diuretics Flashcards
what happens in the PCT?
- Na is taken up and cotransports water
- lots of basal Na/K ATPases to retain Na gradient
- carbonic anhydrase on inside of lumen ensures that bicarbonate is broken down –> allows CO2 and H20 to pass into cell
what happens in descending limb?
only H20 reabsorption via AQA molecules
what happens in the ascending limb?
- impermeable to water (for countercurrent flow)
- triple transporter reabsorbs ions
- Na reabsorbed paracellularly
- generated hypertonic interstitium
describe the permeability of limbs
- asc limb: impermeable to water, permeable to ions
- desc limb: permeable to water and not ions
describe the countercurrent effect
- loop filled w/ isotonic fluid
- Na pumped out of asc limb into interstitium (fluid in asc limb dec. in osmolarity)
- conc. interstitium pulls water into it from desc limb (fluid in desc limb inc. osmolarity)
- more fluid flows into tubule, shifts desc limb fluid into asc limb
- Na pumped again out of desc limb into interstitium (asc limb fluid dec. in osmolarity)
what happens in the early DCT?
- mediated by Na/Cl cotransporter
- draws more ions into interstitium
- impermeable to free water reabsorption (mediated by selective AQA2 channels under VP control)
what happens in the collecting duct?
- aldosterone induces Na-channel production
- VP induces AQA2 synthesis dependant on blood osmolarity
- AQA3/4 constitutively expressed on basal membrane
- impermeable to free water re-uptake
describe the osmolarity as you pass deeper into medulla
increases
how do diuretics work?
- inhibit reabsorption of Na and Cl (raises excretion)
- inc. osmolarity of tubular fluid (dec. osmotic gradient)
what are the 5 main classes of diuretics and give an example of each?
- osmotic diuretic e.g. mannitol
- carbonic anhydrase inhibitors e.g. Acetazolamide
- loop diuretics e.g. furosemide
- thiazides e.g. Bendroflumethiazide
- K-sparing diuretics e.g. spironolactone
how do osmotic diuretics work?
- reduce water re-uptake at any part of nephron
- pharmacologically inert
- not reabsorbed after being filtered
- actions to dec. osmotic gradient by raising osmolarity of tubular fluid so reduce water reabsorption
how do carbonic anhydrase inhibitors work?
- act on PCT
- inc. bicarbonate in tubular fluid
- inc. pH of cell as less H ions are made from CO2 and H2O
- less Na is taken back up by Na/K antiporter
- it inc. tubular fluid osmolarity so dec. water reabsorption
how do loop diuretics work?
- act on asc limb of LoH
- strongest diuretics (15-30%)
- inhibit triple transporter
- results in K, Na, Ca, Mg loss
- Mg and Ca ion loss due to K recycling
what causes the reduced +ve luminal pressure?
- small leak of K into tubule from cell
- furosemide inhibits this
- causes less +ve luminal pressure
- less paracellular transport of ions
how do thiazides work?
- act on early DCT
- inhibit Na/Cl cotransporter
- not as strong as loop diuretic (5-10%)
- results in K and Mg loss and Ca reabsorption
what do macula densa cells do?
detect tubular concentration of Na in late asc thick limb of LoH
what effect do diuretics have on renin secretion?
- dec. Na load in tubule = inc. renin secretion to promote Na reabsorption
- diuretics would promote renin secretion
what diuretic would have greatest effect on renin secretion?
- loop
- retain more Na in tubule
what is spironolactone?
aldosterone receptor agonist
what is amiloride?
aldosterone-sensitive NA channel inhibitor
How do K sparing diuretics work?
- inhibit Na reabsorption in early DCT
- cause dec. reabsorption of Na in DCT and inc. H retention
- dec. effects of Na/H exchange
what are the side effects of diuretics?
- hypovolaemia
- hyponatraemia
- hypokalaemia
- metabolic alkalosis
- hyperuricaemia
- hyperkalaemia (K sparing diuretics)
- metabolic acidosis (carbonic anhydrase inhibitors)
what causes the hyperuricaemia?
- diuretic drugs use organic anion transporter to transport into tubule from drug
- so can compete with uric acid in blood
- can lead to greater blood conc of uric acid
what is the 1st line treatment in many countries?
- thiazides
- Ca channel blockers
- ACEi
how can loop diuretics cause HF?
- acute reduction in congestion
- but will inc. renin secretion = cardiac remodelling
what is chronic use of loop diuretics associated with?
- resistance and RAS activation
