Week 7 - Diuretics Flashcards
Explain tubular reabsorption of Na and H2O in PCT
- NaKATPase on basolateral membrane sets up an Na gradient
- Na symporter on apical membrane allows Na to enter the cell down its concentration gradient
- Water follows by osmosis
Name the Na transporters of the PCT
- Na:glucose
- Na:a’a
- NHE
Name the Na transporters of the loop of henle
-NaKCC2
Name the Na transporters of the DCT
-NCCT
Name the Na transporters of the late DCT and CD
-ENaC
Describe Na resorption and K secretion in Late DCT and CD
- Occurs in principle cells
- NaKATPase on basolateral membrane sets up a Na Gradient
- Na enters the cell via a channel called ENaC
- Influx of Na+ produces a lumen negative potential which favours K+ secretion through K channels
What are the effects of aldosterone at a molecular level?
-Increases expression of NaKATPase, ENaC and K channel
What is meant by a potassium sparing diuretic?
-A diuretic which also decreases potassium secretion in its mechanism of action eg spironolactone
Which diuretics work by direct action? What is meant by this?
- Loop Diuretics
- Thiazide Diuretics
- K sparing diuretics
- > The diuretics work by directly acting on Na transporters to block them and prevent resorption and this water resorption
Which channels do loop diuretics work on?
-NKCC2 in LoH
Which channels do thiazide diuretics work on?
-NCCT in early DCT
Which channels do K sparing diuretics work on?
-ENaC in late DCT and CD
How do direct action diuretics reach their target site?
-They are secreted into the lumen in the PCT
Explain how a diuretic would work by antagonising the action of aldosterone? Name an example
-Aldosterone increases the expression of NaKATPase, ENaC and K channels in late DCT and CD, thus it works to increase Na and water resorption
-Competitive inhibition of aldosterone would decrease expression of these channels and thus increase renal excretion of Na and water
eg spironolactone
Explain how some diuretics work by modification of filtrate. Give an example
-These diuretics are small molecules which are free filtered at the glomerulus but are not reabsorbed
-They increase the osmolarity of the filtrate and thus decrease water resorption
eg mannitol
Explain how inhibiting the activity of carbonic anhydrase would ace as a diuretic
- Inhibition of CA -> decreased CO2 and H20 entering the cell
- Decreased activity of NHE
- Decreased Na and H2O resorption
Give an example of a loop diuretic
-Furosemide
Give an example of a diuretic which inhbits ENaC
-Amiloride
Which diuretics work in PCT?
-CA inhibitors
What is essential to ensure the continual action of NKCC2 in the loop?
-Diffusion of K back into the lumen so it can be used again
Which diuretic also helps to drive reabsorption of Ca and Mg?
-Loop diuretics
Why does decreasing resorption in the loop increase renal excretion?
-Segments downstream have limited capacity for reabsorption and thus cannot reabsorp the flodding of Na and water
Why are loop diuretics used in HF?
- Diuretic effect
- Vaso and venodilation reduce after/pre load
When are loop diuretics used?
To treat fluid retention and oedema in -HF -Nephrotic syndrome -renal failure To treat hypercalcaemia as impairs Ca resorption in the loop
When are thiazide diuretics used?
-Hypertension
Which diuretics are the least potent at Na resorption?
-K sparing
In what situations are K sparing diuretics contraindicated and why?
- When pt on ACE inhibitor, K supplements or patients with renal impairment
- Can lead to life threatening hyperkalaemia
Explain why ACE inhibitor and K sparing diuretics can cause hyperkalaemia when used together
- ACE inhibitor blocs angiotensin I to angiotensin II
- Decrease angiotensin II results in decreased aldosterone
- Decreased aldosterone increases k retention as K secretion is decreased
- K aring diuretics also cause K retention
- Together can lead to hyperkalaemia
When is spironolactone used?
- Hypertension due to primary hyperaldosteronism (conn’s syndrome)
- Ascites and oedema in cirrhosis
- In addition to loop diuretics in HF
What groups of diuretics are not currently used?
- Inhibitors of carbonic anhydrase
- osmotic diuretics
What is an adverse effects of carbonic anhydrase inhibitor diuretics?
-Metabolic acidosis as it decreases the resorption of HCO3
When are carbonic anhydrase inhibitors used?
-Glaucoma as reduces aqueous humor formation
What is IV mannitol used to treat?
-Cerebral oedema
Why is there expansion of ECF in congestive heart failure?
- Increased systemic venous pressure -> oedema as fluid moves into ECF due to increased hydrostatic pressure
- Decreased CO stimulates RAAS which increased Na and H2O retention
Why does nephrotic syndrome lead to increased ECF?
- Increase in glomerular basement membrane to protein
- proteins such as albumin lost in urine
- Results in a lower oncotic pressure leading to peripheral oedema
- causes low circulating volume and activation of RAAS
- Na and water retention leads to more oedema
Why does peripheral oedema ensue in liver cirrhosis?
-Reduced albumin synthesis in liver ->Low plasma oncotic pressure ->Peripheral oedema -> Decreased CO due to low blood volume activates RAAS -> worsening oedema
Why does ascites occur in liver cirrhosis?
- Portal hypertension leads to an increased systemic pressure in GI circulation
- Increased hydrostatic pressure, coupled with low oncotic pressure, causes fluid to move from peritoneal capillaries to peritoneal cavity
- Decreased CO due to low blood volume activates RAAS -> worsening ascites
What does the rate of K secretion in DCT depend on?
- Concentration gradient of K across apical membrane
- Rate of Na absorption
How do loop and thiazide diuretics lead to K loss?
1) Increased Na and H2o delivery to late DCT and CD
- Increased Na resorption by ENaC
- Favours K secretion via creating lumen negative potential
2) increased flow rate -> increased removal of K in lumen -> increased conc gradient favours K secretion
What can you do when giving diuretics to ensure that hyper/hypokalaemia doesnt develop?
- Monitor electrolyte levels
- Give a K sparing diuretic (amiloride/spironolactone) with a K loosing diuretic (loop/thiazide) to minimise K change
Why can loop diuretics cause hypovolaemia?
- Decreases ECF volume by causing excretion of Na and H2O
- Loop diuretics are the most potent as the segments distal do not have capacity to resorb much water
List some adverse effects of diuretucs
- Potassium disturbance
- Hypovolaemia
- Hyponatraemia
- Gout
Why can loop and thiazide diuretics lead to gout?
-Increase uric acid levels in the blood
Name some substances with diuretic effects
- Alcohol
- Coffee
- Lithium
Name some disease which cause diuresis
- Diabetes mellitus
- Diabetes insipidus
What is a diuretic? When are they used?
-A substance/drug that increases urine formation via promoting renal excretion of water and sodium in order to reduce ECF volume
