tubule and collecting duct?

Answer 33

There is is a passive process, driven by electrochemical gradient. The rate of K+ secretion depends on the concentration gradient across the apical gradient. It depends on the rate of sodium absorption as inward movement of sodium ions creates a favourable negative potential for K+ secretion,.

Question 34

Why are Loop and Thiazide diuretics not potassium spearing?

Answer 34

1. The diuretics block Na and H2O absorption in the LoH/early DT. 2. This increases the Na and H2O. delivery to the late DT and CD. 3. There is increased. Na absorption by principal cells. This creates a favourable electrical gradient for K+ excretion. 4. This means more K+ is lost in the urine, leading to hypokalaemia. 5. Also a factor: flow rate occurs in the filtrate in the tubule lumen so K+ is secreted into the lumen is washed away faster so there is lower K+ concentration in the lumen creating a favourable K+ concentration gradient.

Question 35

What can also contribute to hypokalaemia in non potassium spearing diuretics?

Answer 35

Diuretics may reduce circulatory volume activating the RAAS so aldosterone increases, thus there is more. Na absorption and K+ secretion leading to hypokalaemia also.

Question 36

Explain how K+ spearing Diuretics can cause hyperkalaemia?

Answer 36

1. Either ENaC is inhibited or less are added by aldosterone as less aldosterone is made (reduce ENaC. and Na-K-ATPase). 2. This reduces Na+ absorption. 3. This reduces K+ secretion and loss in urine. 4. Causes hyperkalaemia.

Question 37

What is the clinical relevance of diuretics causing K+ abnormalities?

Answer 37

It is important to monitor K+ levels. A combination of potassium spearing and not potassium spearing diuretics should be used to minimise changes in potassium or Loop/thiazide diuretics should be used with potassium supplements.

Question 38

What should you be aware of clinically in potassium spearing diuretics?

Answer 38

Avoid use along with potassium supplements and if there is renal function impairment as this increases the risk of hyperkalaemia. Monitor if used with ACEI like in heart failure.

Question 39

When are diuretics generally used?

Answer 39

Diuretics are used primarily to treat conditions with ECF expansion and oedema.

Question 40

What is increased ECF usually a response to?

Answer 40

Reduced circulating volume.

Question 41

Why is there increased ECF in Congestive Heart Failure?

Answer 41

Drop in CO with reduced renal perfusion causes an increase in systemic venous pressure causing oedema (fluid moves. from intravascular to interstitial compartment). This activates RAAS so there is more Na and water retention and thus an expansion of ECF.

Question 42

What is nephrotic syndrome?

Answer 42

Glomerular disease causes an increase in glomerular basement membrane permeability to protein. Thus protein is filtered and lost in urine (proteinuria). This causes low plasma albumin resulting in low plasma oncotic pressure and subsequent peripheral oedema. There is reduced circulating volume so RAAS is activated so there is sodium and water retention and thus an expansion ECF and thus more oedema.

Question 43

Why does Cirrhosis of the liver cause ascites and peripheral oedema?

Answer 43

1. Decreased albumin synthesis. This causes low plasma albumin resulting in low plasma oncotic pressure and subsequent peripheral oedema. 2. Portal hypertension causes increased venous pressure in the splanchnic (GI) circulation, this creates a high venous pressure and low oncotic pressure so there is movement of fluid in peritoneal capillaries into the peritoneal cavity (transudate). These both causes RAAS to be activated, so there is sodium and water retention and thus an expansion ECF and thus more oedema.

Question 44

What can osmotic diuretics be used to treat?

Answer 44

Mannitol is used to cerebral oedema.

Question 45

What can carbonic anhydrase inhibitors be used to treat?

Answer 45

Acetazolamide is useful in glaucoma treatment.

Question 46

What are the adverse side effects of diuretics?

Answer 46

1. Potassium abnormalities. 2. Hypovolaemia (especially loop diuretics): decreased ECF due to loss of Na and water so monitor weight, BP (postural drop) and for signs of dehydration. 3. Hyponatraemia. 4. Uric acid levels increase in the blood which can precipitate gout. 5. Metabolic effects: Thiazide and loop diuretics can cause glucose intolerance and increase LDL levels. 6. Erectile dysfunction in thiazides. 7. Gynaecomastia: spironolactone produces an oestrogen like effect.

Question 47

How do Carbonic Anhydrase Inhibitors work?

Answer 47

Act on the proximal convoluted tubule. They inhibit carbonic anhydrase in brush border and PCT cells. This can cause metabolic acidosis due to loss of HCO3- in the urine.

Question 48

How do carbonic anhydrase inhibitors treat glaucoma?

Answer 48

Reduce the formation of aqueous humor in the eye by around 50%.

Question 49

How do osmotic diuretics like mannitol work?

Answer 49

Mannitol is a small inert molecule that increases plasma osmolarity which draws out fluid from tissues and cells and in the kidneys increases the osmolarity of filtrate. This acts by altering the driving force for renal water absorption which is osmolarity causing loss of water and sodium and potassium in the urine. There is no inhibition of enzymes of transport proteins.

Question 50

How does alcohol act like a diuretic?

Answer 50

Inhibits ADH release so AQP decrease and thus less water can be reabsorbed.

Question 51

How does coffee act like a diuretic?

Answer 51

Increases the GFR and decreases the tubular Na reabsorption.

Question 52

Give an example of a drug that inhibits the action of ADH on the CD.

Answer 52

Lithium, which is used for bipolar affective disorder.

Question 53

Identify and describe some diseases that cause diuresis (presented as polyuria).

Answer 53

1. Diabetes mellitus: glucose in filtrate causes osmotic diuresis. 2. Diabetes insipidus (cranial): increases pure water loss, decreases ADH release from the posterior pituitary gland and thus reduces reabsorption of water into collecting ducts and causes diuresis. 3. Diabetes insipidus (nephrogenic): increase pure water loss as there is a poor response of the collecting duct to ADH causing diuresis. 4. Psychogenic polydipsia: increased intake of fluid.