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Diuretics: Loop diuretics (Side effects (hypovolemia : hypotension,…
Diuretics: Loop diuretics
general properties and chemical strucsture of loop diuretics
the most effective diuretics
they can inhibit the reabsorption as much as 25% of GFR (called high-ceiling diuretics)
K+ and H+ losing diuretics
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chemical structure
all are organic acids, some with two acidic group (e.g. furosemide -> carbonic acid + aminosulfonic acid )
MOA
mechanism in thick ascending limb of LOH
Na+-K+-2Cl- symporter moves 1Na+, K+ and 2Cl- into the tubular cells (from lumen)
then, these ions are exported into the interstitium via transporters / channels, but K+ is largely returned into the cells by Na/K ATPase -> 2 consequences
Na+-K+-2Cl- symporter creates a hypertonic intertsitium (corticomedullary gradient↑)
because the ions are not followed by water here (thick ascending limb of LOH is not water permeable)
so, the hypertonic interstitium drives the reabsorption of water by extracting water from the leaky descending limb of LOH
Na+-K+-2Cl- symporter creates an interstitium-negative transepithelial potential difference
because effect 1Na+ and 2Cl- moves into interstitium (more negative) -> this drives the reabsorption of Ca2+ and Mg2+
action of loop diuretics
loop diuretics are secreted by the proximal convoluted tubule (basolateral OAT1 -> luminal AOT4 and MRP4)
they travel along the nephron to the thick ascending limb of LOH -> site of action
they bind to Na+-K+-2Cl- symporter (Cl- binding site) and inhibit (Na+-K+-2Cl- symporter is on the luminal membrane of tubular cells)
then, interstitium become hypotonic (corticomedullary gradient↓)
water reabsorption does not occur in the descending LOH (25% GFR escapes reabsorption) -> diuresis (loss of 25% of GFR and Ca2+ and Mg2+)
Effects of loop diuretics
large increase in urine volume
hypovolemia and hypotension may develop
increased urinary excretion of electrolytes
primary
Na+ / Cl- (due to inhibition of Na+-K+-2Cl- symporter)
secondary
Ca2+ and Mg2+ (due to abolishing of interstitium-negative transepithelial potential difference )
K+ and H+ (secretion in the collecting duct) -> K+ and H+ losing diuretics
more Na+ reaches the collecting duct because Na+ reabsorption had been inhibited upstream (ascending limb of LOH)
then more Na+ gets reabsorbed in the collecting duct through the Na+ channels (in principal cells)
lumen negative transepithelial potential difference increases in the collecting duct
so, more K+ and H+ will be driven into the lumen of the collecting duct across the luminal membrane through K+ channel and H+ ATPase
finally, K+ and H+ are lost into urine
Others
loop diuretics block tubuloglomerular feedback by inhibiting NaCl transport into macula densa cells -> good for anuria in acute renal failure
loop diuretics have a venodilator action by inducing PGI2 -> good for congestive heart failure
Pharmacokinetic
oral bioavailability
furosemide
incomplete and highly variable (average is 50%)
bumetanide / torasemide / ethacrynic acid
near complete (80-100%)
plasma protein binding
all are extensive (98%) -> low Vd (in nephrosis syndrome, binding to proteins in the tubular fluid prevents action of loop diuretics)
elimination
furosemide / bumetanide
largely by renal tubular secretion (OAT1 -> OAT4 and MRP4) + partly by glucuronidation at the COOH group
ehtacrynic acid
largely by renal tubular secretion (OAT1 -> OAT4 and MRP4) + partly by glutathione conjugation
torasemide
mainly by C-hydroxylation (CYP) Æ further oxidation into inactive -COOH acid
T1/2: 2hours (except torasemide -> 5hours)
Side effects
hypovolemia : hypotension
hypokalemia (K+ loss) : muscle weakness
hypomagesemia : risk of arrhythmia (hypomagesemia impairs Na/K ATPase activity)
hypocalcemia
. hyperglycemia (loop diuretics open K+ APTase in β-cells -> hyperpolarization -> decreased insulin secretion)
hearing loss (by ehtacrynic acid)
indications
acute pulmonary edema caused by acute heart failure
furosemide(i.v.) -> venodilation and decrease of blood volume
acute hypertensive crisis
furosemide(i.v.) -> venodilation and decrease of blood volume
acute renal failure
furosemide(i.v.) -> to convert oligouric ARF into non-oligouric ARF
acute hypercalcemia
furosemide(i.v.) -> to excrete Ca2+
Drug interactions
pharmacokinetic interactions
loop diuretics are strongly plasma protein bound (99%) and have low Vd -> displace highly protein-bound drugs like warfarin (risk of bleeding)
acidic drugs that undergo extensive tubular secretion decrease tubular secretion of loop diuretics -> decrease effects of loop diuretics e.g. salycilates / NSAID
pharmacodymaic interactions
NSAIDs have antidiuretic effect and diminish the diuretic effect of loop diuretics
NSAID decreases the formation of vasodilatatory PGs in the kidney
so, renal blood flow and blood flow of vasa recta decrease
because of this, the hypertonicity of the interstitium (corticomedullary gradient) is not washed out
finally, the hypertonic intersititum increases water reabsorption, causing antidiuretic effect
loop diuretics
K+ loss : increases effects of digitalis (increases risk for digitalis intoxication)
Mg2+ loss : increases risk of arrhythmia
Na+ loss : promotes Li+ reabsorption in proximal tubule -> risk for Li+ toxicity