Analgesic Nephropathy

Prescott, L. F.

doi:10.2165/00003495-198223010-00004

Cited by 132 publications

(12 citation statements)

References 353 publications

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“…The chronic overuse/abuse of such mixtures by the laity, sometimes in prodigious amounts over periods of years, caused many serious chronic intoxications characterized by anemia, methemoglobinemia, and severe renal damage, with a high incidence of papillary necrosis ("analgesic nephropathy," "phenacetin nephropathy") (172). In 1948, Brodie and Axelrod (36) demonstrated that the major metabolite responsible for the analgesic action of acetanilide and phenacetin is paracetamol, while methemoglobinemia is produced by another metabolite, phenylhydroxylamine.…”

Section: History and Chemistrymentioning

confidence: 99%

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Paracetamol: New Vistas of an Old Drug

et al. 2006

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Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB 1 receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB 1 receptor agonist, completely prevents the analgesic ac- 250CNS Drug Reviews Vol. 12, No. 3-4, pp. 250-275 © 2006 tivity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB 1 agonists are being introduced for pain treatment, it comes out that an indirect cannabinomimetic had been extensively used (and sometimes overused) for more than a century.

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Section: History and Chemistrymentioning

confidence: 99%

“…Kidney is the second target organ of paracetamol toxicity: renal dysfunction occurs in about 25% of cases with significant hepatotoxicity (63,172) and in more than 50% of those with hepatic failure (128,230). Overt renal failure necessitating hemodialysis occurs nearly always among patients with marked hepatic injury (44).…”

Section: Toxicologymentioning

confidence: 99%

Paracetamol: New Vistas of an Old Drug

et al. 2006

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“…The scientific basis supporting the supposed role of phenacetin as the major aetiological agent in analgesic nephropathy seems somewhat circumstantial, if not spurious (for an extensive review see Prescott, 1982). As noted by Kincaid-Smith (this issue) the case against other non-narcotic analgesics such as the acidic anti-inflammatory drugs (e.g.…”

Section: Analgesic Nephropathymentioning

confidence: 99%

“…This action has not been followed by the expected fall in mortality from analgesic nephropathy. There now seems to be sufficient doubt surrounding the presumed primary role of phenacetin as a nephrotoxic agent (Kincaid-Smith, 1970, 1978Prescott, 1982) that we should be concerned about the widespread availability of other non-narcotic analgesics, for example, those which contain acidic NSAIDs such as the salicylates and particularly those which are combination products.…”

Section: Analgesic Nephropathymentioning

confidence: 99%

Paracetamol and Phenacetin

Clissold¹

1986

Drugs

214

107

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Since their synthesis in the late l800s paracetamol (acetaminophen) and phenacetin have followed divergent pathways with regard to their popularity as mild analgesic/antipyretic drugs. Initially, paracetamol was discarded in favour of phenacetin because the latter drug was supposedly less toxic. Today the opposite is true. and paracetamol. along with aspirin. has become one of the two most popular 'over-the-counter' non-narcotic analgesic agents. This marked increase in the wide approval attained by paracetamol has been accompanied by the virtual commercial demise of phenacetin because of its role, albeit somewhat circumstantial. in causing analgesic nephropathy.Both paracetamol and phenacetin are effective mild analgesics, suitable for treating mild to moderate pain. and their actions are broadly comparable with those of aspirin and related salicylates. although they do not appear to possess significant anti-inflammatory activity. Since a major portion of a dose of phenacetin is rapidly metabolised to paracetamol. it seems possible that phenacetin owes some of its therapeutic activity to its main metabolite. paracetamol. whereas its most troublesome side effect (methaemoglobinaemia) is due to another metabolite. p-phenetidine. The mechanism of action of paracetamol is poorly defined. although it has been speculated that it may selectively inhibit prostaglandin production in the central nervous system. which would account for its analgesic/antipyretic properties. The lack of any significant influence on peripheral cyclooxygenase would explain the absence of anti-inflammatory activity.At therapeutic doses paracetamol is well tolerated and produces fewer side effects than aspirin. The most frequently reported adverse effect associated with paracetamol is hepatotoxicity. which occurs after acute overdosage (usually doses greater than 10 to 15g are needed) and. very rarely. during long term treatment with doses at the higher levels of the therapeutic range. Paracetamol damages the liver through the formation of a highly reactive metabolite which is normally inactivated by conjugation with glutathione. Overdoses of par aceta mol exhaust glutathione stores. thus allowing the accumulation of this toxic metabolite which covalently binds with vital cell elements and can result in liver necrosis. Glutathione precursors (notably intravenous N-acetylcysteine) have proved remarkably successful in treating paracetamol overdose, as long as treatment is initiated within 10 hours.Apart from pharmacokinetic drug interactions resulting from changes in gastric emptying rate. there have been very few reports of clinically important drug-drug interactions involving paracetamol or phenacetin.The pre-eminent position of paracetamol and aspirin as the non-narcotic analgesic agents of choice for mild to moderate pain is being seriously challenged by 'newer' nonsteroidal anti-inflammatory drugs. Some of these newer agents have been found to have significantly superior analgesic activity and. in some cases. longer durations of action.

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“…In the case of long-term NSAIDs therapy, a high incidence of severe side effects, including gastrointestinal ulcer and nephrosis, has been reported, especially in rheumatoid arthritis therapy [1][2][3]. Hence, it is considered that the monitoring of NSAIDs is of importance in order to improve the toxicological management of long-term NSAID therapy.…”

Section: Introductionmentioning

confidence: 99%