Since the effectiveness of many diuretics ultimately depends on establishing a negative Na+ balance to mobilize edema fluid, restriction of dietary Na+ intake is generally an essential part of diuretic therapy. Therefore, one cause of therapeutic failure or apparent patient refractoriness to diuretics could be the patient's continued ingestion of large quantities of NaC1.
Some of the older diuretic drugs were self-limiting; that is, prolonged administration resulted in a gradual diminution of their effectiveness. This problem was corrected through the use of intermittent diuretic therapy. Such a program of several days of diuresis followed by several days of drug withdrawal delayed refractoriness to the drug by preventing excessive disturbances in body electrolyte composition.
Many diuretics (e.g., thiazides and loop diuretics) must reach the tubular lumen before they begin to be effective. Because these compounds are organic acids and are bound to plasma proteins, they reach the lu-minal fluid by secretion. Any disease condition or drug that impairs secretion will affect the access of the diuretics to the luminal fluid and hence to their ultimate site of action (e.g., distal tubule or ascending loop). For example, renal dysfunction may lead to a buildup of endogenous organic acids that decrease drug secretion and thereby alter the patient's expected response to the diuretic. Patients with azotemia frequently require large doses of organic acid diuretics to achieve a satisfactory response. The concomitant administration of other drugs that are substrates for the organic acid secretory system (e.g., probenecid or penicillin) may result in an apparent resistance to diuretic action. It should now be obvious that in addition to disease and electrolyte imbalances, the pharmacodynamic handling of the diuretics themselves may be a factor in diuretic resistance.
Although most individuals respond well to the usual doses of loop diuretics, a small number of patients are refractory to these drugs. These patients may be vulnerable to ototoxicity or other adverse effects if larger amounts of the diuretic are employed. Compensatory proximal tubular sodium absorption may contribute to or be responsible for the resistance to loop diuretics. Combinations of diuretics may be used as an alternative approach to treating diuretic resistance once it has been verified that satisfactory Na+ restriction is being followed and that the drug is being adequately absorbed. Administration of a carbonic an-hydrase inhibitor may be sufficient to enhance Na+ delivery to thick ascending limbs, where its reabsorption can be blocked by loop diuretics. Alternatively, thiazide diuretics may be combined with the loop diuretic to limit absorption by distal convoluted tubules. The thi-azidelike diuretic metolazone, which has some proximal tubule effects unrelated to carbonic anhydrase, appears to be the most effective of the thiazide and thiazidelike drugs in this regard.
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