Synergistic toxicity of analgesics

As shown to the left, when phenacetin or acetaminophen is ingested with aspirin, there is a potentiating nephrotoxic effect. The aspirin is converted to salicylate, which becomes highly concentrated and depletes glutathione in both the cortex and papillae of the kidney. With the cellular glutathione depleted, the reactive metabolite of acetaminophen then produces lipid peroxides and arylation of tissue proteins, ultimately resulting in necrosis of the papillae. Patients taking analgesic mixtures that contain aspirin, acetaminophen, and/or phenacetin plus potentially addicting compounds, such as codeine and caffeine, are more likely to abuse such drugs, thereby further enhancing the risk of analgesic nephropathy (as shown in the upper right).