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Paracetamol and Phenacetin Drugs 32 (Suppl. 4): 46-59 (1986) OOI2-6667/86/040<MJ046/$7.00/0 © ADIS Press Limited All rights reserved. Paracetamol and Phenacetin Stephen P. Clissold ADIS Drug Information Services, Auckland Summary Since their synthesis in the late l800s paracetamol (acetaminophen) and phenacetin have followed divergent pathways with regard to their popularity as mild analgesic/anti­ pyretic 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 ofthe two most popular 'over-the-counter' non-narcotic anal­ gesic 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-inflam­ matory 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 (methaemoglo­ binaemia) is due to another metabolite. p-phenetidine. The mechanism of action of para­ cetamol 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 anal­ gesic/antipyretic properties. The lack of any significant influence on peripheral cyclo­ oxygenase 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 he­ patotoxicity. 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 ofthe therapeutic range. Paracetamol damages the liver through the formation ofa highly reactive metabolite which is normally inactivated by conjugation with glutathione. Ov­ erdoses of paraceta mol exhaust glutathione stores. thus allowing the accumulation ofthis toxic metabolite which covalently binds with vital cell elements and can result in liver necrosis. Glutathione precursors (notably intravenous N-acetylcysteine) have proved re­ markably successful in treating paracetamol overdose, as long as treatment is initiated within 10 hours. Apart from pharmacokinetic drug interactions resulting from changes in gastric empty­ ing 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' non­ steroidal 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. Paracetamol and Phenacetin 47 Paracetamol (acetaminophen) and phenacetin persuasive arguments. However, the case for phen­ are both derivatives of acetanilide (for structural acetin is weakened by its apparent lack of any ther­ formulae see fig. I), an aniline-like compound apeutic advantages over paracetamol, the potential which, in the 1880s, was serendipitously found to haematological toxicity of its metabolites, and its possess antipyretic activity. Acetanilide was quickly propensity (unlike other non-narcotic analgesics) introduced into medical practice and it was shown to produce central psychotropic effects which may to have analgesic as well as antipyretic activity. contribute to its liability for abuse. However, it was soon found to have unacceptable toxic effects, the most alarming being cyanosis due 1. Pharmacodynamic Properties to methaemoglobinaemia, and this prompted the 1.1 Mechanism of Action search for less toxic derivatives of aniline. Phen­ acetin was introduced into clinical use in 1887 by The basic pharmacological mechanisms of ac­ von Mering (von Mering, 1893), who also evalu­ tion of paracetamol and phenacetin have not re­ ated the activity of a related compound N-acetyl­ ceived the scientific attention accorded to the sali­ p-aminophenol (acetaminophen, paracetamol). He cylates and, consequently, many explanations for discarded paracetamol in favour of phenacetin be­ their activity appear somewhat speculative. Both cause of the latter's supposedly better toxicity pro­ drugs have analgesic and antipyretic properties file (for an overview of the history and usage of which do not differ significantly from those of as- the aniline derivatives see Bowman and Rand, 1980; Flower et ai., 1980; Meredith and Goulding, 1980). Further studies in the 1940s demonstrated that paracetamol was the major metabolite of both phenacetin and acetanilide and, importantly, met­ haemoglobinaemia was caused by a different me­ Acetanilide tabolite of phenacetin, p-phenetidine (Brodie and Axelrod, 1949). Paracetamol has been freely avail­ able since the mid 1950s and it has steadily gained in popularity. In the United Kingdom paracetamol sales have exceeded those of aspirin since about 1978. Paracetamol has never been quite so popular in the United States, although this position is Paracetamol (acetaminophen) changing and it has recently been reported that one proprietary paracetamol product accounts for about 35% of the 'over-the-counter' analgesic market (see Black, 1984). The rise in popularity of paracetamol has been accompanied by the virtual commercial demise of phenacetin. The major reason for this has been the condemnation of phenacetin, on what now seems Phenacetin to be circumstantial evidence, as being the sole cause of analgesic nephropathy (see section 4.2.1) [see also Kincaid-Smith, this issue]. Protagonists for and against the decisions taken in many coun­ tries to limit the supply of phenacetin are abundant Fig. 1. Structural formulae of acetanilide, paracetamol and within scientific circles, and each 'side' has its own phenacetin. Paracetamol and Phenacetin 48 pirin. However, the 2 drugs lack the potent anti­ demonstrated that paracetamol relieved pain by inflammatory actions of aspirin. blocking impulse generation at bradykinin-sensi­ Why paracetamol is an effective analgesic but tive chemoreceptors which evoke pain - a peri­ only a weak anti-inflammatory agent has not been pheral mechanism. Clearly, further studies are nec­ satisfactorily established, although most recent ex­ essary to evaluate the relative influence of planations involve a selective inhibition of some peripheral and central mechanisms on the overall facet of prostaglandin biosynthesis (for reviews see analgesic properties of paracetamol and phenace­ Hower et aI., 1980; Jackson et aI., 1984; Meredith tin. and Goulding, 1980; Ramwell, 1981). Some evi­ At the present time the mechanism of action of dence suggests that paracetamol has a weak inhib­ paracetamol is poorly understood; it is possible that itory influence on peripheral prostaglandin biosyn­ unknown peripheral and/or central mechanisms thesis (which would account for its lack of may also be involved. substantial anti-inflammatory activity), but that it is a potent inhibitor of prostaglandin production 2. Pharmacokilletic Properties within the central nervous system (presumably ac­ counting for its analgesic and antipyretic proper­ Acetanilide, phenacetin and paracetamol are all ties). Why central nervous system cydo-oxygenase derivatives of aniline, in whose structure reside the is more sensitive to paracetamol (if this is its main intrinsic antipyretic and analgesic properties of this mode of action) than peripheral cydo-oxygenase, group. Paracetamol is the major metabolite of both has not been convincingly explained and further acetanilide and phenacetin (see section 2.3) and the research is needed to clarify the mechanisms in­ pharmacodynamic actions of this compound prob­ volved. The analgesic and antipyretic effects of ably account for much of the therapeutic action of phenacetin are generally attributed to its major these drugs. Consequently, most attention in this metabolite, paracetamol; however, there is evi­ section will be focused on the pharmacokinetic dence that phenacetin itself has inherent pharma­ characteristics of paracetamol, a moderately water­ codynamic activity. and lipid-soluble weak organic acid (pKa 9.5) which is largely un-ionised over the physiological range 1.2 Analgesic Effects of pH. Like the salicylates, paracetamol and phenace­ 2.1 Absorption tin possess analgesic activity which is effective against pain of mild to moderate severity. How­ Paracetamol is invariably taken orally and is ever, unlike the salicylates, which act mainly peri­ only minimally absorbed from the stomach. Ab­ pherally against pain associated with inflammation sorption is by passive diffusion with first-order ki­ (see Oissold, this issue, p. 8), both paracetamol and netics and occurs mainly in the small intestine; the phenacetin have few or no antiinflammatory prop­ rate of absorption therefore depends on the gastric erties and apparently exert their analgesic effects emptying rate (for reviews see Forrest et aI., 1982; via central actions (Bowman and
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