Pharm 21: diuretics Flashcards
in normal kidney physiology what happens in the:
a) PCT ?
absorbs most Na+ (70%), HCO3-, H2O
- Carbonic anhydrase = bidirectional
- on apical memb + inside the cell
- brings CO2 + h2O IN –> converts them to HCO3 +H+ –>
HCO3- gets absorbed into blood (with Na+) - H+ used to five Na+/H+ exchanger on apical memb
- H2O diffuses across cell itself
- Na+/K+ exchanger helps to maintain Na+ conc gradient
o Exogenous agents e.g. metabolised drugs w/ specific sidechains = recognised by basal transporters –> excreted into urine (diuretics produce effects by this way)
in normal kidney physiology what happens in the:
- descending limb ?
Descending limb of LoH = water permeable – reabsorption from tubule lumen (isotonic) into interstitium (hypertonic)
in normal kidney physiology what happens in the:
-ascending limb ?
Ascending limb of LoH = water impermeable
- Has apical TRIPLE transporter on apical memb (Na+/K+/Cl-)
- basal Na+/K+ pump on basal memb = important to maintain ion gradients
describe what is meant by counter current effect ?
- ascending limb - sodium is being extracted but water cant follow –> more diluted
- there is high sodium conc in interstitum btw the 2 loop of hence
- water from descending limb moves into interstitium
in normal kidney physiology what happens in the:
- DCT?
early DCT: little Na+ reaches here – has Na+/Cl- co-transporter;
- Na+ and Cl- moves through cell –> into interstitium via Na+/K+ and K+/Cl- transporter respectively
aldosterone affects late DCT + CD
- increases ability of cell to reabsorb sodium
- -> osmolarity rises further down duct
o CD impermeable to water, needs AQPs in apical membrane to move water
what are the 5 classes of diuretics ?
- Osomotic diuretics
e. g. mannitol - Carbonic anhydrase inhibitors (CAi)
e. g. acetazolamide - Loop diuretics
e. g. frusemide - Thiazides
e. g. bendrofluazide (Loop + thiazides most important) - K+-sparing diuretics
e. g. spironolactone, amiloride
How do diuretics work in general?
what re the 2 diff methods
a) Inhibit reabsorption of Na+ and Cl- (thus, increase excretion)
b) Increase tubular fluid osmolarity (thus, decrease osmotic gradient across epithelia
Describe how an osmotic diuretic works?
Acts at PCT, D-limb, CD
-increase tubular fluid osmolarity throughout (NB + plasma) –> decrease H2O reabsorption where nephron is freely permeable to water (PCT, D-limb, CD)
note: (NO action on Na+ reabsorption)
Describe how a CAi works as a diuretic?
- acts at PCT
1. Less bicarbonate and H+ converted to CO2 + H2O in lumen –> less enters cell
2. Less CO2 + H2O inside cell re-converted –> less H+ and HCO3- in cell
3. Inhibit Na+ + HCO3- reabsorption overall b/c less H+ produced inside cell for antiporter
4. Thus, increases tubular osmolarity + decreases medullary interstitium osmolarity –> decreases H2O reabsorption in CD - Other effects:
o increase delivery of HCO3- to DCT –> increase K+ loss
o Ca2+ & Mg2+ also lost –> loss of K+ recycling
Describe how loop diuretic works ?
- frusemide acts at Ascending-limb
- action on Na+ reabsorption= inhibits Na+/2Cl-/K+ triple transporter (roughly 30% of Na+ enters LOH)
- action on H2O reabsorption = increases tubular fluid osmolarity + medullary interstitium - osmolarity falls –> less H2O reabsorption in CD
Other effects:
o Increased delivery of Na+ to distal tubule –> greater K+ loss due to greater Na+/K+ exchange –> hypokalaemia –> CVS risks (also seen in thiazides)
o Ca2+/Mg2+ loss –> loss of K+ recycling (in LOH) = K+ constantly recycled between tubule + cell; recycling creates positive lumen potential –> pushes other cations e.g. Na+, Ca2+, Mg2+ via paracellular route into interstitium then blood
- If no recycling –> less cations reabsorbed –> more excreted
Describe how thiazides works as a diuretic?
- acts on DCT
inhibits Na+/Cl- cotransporter (5-10% of Na+ reaches DCT)
–> increased tubular fluid osmolarity –> decreased H2O reabsorption in CD - Other effects:
o delivery of Na+ to distal tubule –> K+ loss
o increases Mg2+ loss
o increases Ca2+ reabsorption (unknown)
What is the issue with loop diuretics + thiazides?
- chronic diuretics –> blood sodium falls
- if blood sodium falls –> filtering falls
- which is a stimuli for renin secretion
- sensed by macula densa –> increases renin secretion
w loop diuretic –> affects triple protein that drives Na+ into cell –> stops na+ getting into macula densa in the first place –> as MOST PROFOUND effect on increase in Renin release
Describe how K+ sparing diuretics works?
- acts on distal tubule
- 2 classes:
1. Aldosterone-R antagonists
e. g. spironolactone - stops MR binding –> decreases Na+ channel insertion on apical memb –> less Na+ reabsorption –> tubular fluid osmolarity –> decreases H2O reabsorption in CD
- Inhibitors of aldosterone-sensitive Na+ channels
e.g. amiloride
- Action = directly inhibit Na+ reabsorption (+ K+ secretion)
in early distal tubule –> tubular fluid osmolarity –> decreases H2O reabsorption in CD
- Other effects:
o decreases reabsorption of Na+ in distal tubule –> H+ retention (decrease Na+/H+ exchange)
what are common side effects of diuretics?
Common SE in loop + thiazides:
- Hypokalaemia
- hyponatraemia
- metabolic alkalosis
- Hyperuricaemia - thiazides interferes w uric acid transporter on basal memb –> less uric acid excreted –> hyperuricaemia –> gout
K+ sparing diuretics SE = Hyperkalaemia
What are the clinical uses of diuretics?
a) hypertension
- usually thiazides
- 1st line treatment in hypertension
b) heart failure
normal physiology:
- in HF –> reduced CO
- SNS increases –> which causes increases renin production –>increased ATII = vasoconstriction.
WHICH ALSO increases Aldosterone –> more Na+ and water retention –>
- Loop diuretics = decrease Na+ and water retention –> reduce workload of heart
- BUT in long term, loop diuretic cause greater renin release –> greater Na+ and water retention –> greater work needed to be done by heart again = rebound increase in RAAS system (so give ACEi too)
- Or give K+ sparing diuretic alongside –> decreases risk of death by interfering w RAAS
