Diuretics Flashcards
What is a diuresis?
Increased formation of urine by the kidney
What is a diuretic?
A substate / drug that promotes a diuresis by increasing renal excretion of water and sodium which reduces the ECF volume.
When are diuretics useful?
In clinical conditions where Na+ and water retention can cause expansion of ECF volume. e.g. heart failure.
Summarise how diuretics work
Act by lowering reabsorption of sodium and water by the tubule.
Fractional excretion (FE) of Na is usually under 1% but, diuretics increase the FE of Na.
What does aldosterone do to channels in late DCT and CD?
Aldosterone increase the expression of NaKATPase, ENaC and K+ channels.
How do diuretics work?
- By direct action on cells to back Na+ transporters in the luminal membrane.
- By antagonising the action of aldosterone.
- By modification of filtrate content - osmotic diuretics (no longer used)
- By inhibiting activity of the enzyme carbonic anhydrase in the PCT to interfere with Na and HCO3- reabsorption in PCT. (no longer used)
How do loop diuretics work (summary)?
Act on loop of Henle - block Na-K-2Cl cotransporter
How do thiazide diuretics work (summary)?
Act on the early distal tubule to block Na-Cl cotransporter
How do K+ sparing diuretics work?
Act on late DT and CD to block ENaC (amelioride).
Why does antagonising aldosterone have a diuretic effect?
Aldosterone upregulates expression of NaKATPase/
Aldosterone acts on Principle cells of late DT and CD to increase Na+ reabsorption via ENaC.
Aldosterone antagonists work by competitively inhibiting aldosterone receptors which decreases Na reabsorption and wherefore water so more is excreted as urine.
They also have a K+ sparing effect.
How to osmotic diuretics work?
They modify the filtrate content.
Small molecules freely filtered at glomerulus bur bot reabsorbed.
Increases osmolarity of filtrate and reduces water and Na+ reabsorption through the tubule.
How do loop diuretics work - Detailed?
Loop diuretics block apical NaKCl transporter.
This means that Na and Cl are not reabsorbed so it reduces the medullary tonicity.
This results in less water is reabsorbed further down the tubule meaning both Na and water are lost.
Also, K+ carried across apical membrane drifts back into lumen via K+ channels.
This creates a lumen positive potential.
This helps to also drive the absorption of the positively charged ions calcium and magnesium.
When do we use loop diuretics?
Used in heart failure to treat symptoms -breathlessness and oedema.
As well as their diuretic effect, they cause vaso and venodilation (reduce preload and after load).
This reduces the symptoms but has no effect on mortality.
Also used in acute pulmonary oedema - IV furosemide.
Fluid retention and oedema in:
- Nephrotic syndrome
- Renal failure
- Cirrhosis of liver
Useful in hypercalcaemia as :
- Impairs calcium absorption in the LoH
- Increases urinary excretion of calcium
- Furosemide given together with IV fluid.
How do thiazide diuretics work (detailed)?
Thiazide diuretics block NaCl transporters in the early DCT.
Secreted into PCT Travel downstream to act at DCT
Increases Na+ (and water) loss in urine
Increases calcium absorption so reduces its loss in the urine.
When do we use thiazide?
They are less potent than loop diuretics so they are ineffective in renal failure.
We use thiazide in hypertension because of its vasodilatory effects.
How do potassium sparing diuretics work?
They either inhibit ENaC (Amiloride) or antagonise aldosterone (Spironolactone).
Both groups:
- Reduce ENaC activity
- Reduce the loss of K+
- Both can produce life threatening hyperkalaemia -especially if used with ACE inhibitors, K+ supplements or in patients with renal impairment.
- Both are mild diuretics (affect only2% of Na reabsorption)
What is spironolactone used for?
Shown to reduce mortality in heart failure
Used in long term treatment if heart failure.
Preferred drug for ascites and oedema in cirrhosis
Used as additional therapy in hypertension but controlled by ACEI+CCB+Thiazide
Treatment of hypertension due to primary hyperaldosteronism (Conn’s)
When are ENaC blockers used?
Usually used in combination with K+ losing diuretics such as loop or thiazide diuretics to minimised K+ loss.
What does the rate of potassium secretion depend on?
Concentration gradient across apical membrane.
Rate of sodium absorption -inwards movement of Na+ creates a favourable lumen negative potential for K+ secretion.
How do loop diuretics and thiazide cause hypokalaemia?
The reduced circulatory volume can active RAAS which increases adosterone secretion, Na absorption and K secretion which can also contribute to hypokalaemia.
Why can potassium sparing diuretics cause hyperkalaemia?
How do you minimise changes in potassium while using diuretcs?
- Monitor K+ levels
- Use a combination of loop / thiazide diuretic with a K+ sparing diuretic
- Loop / thiazide diuretic with K+ supplements.
When do you not use K+ sparing diuretics?
- K+ suppliments
- Impared renal function
As these increase the risk of hyperkalaemia.
In combination wiht ACEI, ARB - regular K+ monitoring is required.
Why does ECF expansion occur?
Usually an adaptive response to reduced circulating volume.
In congestive heart failure this is due to:
- Drop in cardiac output with reduced renal perfusion
- Increase in systemic venous pressue –> oedema so dluid moves from intravascular to insterstilial comprtment.
These things lead to RAAS activation - More Na and water retention, expansion of ECF
