Diuretics Flashcards
What is the function o the Na+/K+ ATPase in the kidney
To maintain the ceoncetration gradient of sodium
From the filtrate into the cell
(kidney wants to reabsorb as much sodium as possible) `
How is water absorbed in the kidney
Due to sodium (osmosis)
Due to oncotic pressure of the proteins in the blood moves H2O from filtrate to the blood
As well as transcellular movement what is the pathway, and what can move via this pathway
Paracellular
H2O, Na+, Cl-, HCO3-
Outline physiology in the PCT
Why is CA necessary for bicarbonate absorption
Present in the cell and on the apical membrane
HCO3- in the filtrate reacts with H+ (which is exchanging with Na+, AA and glucose being pumped in) to form H2CO3… this is broken down into CO2 and H2O by CA, and then these are absorbed into the cell
Now within the cell, Carbonic anhydrase does the following to the CO2 and H2O:
CO2 + H2O–> H+ + HCO3-
Bicarbonate absorbed into blood (symport with Na+)
Hydrogen goes out with Na+/H+ antiporter (H+ out and Na+ in)
Then Glucose and amino acids enter via symport with Na+
Big gaps so more paracellular transport here
Why is CA necessary for bicarb absorption:
there are no HCO3- channels, so it cannot diffuse in
As well as reabsorption of nutrients, what is another important function of the PCT
To remove exogenous angents across from the capillaries into the PCT and then into the filtrate for excretion
There are special transporters on the basolateral membrane which recognise side chains and functional groups revealed in phase I metabolism, and the kidney then moves these molecules into the filtrate for excretion
What proportion of each substance is reabsorbed in the PCT
Almost 100% of glucose
70% of Na+ and HCO3-
What happens in descending limb of the nephron
Water moves across (permeable)
Not permeable to Na+
No protein transport
Hypertonic in the interstitium with respect to the lumen so water moves by osmosis out of the tubule
The filtrate is isotonic (300mOsm)
Characterise the ascending limb
IMPERMEABLE to water
Permable to Na+, Cl- and K+ due to the triple transporter Na+/K+/2Cl-…. k+ then flows back out into the lumen
Reduced paracellular route (Na+ flows through though, and a small amount of water, but ALOH is essentially impermeable to water)
NOTE: THE TRIPLE TRANSPORTER IS BRINING IN Na+ and Cl- FROM THE LUMEN INTO THE ALOH CELLS. THEN THE BASOLATERAL PROTEINS BELOW WILL DUMP IT INTO THE MEDULLARY INTERSITIUM TO INCREASE OSMOLARITY OF THE INTERSTITIUM
Basolateral proteins are the Na+/K+ and then K+/Cl- symporter
How is the countercurrent effect achieved
Na+ moves out of the tubule, but the water cannot follow
So reduced concentration in ascending limb,
but higher concentrated in the interstitium
This then causes water to moves out of the descending limb to equilibrate with the surrounding interstitium
So descending limb increases in osmolarity
How is the countercurrent exchange mechanism cyclic
Because after the first round has taken place, new filtrate will come into the nephron.
This will mean the more concentrated filtrate in the DLOH will be pushed around to the ALOH and some isotonic filtrate will enter the top of the DLOH
Now, more Na+ can be pumped out of the concentrated fluid that just entered the ALOH and, equilibration can occur again
A difference of 200mOsm can be maintained between the ALOH cell and the filtrate
Why is the countercurrent system important
Because, WHEN THE COLLECTING DUCT BECOMES PERMEABLE TO WATER (when aqp inserted)
Then water will move into the interstitium if it is concentrated
Where is aldosterone present
Only the late part of the distal tubule
What is present in the early DCT
Apical membrane:
Na+/Cl- symporter
BL membrane:
Na+/K+ ATPase
K/Cl- symporter
Aldosterone not effective here
Also no aquaporins and not ADH responsive
What is important in the end of the DCT/collecting duct
Aldosterone diffuses into cell and binds to MR
Increases number of Na+ channels and the number of Na+/K+ ATPase in the BL membrane
ADH binds to V2 receptors increases number of AQP 2 in the apical membrane
T/F the DCT and collecting duct are permeable to water
F…. only with aquaporins. There are tight junctions between cells
What is present in the collecting duct
No aldosterone, just ADH
Differentiate principal cells and intercalated cells in the late DCT/ CD
Principal cells are the main Na+ reabsorbing cells and the site of action of aldosterone, K+-sparing diuretics, and spironolactone
Type A interacalated secrete acid and absorb HCO3
Type B intercalated secrete HCO3- and absorb H+
How do diuretics work
Inhibit the reabsorption of Na+ and Cl-
i.e. inrease excretion
Increase osmolarity of tubular fluid, so there is less difference between blood and filtrate osmolarity (reduce osmotic gradient across epithelia)
What are the 5 classes of diuretic, and site of action for first 2
- Osmotic diuretics
- whole kidney tubule e.g. mannitol (these are filtered but NOT reabsorbed, increase osmolarity of the filtrate, leading to increased reabsorption at PCT, DLoH and collecting duct ). Pharmacologically inert - Carbonic anhydrase inhibitors
e. g. acetazolamide (works in PCT)
ABOVE NOT USED FOR DIURETIC EFFECT
- Loop diuretics
e. g. frusemide (furosemide) - Thiazides
e. g. bendrofluazide (bendroflumethiazide) - Potassium sparing diuretics
e. g. amiloride, spironolactone.
What is the action of carbonic anhydrase inhibitors
Why do CA inhibitors increase K+ loss
CA is inhibited on the membrane and intracellularly.
Less H+ produced, which means less antiporting with sodium. Also less absorption of HCO3- as this cannot combine with the H+.
Less water reabsorption in the DLoH because of the increased Na+ and HCO3- in filtrate.
K+ excretion increased in attempt to reabsorb some Na+ at the collecting duct.
Therefore ↑ urine volume and ↑K+, ↑Na+ and ↑HCO3- excretion+
USED IN GLAUCOMA
What is the target of frusemide
LOOP DIURETIC
Work on the ALOH.
Blocks the Na+/2Cl-/K+ channel that moves ions from the filtrate into the cell (these ions are then moved into the interstitium by basolateral proteins)
Why is Na+, Ca2+ and Mg2+ lost with loop diuretics
Because of K+ handling
Normally when K+ is absorbed form the filtrate into the ALOH cell, it leaks back into the filtrate. This is potassium recycling
Because the 2Cl- that was reasorbed with the Na+ and K+ is moved into the interstitium via K+/Cl- symport and Cl- basolateral channels,
2 negative ions are moving out of the tubule, but and 1 positive ion is moving back in, causing a POSITIVE LUMEN POTENTIAL
But if the triple transporter is blocked, you can’t bring K+ into the cell, thus it can’t leak back into the tubule lumen
you get reduced positive lumen potential
Positive lumen potential is linked to Na+, Mg2+ and Ca2+ reabsorption via the paracellular route due to the positive charged repelling this cations through the paracellular route into the blood stream.
This is lost with loop diuretics
Effect of loop diuretics on
Na+ reabsoption
H2O reabsoprtion
Other effects
Action on Na+ reabsorption: Inhibit Na+ and Cl- reabsorption in ascending limb – 30% (as the other 70% of the Na+ was reabsorbed in the PCT). Na+ reabsorption also reduced because of lack of positive lumen potential
Action on H20 reabsorption: increases tubular fluid osmolarity/ reduce osmolarity of medullary interstitium = reduced H2O reabsorption in the collecting duct.
Other effects of loop diuretics not related to Na+ or H2o
Other effects: increase deliery of Na+ to distal tubule so K+ loss increases (aldosterone increases Na+/K+ transporter)… in common with thiazides.
Ca2+ and Mg2+ loss (due to the K+ effect), whereas with thiazides, Ca2+ absorption increased and only Mg2+ lost (unknown)
How does bendrofluazide work
Effects on Na+ reabsorption
Effects on H2O reabsoprtion
Thiazide!
Blocks Na+/Cl- in DCT
Action on Na+ reabsorption: Inhibit Na+ and Cl- reabsorption in early distal tubule – 5-10% (most has been absorbed by the PCT and the ALOH by this point)
Action on H20 reabsorption: increases tubular fluid osmolarity = reduced H2O reabsorption in the collecting duct.
Note that the DCT is impermeable to water so this is referring to medulary interstitium concentratin when aqauporins open :D
Side effects of thiazides
Increase delivery of Na+ to distal tubule increased K+ loss (increased Na+/K+ exchange) – in common with loops
Increased Mg2+ loss and increased Ca2+ reabsorption (unknown why…. not to do with positive lumen potential though as this is unaffected by thiazaide diuretics)
Why are thiazides less powerful than loop diurects.
- The further along the kidney you get, the less powerful the diuretic effect becomes
- This is because there is less fluid and less sodium to impact
- So with thiazides, max 5-10% Na+ loss and water loss
What is the major problem encountered with thiazides and loop diurectics
How can this be improved
Because increased excretion of Na+ which occurs with diurectics will reduce blood Na+ levels
The reduced Na+ concentration of the filtrate is sensed by the macula densa cells which causes renin release and eventually aldosterone
This will increase reabsorption of Na+ and thus water via principal cells. This will render the diurects less useful
Improve by giving ACE inhibitor so that the increased angiotensin I produced by renin (angiotensinogen –> angiotensin I) cannot be converted to angiotensin II and thus cannot increase aldosterone release
……
…..
Why does renin increase with diuretics
Because increased excretion of Na+ which occurs with diurectics will reduce blood Na+ levels
Over time, the reduced blood Na+ will be reflected in reduced Na+ concentration of the filtrate (I know that diuretics are increasing Na+, but this is the long term effect of hyponatraemia)
Hyponatreamia is sensed by the macula densa in the JGA in the DCT cells which causes renin release and eventually aldosterone
Which diuretic has the biggest effect on renin secretion and why
The same triple channel that is blocked by loop diuretics in the ascending limb is the one responsible for moving the Na+ into the macula densa cells, and thus the sensing capability of these cells
the macula densa cells will think there is no Na+ as the triple trnaporter is blocked by the loop diuretic.
There would be huge release of renin, in addition to the indirect effect of reduced Na+ in the filtrate due to the hyponatraemia (long term)
What are the targets of amiloride and spironolactone
Amiloride and spironolactone both POTASSIUM SPARING DIURECTICS
Aldosterone receptor antagonists
e.g. spironolactone (I.E. block the intracellular MR)
Inhibitors of aldosterone-sensitive Na+ channels
e.g. amiloride (i..e block the apical Na+ channels on principal cells responsible for the increased Na+ reabsorption mediated by aldosterone)
Summary of action of potassiunm sparing diurectics
Why are they referred to as potassium sparing
Action on Na+ reabsorption: Inhibit Na+ reabsorption (and concomitant K+ secretion) in early distil tubule – 5%
Action on H20 reabsorption: increases tubular fluid osmolarity = reduced H2O reabsorption in the collecting duct.
What are the other effects of potassium sparing diuretic
reduced reabsorption of Na+ in distal tubule increases H+ retention (reduces Na+/H+ exchange, which is antiporter)
You can think about it that with all the other diuretics, the increased Na+ can attempt to be reabsorbed in the DCT in exchange for K+, which increases K+ loss.
However, with potassium sparing, you have affected the machinery so that the Na+ and Na+/K+ are impaired so that you can’t absorb Na+, nor can you excrete K+ with spironolactone so they are potassium sparing.
Common side effects and why
Loop and thiazides:
- Hypokalaemia
- Hyponatraemia
- Hypovolaemia (wanted)
- Metabolic alkalosis (due to Cl- loss)
- Hyperuricaemia
K+ sparing diuretics:
1. hyperkalaemia (less Na+/K+ exchange)
Why is there hyperuricaemia in loop and thiazide diurectics
To have an effect, the diuretic must get from the blood to the lumen, and must use a transporter.
The transporter for loops/thiazide is called the ORGANIC ANION TRANSPORTER
It is shared by uric acid transporter so uric acid cannot get from the blood into the filtrate
How are thiazides used clinically
HTN:
First line in most countries but
Not used unless ‘salt sensitive HTN’ in UK (over 55 or afrocaribbean)
because they cause you to go to the toilet a lot and patients don’t like it
Similarly effective, if not more effective than ACEi or CCB for lowering BP
Why are thiazides used over other diuretics
Loop diuretics do cause more water loss (as more of the Na+ is still in the filtrate)
But diuretics don’t only lower BP due to reducing plasma volume (if they did, loop diuretics would be better)
plasma volume is restored after 4-6 weeks due to renin
Why thiazides then
Chronic thiazide use doesn’t just reduce blood volume, but BUT
Thiazides also vasodilate, so they can reduce TPR long term after the blood volume has been restored
Outline chronic thiazide use in HTN
Activation of eNOS (endothelium) , Ca2+ channel antagonism, opening of KCa channel (smooth muscle)
As well as HTN, what else is diuretics used for
HF
What is the impact of HF
Reduced CO output
SNS will increase
Increased RAS
Increased Ang II… vasoconstrictor (increases TPR, afterload)
Increased ang II and aldosterone affects heart remodelling
Aldosterone increases Na+ and water, so increased volume, increased pressure on heart
T/F SNS is helpful when activated in HF
F
Which diuretics are used in HF
Loop diuretics (affect 30% of Na+ load)
acute reduction in congestion
massive fluid loss
Less venous return/pressure on failing heart
Why can loop diuretics not be used long term in HF
Loop diuretic will increase renin secretion (RAS) which will reduce the fluid loss effects
this can also exacerbate HF because of the angiotensin and aldosterone in cardiac remodelling
What else can be used for HF relating to diuretics
You can use the loop diuretic in combination with a potassium sparing diuretic
This will prevent aldosterone effects due to RAS activation due to the loop diuretics
What is the effect of spironolactone with loop diuretics
Spironolactone is a potassium sparing diuretic
30% reduction in risk of death compared to ACEi/loop diuretic
