Mechanism of Action

The site of action of loop diuretics is the thick ascending limb of the loop of Henle, and diuresis is brought about by inhibition of the Na+-K+-2Cl" transporter. This seg ment of the nephron is critical for determining the final magnitude of natriuresis. As much as 20% of the filtered Na+ may be reabsorbed by the loop of Henle. The importance of the loop is further emphasized by the realization that drugs that primarily inhibit proximal Na+ and fluid reabsorption have their natriuretic response reduced by the ability of the ascending limb to augment its rate of Na+ reabsorption in the presence of an increased tubular Na+ load. Thus, any agent that greatly impairs active reabsorption in the thick ascending limb may induce a very large Na+ and water loss. Furthermore, the relatively limited capacity of the distal tubule and collecting duct for Na+ reabsorption makes it impossible to recapture much of the suddenly increased tubular Na+ reaching them.

Since the thick ascending limb is responsible for initiating events that lead to the hyperosmolar medullary interstitium (and therefore providing the driving force for water reabsorption from the collecting ducts under the influence of ADH), it is this nephron segment that underlies urinary concentration. Thus, drugs that interfere with this concentrating function will have marked effects on urinary output.

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