Diuretic Agents: Loop Diuretics

Physiological Effects:

While the descending limb of the Loop of Henle reabsorbs 25% of the filtered water, the ascending limb is practically impermeable to it. The thin ascending limb, like its thick counterpart, is impermeable to water; hence it is also referred to as a diluting segment of the nephron. However, NaCl and urea are free to diffuse across it. After passing through the descending limb of the Loop of Henle, the tubular fluid is concentrated with NaCl; as a result, NaCl diffuses out. Urea, on the other hand, is more concentrated in the interstitium of the medulla; thus, one sees it move into the thin ascending limb. Like its thin counterpart, the thick ascending limb is water impermeable. It also has low permeability to urea.

The loop diuretics (e.g. furosemide) target the Na+-K+-2Cl- symporter in the thick ascending limb. Like many other diuretics, most loop diurects (like furosemide, bumetanide, and torsemide) are sulfonamide diuretics and thus have the potential of causing allergies. Ethacrynic acid, a phenoxyacetic acid derivative, is an exception that works by the same mechanism. The following effects are synergistic to the effects of thiazide diuretics when used in conjunction. The loop diuretics also have pulmonary vasodilating effects, whose mechanism is not known.

Na+: Since they block the Na+-K+-2Cl- symporter, large doses of loop diuretics cause massive diuresis of sodium chloride in a short period of time. Thus, the amount of sodium in the urine largely increases while the body concentration of sodium is not largely affected (since also excrete water with the Na+).

K+/H+: Once the tubular fluid reaches the collecting duct, the transporters make one last effort to reabsorb the sodium left by Na+-K+-2Cl- symporter blockage in the ascending limb. As a result, K+ and H+ are exchanged for the Na+ (see collecting duct); the urine amounts of K+ and H+ increase (therefore the urine pH decreases), while body concentrations of K+ and H+ decrease (therefore body pH increases).

Ca2+/Mg2+: Because the Na+-K+-2Cl- symporter no longer functions, the positive potential in the lumen is soon reduced (since there is no longer a potential for K+ to exit the cell), reducing the gradient for paracellular reabsorption of the divalent cations. As a result, there is decreased reabsorption of Ca2+ from the urine, resulting in increased urine Ca2+ content.

Water: Since the loop diuretics act in the diluting segment of the nephron, they can impair water excretion. If the perfusion to peripheral tissue is adequate, edema fluid can be rapidly excreted and blood volume can be reduced.

Clinical Uses

Loop diuretics can be used for:

  1. Edema - Edematous states like congestive heart failure and ascites are greatly helped by diuretics. Due to their pulmonary vasodilating effects, these drugs are particularly useful fir acute pulmonary edema.

  2. Hypertension - When thiazides do not help hypertension much, loop diuretics can be used. However, due to their short duration, the loop diuretics are less desired.

  3. Severe hypercalcemia - This condition can be induced by malignancy. Loop-diuretic use should be coupled with volume and electrolyte (NaCl and KCl) resuscitation. Without volume replacement, the resulting hemoconcentration can actually increase serum calcium concentration.

  4. Renal Failure - The diuretics can increase NaCl excretion in the face of renal failure, when the kidneys may be unable to do so on their own.

Side Effects

Loop diuretics may lead to: