Phenacetin nephrotoxicity

Large doses of caffeine cause diuresis. Daily consumption of caffeine citrate increased the mean urinary excretion rate of tubular cells and erythrocytes in volunteers (25). The nephrotoxicity of analgesic antipyretic drug combinations may result from a combined effect, in which aspirin, phenacetin, and caffeine all play a role (SEDA-4, 5). In 10 asymptomatic women and 20 women with confirmed detrusor instability, caffeine caused a significant increase in detrusor pressure on bladder filling in the latter, but no difference in volume at first contraction, height of contraction, or bladder capacity (26). 

Phenazone nephrotoxicity is well-established, but information is limited. Experimental papillary necrosis can easily be provoked analgesic nephropathy is probably a real danger with antipyrine, especially when it is combined with a stronger inhibitor of prostaglandin sjmthesis. The effect is probably toxic, since inhibition of prostaglandins is not a marked characteristic of phenazone. Two reports have suggested a causal link between phenazone and renal carcinoma, as is well-known for phenacetin (3,4), but this has not been confirmed. 

The withdrawal of phenacetin from analgesic mixtures in Western Europe and the United States, gave rise to question the nephrotoxic potency of the different kinds of products without phenacetin, available on the market [10]. The nephrotoxic potency of the newer analgesic mixtures could be demonstrated using different kinds of epidemiological observations [46]. 

The molecular structure of 5-ASA is very close of that of salicylic acid, phenacetin and aminophenol, drugs with a well-documented nephrotoxic potential (Figure 6). In rats, it is demonstrated that after a single intravenous injection of 5-ASA, at doses of 1.4, 2.8, 5.7 mM per kg body weight (high pharmacological doses), necrosis of the proximal convoluted tubules and papillary necrosis developed [107]. 

The discontinued analgesic phenacetin is metabolized to A/-hydroxyphenacetin and subsequently conjugated with sulfate. lite O-sulfate conjugate of A/-hydroxyphenacetin binds covalently to microsomal proteins. This pathway may represent one route leading to reactive intennediates that are responsible for the hepatotoxicity and nephrotoxicity... 

Aspirin also has the potential to increase acetaminophen nephropathy. Aspirin inhibits the cyclooxygenase component of prostaglandin H synthase without effect on the prostaglandin hydroperoxidase component, while salicylic acid (the deacetylated metabolite of aspirin) decreases renal glutathione concentrations. Thus, coadministration of aspirin with acetaminophen (or phenacetin) results in a synergistic nephrotoxicity. 

Phenacetin is nephrotoxic, with positive results in mutagenicity and tumorgenicity studies. 

B. Miscellaneous - The nephrotoxicity of phenacetin has been highlighted by a communi cat ions instancing 14 patients with chronic renal disease after taking large quantities of the drug. 

---