Paracetamol and Phenacetin

Abstract

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.

Antinociceptive, Anti-inflammatory and Antipyretic Effects of <i>Solanum nigrum</i> Chloroform Extract in Animal Models

“…The blocking of central COX activity 43) by CESN is also believed to take place based on Pini et al 40) report that paracetamol, often classiˆed as an NSAID, exerted its central antinociceptive eŠect as assessed using the hot plate test via inhibition of the central COX. 45) The CESN showed a characteristic of strong analgesics like opioid agonists since it blocked both the chemicallyand thermally-induced nociceptive action, as well as the early and late phases of the formalin test. 33,46) Although not yet proven, it is plausible to associate the centrally-mediated depressant activity demonstrated by Perez et al 24) with the antinociceptive activity of S. nigrum.…”

Paracetamol: New Vistas of an Old Drug

“…Phenacetin and paracetamol were introduced into clinical use in 1887 by von Mering (220), who soon discarded paracetamol in favor of phenacetin, because he assumed that the latter was less toxic (for reviews see: 33,54,83,91,138,202). Albeit in part overshadowed by aspirin, introduced into medicine by Dreser in 1899, phenacetin has known for many decades an extraordinary popularity and has been indiscriminately used, especially as an ingredient of proprietary analgesic mixtures (particularly over-the-counter "headache mixtures," usually containing phenacetin, an aminopyrine derivative or aspirin, caffeine, and sometimes a barbiturate) and widely advertised to the public.…”

“…It rapidly gained in popularity, and in many countries, including the United Kingdom, paracetamol sales exceeded those of aspirin since about 1980. This was accompanied by the virtual commercial demise of phenacetin, blamed as the cause of "analgesic nephropathy," hematological toxicity, and psychotropic effects which may contribute to its liability for abuse (54).…”

Plasma concentrations after high-dose (45 mg · kg−1) rectal acetaminophen in children

“…Inhibition of prostaglandin synthesis in other tissues does not occur, thus acetaminophen produces no anti-inflammatory effects or effects on platelet function that may be associated with the use of non-steroidal anti-inflammatory drugs. 1 While the plasma concentrations required for analgesia have not been defined, the "accepted" therapeutic plasma concentration range for an anfipyretic effect is 35-130 tLmol" L -t (5-20 ttg" ml-l). 2 Optimal analgesic plasma concentrations may be higher than this as clinical studies have shown that a typical oral dose of 10 nag.…”