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
c

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↑)

Na+-K+-2Cl- symporter creates an interstitium-negative transepithelial potential difference

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

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

Pharmacokinetic

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

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