Diuretics Flashcards
permeability of proximal tubule cells to sodium and water
Very permeable
Explain effect of the oncotic force in the kidney
- Throughout the kidney there is a protein-based osmotic force (oncotic pressure) that draws water out of the lumen back into the blood
The paracellular route At the PCT allows …
Electrolytes and water
Where is carbonic anhydrase found in the PCT
On the apical cell surface and within the cell
What does carbonic anhydrase do
allows the cell to convert CO2 and H2O to H+ and HCO3- and vice versa
What does the apical carbonic anhydrase do and why
HCO3- and H+ will be converted to CO2 and H2O on the apical side of the cell, this CO2 and H2O can then enter the cell easily by diffusion
What does the intracellular carbonic anhydrase do
converts CO2 and H2O to H+ and HCO3-
Once intracellular carbonic anhydrase has formed H+ and HCO3-, what happens to the ions?
The HCO3- is then transported into the blood with Na
The H+ ions are used in an antiport protein to swap Na+ and H+ at the apical cell membrane
What transports water into the blood?
It does it itself through the osmotic gradient
How does Na enter the PCT cells? (2)
There is free movement of Na+ into the cell, accompanied by movement using Na/H antiporters
How are glucose and amino acids moved into PCT cells?
coupled to sodium movement
what does the PCT absorb?
Glucose, amino acids, H2O, Na, CO2
what does the PCT excrete?
H and exogenous drugs
how does the PCT recognise exogenous drugs to excrete
Big polar conjugate side chains that have been added on to the drugs
Permeability of the descending limb of the LOH to water?
Very permeable
General permeability of the ascending limb of the LOH to water? (exception?)
Impermeable (a little bit can move paracellularly)
Basal side of the membrane of the cells of the kidney lumen faces…
Blood
Apical side of the membrane of the cells of the kidney lumen face …
Lumen
Transport proteins in the DL of the LOH?
Not many
Transport proteins in the AL of the LOH?
Na+/Cl-/K+ triple transporter (apical)
Na/K ATPase (basal)
K/Cl cotransporter (basal)
what does the Na+/Cl-/K+ triple transporter do (numbers)
2x Cl- moved and 1x Na+ and K+ from the lumen to inside the cell
Which surface of the ALoftheLOH has the Na+/Cl-/K+ triple transporter
Apical
What travels paracellularly in the AL of LOH
Water and Na (heavily restricted)
Reason for the countercurrent gradient?
- Promote water movement from the collecting duct Creates an osmotic gradient for water to move out of the collecting duct, into the interstitium and eventually into the blood (when vasopressin recruits aquaporins)
High osmolarity means concentration of water is …
Low
High osmolarity means concentration of dissolved stuff is …
High
Water moves from regions of X osmolarity to X osmolarity
Low to high
Transporters on apical surface of DCT?
Na/Cl cotransporter
Transporters on basal surface of DCT?
Na/K ATPase
K/Cl cotransporter
Effect of aldosterone on DCT, binds to what and this does what (2)
mineralocorticoid, binds to mineralocorticoid receptor and causes increased capacity of cells to reabsorb sodium. via More sodium channels apically and more Na+/K+ ATPase basally
Effect of vasopressin on DCT, binds to what and this does what (2)
binds to the V2 receptor, causes movement of AQP2 apically
Which AQP is found apically
AQP2
Which AQP is found basally
AQP3/4
Job of diuretics? (2)
increase excretion of salt/water in the urine
- Inhibit the reabsorption of Na+ and Cl- i.e. increase excretion
- Increase the osmolarity of tubular fluid i.e. decrease the osmotic gradient across the epithelia
5 classes of diuretics?
- OSMOTIC DIURETICS e.g. mannitol
- CARBONIC ANHYDRASE INHIBITORS e.g. acetazolamide
- LOOP DIURETICS e.g. frusemide (furosemide)
- THIAZIDES e.g. bendrofluazide (bendroflumethiazide)
- POTASSIUM SPARING DIURETICS e.g. amiloride, spironolactone
Where do osmotic diuretics work?
PCT, LOH, CD
Where do carbonic anhydrase inhibitors work?
PCT
Where do loop diuretics work?
AL of the LOH
Where do thiazides work?
Distal tubule start
Where do potassium sparing diuretics work?
Distal tubule end
What diuretics act on the PCT?
Osmotic diuretics and carbonic anhydrase inhibitors
What diuretics act on the LOH?
Osmotic diuretics
What diuretics act on the AL of the LOH?
Loop diuretics
What diuretics act on the start of the DCT?
Thiazides
What diuretics act on the end of the DCT?
Potassium sparing diuretics
What diuretics act on the CD?
Osmotic diuretics
Example of a loop diuretic?
Frusemide
How do loop diuretics work? (2)
Inhibit Na+ K+ and Cl reabsorption in ascending limb – 30% less water reabsorbed in the CD due to increased ions in tubular fluid
Increase tubular fluid osmolarity/decrease osmolarity of medullary interstitium
What transporter do loop diuretics target?
Na/K/Cl triple transporter
How do loop diuretics cause an increased K loss
Na/K/Cl not absorbed in the AL of LOH, DT tries to desperately absorb Na via Na/K exchanger (and Na/Cl co transporter), meaning potassium is going to be lost from blood to try Na in
How do loop diuretics cause an increase in Ca/Mg ion loss (K recycling)
K+ recycling – potassium is constantly reabsorbed but also lost This constant movement of potassium constantly replenishes positive charge in the lumen which contributes to the net positive charge in the lumen – this causes calcium and magnesium and sodium (all positive) to be ‘repelled’ via the paracellular route back to the blood – Reducing this K+ recycling causes more loss of Na, Ca and Mg
What transporter do thiazides target
Na/Cl cotransporter in early distal tubule
What % of water loss do loop diuretics cause
about 30%
Action of loop diuretics on Na reabsorption?
Inhibit Na+ K+ and Cl reabsorption in ascending limb – 30% less water reabsorbed
Action of thiazides on Na reabsorption?
Inhibit Na+ and Cl- reabsorption in early distal tubule – 5-10%
Action of loop diuretics on H2O reabsorption?
Increase tubular fluid osmolarity/decrease osmolarity of medullary interstitium, so less water is absorbed in the CD
Action of thiazides on H2O reabsorption?
Increase tubular fluid osmolarity so causes decreased H2O reabsorption in the collecting duct
Action of thiazides on K?
- Increase delivery of Na+ to distal tubule and increase K+ loss (via increasing Na+/K+ exchanger as the Na+ is trying to be absorbed by the DT)
Action of thiazides on Mg and Ca?
Increased Mg2+ loss and increased Ca2+ reabsorption (unknown reasons, happens after chronic diuretic use)
Problem with chronic thiazide and loop diuretic use?
They cause hyponatraemia over time, stimulating renin secretion (low sodium passing through lumen of distal tubule after chronic use sensed by the macula densa) – this increases sodium and water reabsorption by stimulating aldosterone (a rebound effect)
What do we do to fight the rebound effect of thiazides and loop diuretics
give diuretics in conjunction with ACE inhibitors
2 classes of K sparing diuretics?
- ALDOSTERONE RECEPTOR ANTAGONISTS (MR inhibitors)
2. INHIBITORS OF ALDOSTERONE-SENSITIVE Na+ CHANNELS
Effectiveness of K sparing diuretics? (%)
5% water loss, not v powerful
Action on Na+ reabsorption of K sparing diuretics?
Inhibit Na+ reabsorption (and concomitant K+ secretion) in early distal tubule
Action on H20 reabsorption of K sparing diuretics?
Increase tubular fluid osmolarity -> Decrease H2O reabsorption in the collecting duct
Permeability of distal tubule to water?
Only permeable with AQP
Where do AQPs act?
DCT
What do ALDOSTERONE RECEPTOR ANTAGONISTs do
Bind to MR in distal tubule cell stopping aldosterone from increasing Na channels apically and Na/K exchangers basally
What do INHIBITORS OF ALDOSTERONE-SENSITIVE Na+ CHANNELS
Block Na channels in the DCT which were in place by aldosterone effects
What is amiloride an example of
INHIBITORS OF ALDOSTERONE-SENSITIVE Na+ CHANNELS
What is spironolactone and example of
ALDOSTERONE RECEPTOR ANTAGONISTS
Example of INHIBITORS OF ALDOSTERONE-SENSITIVE Na+ CHANNELS
Amiloride
Example of ALDOSTERONE RECEPTOR ANTAGONISTS
Spironolactone
How do K sparing diuretics lead to H+ retention
Decrease reabsorption of Na+ to distal tubule increase H+ retention (decrease Na+/H+ exchange)
Side effects of K sparing diuretics? Why?
Hyperkalemia as there is less Na/K exchange
Side effects of thiazides and loop diuretics? (5)
Hypovolemia, hyponatremia, hypokalaemia, metabolic acidosis, hyperuricemia
Side effects of carbonic anhydrase inhibitors?
Metabolic acidosis
How do loop diuretics and thiazides cause hyperuricemia
because they directly affect the transporter than moves uric acid into the lumen
What does a build up of uric acid in blood lead to
Gout
What can diuretics be used to treat (2)
Hypertension
Heart failure
First line treatment for hypertension?
Thiazides
Why use thiazides as antihypertensives instead of other diuretics
Chronic use of thiazides is associated with vasodilation
Could be associated with eNOS, Ca channel antagonism and K channel opening
Why do you lose the diuretic effect after using a diuretic for about 6 weeks? How do you amend this
Renin increase, to fix give an ACEi
