Phenacetin analgesic nephropathy

Toxicity. The estimated minimum lethal dose is 5g. Prolonged use of phenacetin is associated with analgesic nephropathy it may also produce haemolytic anaemia and methaemoglobinae-mia. 

The prevalence of analgesic nephropathy is particularly high when there is intensive use of analgesics. There is evidence from animal and clinical work to suggest that hypovolemia plays a part, and that the risk of nephropathy is greatest in women and the elderly. Because of the long latent period of over 10 years, the condition has continued to appear despite the withdrawal of phenacetin. 

In Belgium, the distribution of analgesic nephropathy in patients with terminal renal insufficiency was well correlated with the sale of drugs containing either aspirin -I- phenacetin or paracetamol + caffeine (SEDA-7,75), and it is estimated that Belgium, after Australia, had the second highest incidence of analgesic nephropathy in the world. 

By the early 1980s, most countries had severely restricted or entirely prohibited the sale of phenacetin. Subsequent data from several of these countries suggested that the number of new patients with analgesic nephropathy fell as a result of the prohibition of phenacetin in analgesic mixtures. 

It soon became clear that the major causative agent in analgesic nephropathy was phenacetin, improperly used long-term and especially in combinations with other analgesics, and this identification led to its virtual disappearance in the mid-1970s, following regulatory action. 

Prescott LF. Analgesic nephropathy a reassessment of the role of phenacetin and other analgesics. Drugs 1982 23 (l-2) 75-149. 

McCredie M, Stewart JH, Mahony JF. Is phenacetin responsible for analgesic nephropathy in New South Wales Clin Nephrol 1982 17(3) 134-40. 

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. 

Murray RM. Analgesic nephropathy removal of phenacetin from proprietary analgesics. Brit Med J 1972 4 131-132. 

NSAIDs block the synthesis of COX products of arachidonic acid, which have a critical role in renal hemodynamics, control of tubular function, and renin release. It is now apparent that two isoforms of COX synthesize prostaglandins. COX-1 is a resident or constitutive form and COX-2 is an inducible form that increases with disorders of inflammation. NSAIDs are nonspecific inhibitors of both COX isoforms. Analgesic nephropathy is a common cause of ESRD in a number of countries, reaching 10% in Switzerland and Australia, but is essentially a preventable condition for which biochemical monitoring has proved useful. The incidence of this disease has decreased over the last decade as awareness has improved and phenacetin was withdrawn from over-the-counter analgesic mixtures. In the United States, 1 in 5 citizens (50 miflion) report that they use an... 

Prevention has depended primarily on pnblic health efforts to restrict the sale of phenacetin and combination analgesics. This has effectively rednced analgesic nephropathy in Anstralia and Europe. However, risk continues with continued availability of OTC combination analgesics containing aspirin, acetaminophen, and caffeine in the United States and thronghont the world. 

Figure 2, Analgesic nephropathy is caused by abuse of analgesic mixtures plus caffeine/codeine. Left the potentiating effect of aspirin with both phenacetin and acetaminophen (see text). Adapted from [5, 9], with permission.

Bennett WM, De Broe ME. Analgesic nephropathy - a preventable renal disease. N Engl J Med 1989 320 1269-1271. Mihatsch MJ, Staehelin HB, Musfeld D, Perret E, Oberholzer M. Phenacetin-Abusus Kardiovaskulare Risikofactoren. Nieren Hochdruck 1983 3 83-92. 

Mechanisms of analgesic nephropathy remain unclear. The renal lesion begins in the papillary tip as a result of accumulated toxic metabolites, decreased blood flow, and impaired cellular energy production. The metabolism of phenacetin to acetaminophen, which is then oxidized to toxic free radicals that are concentrated in the papilla, appears to be the initiating factor that causes toxicity by mechanisms analogous to acetaminophen hepatotoxicity. Toxicity is prevented by availability of reduced glutathione. However, salicylates deplete renal glutathione and thereby facilitate phenacetin and acetaminophen toxicity (Silva 2004 Braden et al. 2005). 

Patients with a high consumption of analgesics like phenacetin have an elevated risk of developing TCC. Human papilloma virus as well as Balkan endemic nephropathy have also been suggested risk factors for TCC. In up to 5% of the cases, the patients present with bilateral TCC. Up to 13% of patients with TCC develop metastases in the upper urinary tract. 

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