renal system Flashcards
renal physiology: explain the physiology of the renal system and how drugs impact ionic composition
what areas in kidney are targeted by diuretics
proximal tubule, loop of Henle, distal tubule
structure of proximal tubule cell
surround lumen with microvillis, with intersitium and capillaries outside of basal interdigitation
physiology of proximal tubule cells: transcellular movement of H2O and Na+
H2O and Na+ diffuse across apical membrane of proximal tubule cell (through channels), with Na+ being exchanged for K+ (Na+/K+-ATPase) at basal membrane to ensure Na+ concentration gradient, with interstitium having oncotic pressure to draw H2O across via channels
physiology of proximal tubule cells: paracellular movement
H2O, Na+, Cl-, HCO3- move into interstitium due to oncotic pressure gradient
physiology of proximal tubule cells: transcellular movement of glucose and amino acids
associate with Na+ and pumped across apical membrane of proximal tubule cell in exchange for H+
physiology of proximal tubule cells: transcellular movement of HCO3-
HCO3- and H+ react in lumen by carbonic anhydrase on apical membrane to form CO2 and H2O, which diffuse across apical membrane of proximal tubule cell; broken down IC to H+ and HCO3- by carbonic anhydrase, with H+ exchanged for Na+ (and amino acids/glucose) at apical membrane (H+ out, Na+ in), and with HCO3- pumped out of basal membrane along with Na+
physiology of proximal tubule cells: exportation of exogenous agents
exogenous agents e.g. glucoronides attached to drugs exported into lumen
% of filtered Na+ absorbed in proximal tubule
65-70%
physiology of descending limb of loop of Henle: transcellular pathway
H2O permeable, ion impermeable; H2O diffuses across cell from isotonic lumen to hypertonic interstitium via channels
physiology of ascending limb of loop of Henle: transcellular pathway
H2O impermeable, ion permeable; Na+, 2Cl- and K+ pumped in across apical membrane of ascending limb cell via triple transporter, with Na+ pumped out in exchange for K+, and K+ and Cl- pumped out together, across basal membrane (K+ can diffuse across apical membrane also, and Cl- can diffuse across basal membrane also)
physiology of ascending limb of loop of Henle: paracellular pathway
Na+ absorbed
describe countercurrent effect of kidney in loop of Henle
loop filled with isotonic fluid -> Na+ pumped from ascending limb (so fluid in ascending lumb decreases osmolarity) -> descending tubule increases osmolarity (permeable to water so water drawn into medullary interstitium) -> more fluid enters and forces fluid from descending to ascending limb, which has increased osmolarity -> second/third etc. round of Na+ pumping
how is countercurrent effect important in collecting duct
when aquaporins inserted, water flows into interstitium down concentration gradient
physiology of distal tubule cell: transcellular pathway H2O
late: early stage is H2O impermeable, but in late stage H2O diffuses in through AQP2 (apical) and into interstitium through AQP3/4 (basal), in presence of ADH (and V2)
physiology of distal tubule cell: transcellular pathway ions
early: Na+ and Cl- contransported across apical membrane, with Na+ exchanged for K+ at basal membrane, and K+ and Cl- cotransported across basal membrane; late: aldosterone binds to MR, increasing Na+ absorption
physiology of collecting duct cell: transcellular pathway
similar as distal tubule cell with regard to water and ions, with H2O reabsorbed in presence of ADH (and V2)
2 methods of action of diuretics in kidney
inhibit reabsorption of Na+ and Cl- (increase excretion), increase osmolarity of tubular fluid (decrease osmotic gradient across epithelia)
5 main classes of diuretics
osmotic diuretics, carbonic anhydrase inhibitors, loop diuretics, thiazides, K+-sparing diuretics
location of action of osmotic diuretics
proximal tubule, descending limb of loop of Henle, collecting duct
location of action of carbonic anhydrase inhibitors
proximal tubule
location of action of loop diuretics
ascending limb of loop of Henle
location of action of thiazides
distal tubule (early)
location of action of K+-sparing diuretics
distal tubule (late) and collecting duct
example of osmotic diutetic
mannitol
example of carbonic anhydrase inhibitor
acetazolamide
example of loop diuretic
frusemide
action of frusemide on Na+ reabsorption from ascending limb of loop of Henle
inhibit Na+ and Cl- reabsorption in triple transporter, interfering with counter current effect
action of frusemide on H2O reabsorption from ascending limb of loop of Henle
increase tubular fluid as interferes with counter current effect, increases tubular fluid osmolarity and decreases osmolarity of medullary interstitium, causing decrease of H2O reabsorption in collecting duct; powerful so can cause large amounts of water loss
what action does frusemide have in common with thiazides
increased delivery of Na+ to distal tubule, increasing K+ loss (increase Na+/K+ exchange), causing hypokalaemia
effect of frusemide on Ca2+ and Mg2+ reabsorption and why
loss of K+ recycling, so as K+ recycling drives positive lumen potential, Ca2+ and Mg2+ less well absorbed through paracellular route
example of thiazide
bendrofluazide
action of bendrofluazide on Na+ reabsorption from early distal tubule
inhibit Na+ and Cl- reabsorption (cotransport protein) in early distal tubule
action of bendrofluazide on H2O reabsorption from distal tubule
increase tubular fluid osmolarity so decrease H2O reabsorption in collecting duct; less powerful as not affecting counter current effect
what action does bendrofluazide have in common with loop diuretics
increased delivery of Na+ to distal tubule, increasing K+ loss (increase Na+/K+ exchange), causing hypokalaemia; less so than loop diuretics as affects later on and affect countercurrent
effect of thiazides on Mg2+ and Ca2+
increase Mg2+ loss (hypokalaemia causing inhibition of distal tubular cell Mg2+ uptake), increase Ca2+ reabsorption (increased proximal Na+ and H2O reabsorption due to volume depletion, leading to increased passive proximal Ca2+ reabsorption)
problem of thiazides and loop diuretics in macula densa cells (RAAS)
if take long-term, promote Na+ and water loss, so as reduced renal perfusion pressure and loss of Na+ concentration at distal convoluted tubule, more renin released from granular cells (bigger issue with loop diuretics as stops Na+ entering macula densa cell)
2 examples of K+-sparing diuretics
amiloride, spironolactone
S47
S47
2 classes of K+-sparing diuretics
aldosterone receptor antagonists (spironolactone), inhibitors of aldosterone-sensitive Na+ channels (amiloride)
mechanism of action of spironolactone
inhibits aldosterone action of pumping Na+ into distal tubule cell (blocks new Na+ channels being created), and Na+ pumping across basal membrane into interstitium (blocks new Na+/K+-ATPase being created)
mechanism of action of amiloride
prevent Na+ being pumped into distal tubule cell through Na+ channels
action of K+-sparing diuretics on Na+ reabsorption from distal tubule
inhibit Na+ reabsorption (and concomitant K+ secretion) in early distal tubule
action of K+-sparing diuretics on H2O reabsorption from distal tubule
increase tubular fluid osmolarity so decrease H2O reabsorption in collecting duct (as furthest along, worst diuretic at preventing water reabsorption)
action of K+-sparing diuretics due to decreased Na+ reabsorption from distal tubule
increased H+ retention (as reduced Na+/H+ exchange)
5 common side effects of loop diuretics and thiazides
metabolic alkalosis (Cl- loss), hypovolemia, hyponatraemia, hypokalaemia, hyperuricemia
common side effect of K+-sparing diuretics
hyperkalaemia (less Na+/K+ exchange)
how is hyperuricemia a common side effect of diuretics
diuretic must get from bloodstream to other side of lumen, so excreted by kidney into lumen (accesses target); transport protein is same that excretes uric acid, so diuretic competes, so uric acid builds up in blood
