Figure 616

Metabolism of acetaminophen and its excretion by the kidney. Prolonged exposure to drugs can cause chronic TIN. Although a number of drugs (eg, lithium, cyclosporine, cisplatin, and nitrosoureas) have been implicated, the more commonly responsible agents are analgesics. As a rule, the lesions of analgesic nephropathy develop in persons who abuse analgesic combinations (phenacetin, or its main metabolite acetaminophen, plus aspirin, with or without caffeine). Experimental evidence indicates that phenacetin, or acetaminophen, plus aspirin taken alone are only moderately nephrotoxic and only at massive doses, but that the lesions can be more readily induced when these drugs are taken together. In all experimental studies the extent of renal injury has been dose-dependent and, when examined, water diuresis has provided protection from analgesic-induced renal injury. Relative to plasma levels, both acetaminophen (paracetamol) and its excretory conjugate attain significant (fourfold to fivefold) concentrations in the medulla and papilla, depending on the state of hydration of the animal studied. The toxic effect of these drugs apparently is related to their intrarenal oxidation to reactive intermediates that, in the absence of reducing substances such as glutathione, become cytotoxic by virtue of their capacity to induce oxidative injury. Salicylates also are significantly (sixfold to thirteenfold above plasma levels) concentrated in the medulla and papilla, where they attain a level sufficient to uncouple oxidative phos-phorylation and compromise the ability of cells to generate reducing substances. Thus, both agents attain sufficient renal medullary concentration to individually exert a detrimental and injurious effect on cell function, which is magnified when they are present together. By reducing the medullary tonicity, and therefore the medullary concentration of drug attained, water diuresis protects from analgesic-induced cell injury. A direct role of analgesic-induced injury can be adduced from the improvement of renal function that can occur after cessation of analgesic abuse.

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