Phenarctin

1 The rate of absorption of oral paracetamol depends on the rate of gastric emptying and is usually rapid and complete. The mean systemic availability is about 75%. 2 Paracetamol is extensively metabolized and the plasma half-life is 1.5-2.5 hours. About 55% and 30% of a therapeutic dose is excreted in the urine as glucuronide and sulphate conjugates, respectively, whereas mercapturic acid and cysteine conjugates (representing conversion to a potentially toxic intermediate metabolite) each account for some 4% of the dose. Paracetamol metabolism is age- and dose-dependent. 3 With hepatotoxic doses, paracetamol metabolism is impaired and the half-life prolonged. Sulphate conjugation is saturated and the proportion excreted as mercapturic acid and cysteine conjugates is increased. 4 The renal clearance of paracetamol depends on urine flow rate by not pH. The renal clearances of the glucuronide and sulphate conjugates often exceed the glomerular filtration rate and are independent of urine flow and pH. 5 Phenacetin absorption depends on formulation. It is extensively metabolized to paracetamol and minor metabolites are probably responsible for toxicity.

Prolonged ingestion of mixed analgesics containing phenacetin has been associated significantly with the development of a chronic interstitial nephritis frequently associated with papillary necrosis. This disease is frequently underdiagnosed. If an adequate history of headache and/or backache (of which most of these patients complain) is not taken, the central causative effect of phenacetin ingestion may never be appreciated. Laboratory tests show the usual abnormalities seen in any form of chronic interstitial nephritis such as poor urinary concentration, renal failure with large urine output, and no hypertension. Papillary necrosis is helpful but not pathognomonic. The type of medications ingested appears to be changing to prescription compounds. The with significant improvement in renal function.

Since their synthesis in the late 1800s 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 paracetamol 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.