Diuretics

Question 1

What is diuresis?

Answer 1

Diuresis – increased formation of urine by the kidney

Question 2

What is a diuretic?

Answer 2

Diuretic – a substance that promotes a diuresis

Question 3

How do we cause diuresis?

Answer 3

This is done by increasing the renal excretion of water and sodium thereby causing a reduction of ECF volume.

Question 4

When we diuretics useful and for which diseases?

Answer 4

This is clinically useful in conditions where Na+ and water retention cause expansion of ECF volume such as heart failure, cirrhosis and nephrotic syndrome.

Question 5

What is the normal fraction of excretion of Na+

Answer 5

Fraction of excretion of Na+ is usually about 1%, diuretics increase this.

Question 6

How do most diuretics act?

Answer 6

Diuretics act by blocking reabsorption of sodium and water by the tubule.

Most act directly on cells to block Na+ transporters in the luminal membrane. The drug is secreted in the lumen in the PCT and acts from within the lumen on the transporters.

Question 7

Describe how Acetazolamide works in the proximal tubule?

Note not currently used clinically!

Answer 7

Carbonic anhydrase inhibitors (Acetazolamide). Causes increase in retention of HCO3 in urine (potentially leading to metabolic acidosis) and also inhibits Na/H antiporter giving a diuretic effect. Useful in treatment of Glaucoma by reducing formation of Aqueous humor in the eye by about 50%.

Question 8

Describe how Mannitol works in the proximal tubule?

Note not currently used clinically!

Answer 8

Osmotic diuretics (also act at other sites of water absorption) such as Mannitol. Osmotic diuretics modify the filtrate content. These are small molecules that are freely filtered at the glomerulus but are not reabsorbed. Useful in treating cerebral oedema. Increases the osmolarity in the filtrate causing water to be retained. Leads to loss of Na+ and K+ as well because the increase in urine volume increases the urine flow rate and so there’s less time for reabsorption of solutes.

Question 9

Describe how furosemide and bumetanide work in the loop of henle?

Answer 9

Loop diuretics such as furosemide and bumetanide. These inhibit the Na/K/2Cl symporter. Normally the K+ is excreted back into the lumen straight away creating a lumen positive potential helping to drive the reabsorption of Ca++ and Mg++. This section of the loop normally reabsorbs 25-30% of Na+, blocking this results in a flood of sodium and water which the segments beyond have little capacity to deal with.

Question 10

When are loops diuretics used and why?

Answer 10

These are used in heart failure as they have a diuretic and vaso/venodilation effect (increased production of prostaglandins) so decreases the afterload and preload. Used also in acute pulmonary oedema for rapid action. They are also used in nephrotic syndrome, renal failure and cirrhosis of the liver. Useful in hypercalcaemia as it impairs Ca++ reabsorption and increasing renal excretion of Ca++.

Question 11

Describe how metalozone indapamide and Bendroflumethiazide work in the early DCT

Answer 11

Thiazide diuretics such as Metalozone, indapamide and Bendroflumethiazide. These inhibit the Na/Cl symporter Unlike in loop of Henle these increase the Ca reabsorption because by decreasing Na+ conc in the cell they increase the activity of a basolateral Na+/Ca++ antiporter.

Question 12

Describe why thiazides aren’t used for renal failure but are in hypertension?

Answer 12

Less potent diuretic than loop as normally only 5% of Na+ reabsorption is inhibited and so is ineffective in renal failure, but are widely used in hypertension as they cause vasodilation during chronic use (mechanism unknown).

Question 13

Describe how amiloride and triamterene work in the late DCT

Answer 13

Potassium sparing diuretics (ENaC blockers) such as amiloride and triamterene. These inhibit renal Na Channels. Usually used in combination with K+ losing diuretics such as Loop or Thiazides to minimise K+ gain/loss.

Question 14

Describe how spironolactone works in the late DCT

Answer 14

Aldosterone antagonist’s such as spironolactone. Aldosterone usually acts on principal cells of later DT and CD to increase Na+ reabsorption via the ENaC channels and K+ secretion. These diuretics are competitive inhibitors of the aldosterone receptor and so cause a decrease in Na+ reabsorption.

Question 15

Why do aldosterone antagonists and ENaC blockers have a K+ sparing effect?

Answer 15

They both inhibit the ENaC channels and so inhbit the Na/K ATPase and so K+ does not enter the tubular cells and so isn’t excreted.

Question 16

When are aldosterone antagonists used?

Answer 16

. Best drug for treatment of hypertension causing by primary hyperaldosteronism (Conn’s syndrome – adrenal hyperplasia/Tumour). Preferred drug for Ascites, oedema and cirrhosis. Used in addition with Loop diuretics in heart failure and as an additional therapy for general hypertension where ACEI, CCB and thiazides are not in use.

Question 17

How does using diuretics cause hypokalaemia?

Answer 17

Increase in Na+ concentration reaching the DT and CD leads to increased Na reabsorption by principle cells. This creates a favourable electrical gradient for k+ excretion

Faster flow rate of filtrate so K+ that is excreted is flushed away quickly favouring more excretion.

Prevention of Na+ reabsorption results in a decrease in ECF. This stimulates angiotensin system and so an increase in aldosterone. Aldosterone stimulates Na+ reabsorption and K+ secretion - Hypokalaemia.

Question 18

How do we prevent potassium problems when using diuretics?

Answer 18

To prevent issues with Potassium balance when using diuretics you must constantly monitor electrolytes balance and combine K+ sparing diuretics with K+ losing diuretics. Or alternatively use K+ losing diuretics with a K+ supplement.

Question 19

Why does a reduced circulating volume usually result in expansion of the ECF?

Answer 19

Expansion of ECF is usually an adaptive response to a reduced circulating volume. The reduced renal perfusion causes activation of RAAS leading to water and Na+ retention and so the expansion of the ECF.

Question 20

Why are diuretics used in congestive heart failure?

Answer 20

Increase is systemic venous pressure leading to peripheral oedema. This movement of fluid from intravascular to interstitial fluid compartment results in reduced intravascular volume. And reduced ejection fraction so drop in CO. Both lead to reduced renal perfusion and so activation of the RAAS system.

Question 21

Why are diuretics used in nephrotic syndrome?

Answer 21

Glomerular disease leads to increased permeability of the GBM to proteins. These proteins are lost in the urine (low plasma albumin) resulting in low plasma oncotic pressure. Thus, fluid moves out of the blood into the interstitium leading to peripheral oedema. Reduction in circulating volume so RAAS activated  expansion of ECF and so more oedema.

Question 22

What 2 consequences of liver cirrhosis require treatment with diuretics?

Answer 22

Hypoalbuminaemia and portal hypertension

Question 23

Why are diuretics used in Hypoalbuminaemia?

Answer 23

Reduction in production of albumin leading to low plasma oncotic pressure, causing oedema and so reduced ECF. This activates RAAS causing expansion of ECF and so more oedema.

Question 24

Why are diuretics used in portal hypertension?

Answer 24

Hypertension of the portal vein leads to increased venous pressure in splanchnic circulation. This results in movement of fluid from visceral peritoneal capillaries into the peritoneal cavity as a transudate. This presents as ascites.

Question 25

What are the adverse effects of using diuretics?

Answer 25

Potassium abnormalities
Hypovolaemia
Hyponatraemia
Attack of Gout due to increase in Uric acid levels (thiazides and Loops only)
Glucose intolerance
Increased LDL levels
Erectile dysfunction (reversible if treatment stopped)
Spironolactone can have an oestrogen like effect