Kidney and Diuretics Flashcards
What is the main function of the PCT and what facilaitates this?
To reabsorb H20. Na reabsorption passively at the apical membrane, then the Na/K ATPase on the basal membrane pumps Na back into the interstitum. This creates an oncotic pressure that pulls water from the tubule fluid across the PCT cell to the interstium as well.
The Na/K ATPase is key here, to maintain the Na gradient across the PCT. Na uptake is also coupled with amino acid and glucose uptake in the PCT.
65-70% of HC03, Na and H20 reabsoprtion in the PCT.
How does bicarbonate reabsorption work in the PCT?
Carbonic anhuydrase on the paicl mebrane converts HC03 and H in the tubule fluid to C02 and H20 which passes passively ino the PCT. cARBONIC anhydrase in the PCT converts CO2 and H20 to H and HOC03 again. H is pushed back into the tubule fluid in exchange for Na. HC03 is taken up into the interstitum with a Na co-transporter.
The Na/H exchanger on the apical membrane is key here, as welll as the two populations of carbonic anhydrase.
Describe the transporters in the ascending loop.
What is concurrent multiplication?
Apical membrane: Na,2Cl and K triple transporter (inhibited by furesemide and hypercalcaemia). K diffuses straight back through to the tubule fluid almost immediately, so a positive lumen potential is created. Basal membrane has Na/K ATPase and a coupled K/Cl transporter into the interstitum. This creates a hypertonic meduallry interstitum (and hypotonic tubule fluid) , which draws water from the tubule fluid of the descending limb of LOH (impermeable to solutes). Less and less water drawn out as the water descends down the descending limb and most solutes strat to be pumped at the bottom of the LOH. Concurrent multiplication- drives reabsorption of water from the collecting duct (medullary interstitum now increasing in osmolarity as you go down)
Describe the transporters in the early DCT. How does this compare to late DCT?
Na and Cl coupled at the apical membrane. Na/K ATPase at the basal membrane, with a K and Cl coupled (same as ascending loop).
Late DCT you get ADH dependent AQP2 on apical membrane, as well AQP3/4 on basal membrane. Aldosterone can upregulate Na channels on apical membrane and Na/K ATPase on basal membrane.
What are the 5 diuretic classes and give an example of each
1) Osmotic diuretics- mannitol. 2) Carbonic anhydrase inhibitors - acetazolamide. 3) Loop diuretics- furosemide. 4) Thiazides- bendrofluazide. 5) Potassium sparing diuretics- spironalactone and amiloride.
What is the MOA of mannitol?
Mannitol is an osmotic diuretic. It is pharmacologically inter- filtered by the glomerulus but not reabsobred. Increases the osmolarity of tubule fluid, so reduces water reabsorption where neprhon is permeable to water e.g. - at the PCT, the descending LOH and the collecting duct.
What is the MOA of acetazolamide? What is a major side effect?
Another one? (gen)
Acetazolamide is carbonic anhydrase inhibitor. It inhibits HC03 and Na reabsorption in the PCT (Remeber how Na is exchanged for H on apical membrane?). This increases tubule fluid osmolarity and decreases medullary interstial osmalarity, which reduces water reabsorption form the collecting duct.
Causes hypokalemia.
- There is increased HC03 delivery to distal tubule, so compensatory HCO3 reupatke there. This necessiates Na exchange, so more Na/K ATPase action–> K loss.
Also causes metabolic acidosis (loss of HCO3)
What is the MOA of furosemide? 2 major side effects?
Furosemide is a loop diuretic. Inhibits Na and Cl reabsorption in the ascending limb of LOH by 30%. (Basically inhibits triple transporter). This incraeses the osmolarity of the tubule fluid, decreases osmolarity of meduallry interstium, leads to decreased water reabsorption from collecting duct.
Side effects: incraesed Na deleivery to distal tubule–> increased compensatory Na/K ATPase action–> K loss.
Also, postassium recylcing is dependnet on the triple transporter and usually maintains a positive lumen potential. Loss of positive lumen potential means less paracellular reuptake of Ca, Mg–> loss of Ca and Mg.
What is the MOA of bendrofluazide?
3 side effects.
Bendrofluazide is a thiazide which inhibits the Na and Cl reupatke in the ealry DCT (5-10%). Increases tubular fluid osmolarity which decreases water reabsorption at the collecting duct.
Side effects: incraesed Na delivery to distal tubule–> compensatory increase in Na/K ATPase activity–> K loss.
Also Mg loss due to impaired positive lumen potential
Also Ca reabsoprtion increased- unkwon mechanism..
What is the problem with chornic use of thiazides and loop diuretiucs?
They inhibits transporters that usually take up Na from the tubular fluid. This means Na in the tubule fluid cannot be sensed by the macula densa cells, which actiavtes the RAS in response. So although thiazides and loop diuretics (more potent) cause an acute drop in water renton, they can actually raise BP over times.
What is the MOA of amiloride and spironalactone?
One potential side effect?
Amiloride and spironalactone are potassium sparing diuretics that inhibit Na reabsorption (and hence concomiatnt K secretion) in early DCT (only about 5%).
Amiloride inhibits Na ion channels on apical membrane whereas spironalactone is an MR antagonist.
Hence they incraese tubular fluid osmorality which decreases water re absorption form the collecting duct.
Side effect: because Na is being retained in the tubular fluid, there is less N/H exchange across the apical membrane–> H retention. Could also cause a hyperkalaemia.
Name 5 side effects of loop diuretics and thiazides
Hypovolaemia (LD=30% loss, T=10% loss), hypokalemia, metabolic alkalsosis (Cl loss), hyperuricaemia (Organic Anion transporter comeptition in DCT), hyponatriemia.
Clinical use of thiazides
E.g. bendrofluazide. First line for hypertension.
Inital loss of voume works over 4-6 weeks. Then, UNLIKE OTHER DIURETICS, thiazdes can decrease TPR by 1) activation of eNOS, 2) Ca channel anatagonism and 3) opening of KCa for smooth muscle.
Treatment of heart failure
Give Furesomide IV first for acute diuretic effect within 30 mins. This decreases ventricular filling pressures.
Then give a potassium sparing diuretic to maintain effect (despite RAS activation)
