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Ann. Rev. PharmacoL ToxicoL Copyright ©

1983

1983. 23:87-101

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THE TREATMENT OF ACETAMINOPHEN
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POISONING
L. F. Prescott

and J. A. J.

H Critchley

Regional Poisoning Treatment Centre, and University Department of Therapeutics and Clinical Pharmacology, The Royal Infirmary, Edinburgh, EH3
9YW, Scotland

INTRODUCTION
Acetaminophen (paracetamol, N-acetyl-p-aminophenol, 4-hydroxyacetani­ lide) is a non-prescription antipyretic analgesic that was first introduced into clinical medicine towards the end of the last century (1). It attracted little interest until it was found to be the major metabolite of both acetani­ lide and phenacetin (2, 3) and in recent years it has become an increasingly popular substitute for aspirin. Acetaminophen seemed to be remarkably safe when taken in recommended doses and formal toxicity studies were never carried out. In 1964 Eder (4) first reported liver damage in cats given 25-50 mglKg of acetaminophen daily for 26 weeks, and two years later Boyd & Bereczky described extensive hepatic necrosis in acute toxicity studies in rats (5). At the same time liver damage was first reported in man following acetaminophen overdosage (6, 7). The use of acetaminophen for self-poisoning has since increased dramatically in many countries and acute hepatic necrosis, sometimes fatal, has attracted much attention as the major complication (8-16).

CLINICAL MANIFESTATIONS AND COMPLICATIONS OF ACETAMINOPHEN POISONING
Apart from nausea and vomiting there are no specific early signs of severe intoxication and consciousness is not impaired. However, 12 to 36 hours after ingestion biochemical evidence of acute hepatic injury may become apparent with maximum abnormalities of liver function usually occurring
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on the third day. The pattern is characteristic of extensive acute necrosis with gross elevation of plasma aspartate and alanine aminotransferase (AST or SOOT, ALT or SGPT) activity, mild hyperbilirubinemia, and prolonga­ tion of the prothrombin time (9-11). Associated abnormalities include im­ pairment of bromsulphthalein clearance (17). abnormal glucose tolerance (7. 18), and increased serum concentrations of bile acids and ferritin (19. 20). In survivors hepatic regeneration is normally rapid and complete with return of liver function tests to normal within one to three weeks. Fulminant hepatic failure (which is usually fatal) develops on the third to the sixth day in a small minority of severely poisoned patients. and renal failure due to acute tubular necrosis is another uncommon complication (10. 21. 22). Liver biopsies and post-mortem studies reveal extensive cen­ trilobular hepatic necrosis without inflammatory reaction (6, 11, 23, 24). The acute hepatotoxicity of acetaminophen has been confirmed repeatedly in animals but there are marked species differences in susceptibility (25-27). Contrary to popular belief, severe liver damage (arbitrarily defined as elevation of the plasma AST or ALT activity above 1000 u/l) and fatal hepatic failure are not inevitable complications of acetaminophen overdos­ age. Indeed. without specific therapy fewer than 10% of unselected patients referred to hospital develop severe liver damage, about 1 % suffer acute renal failure. and 1 to 2% die in hepatic failure (26). Until the development of rational therapy based on the biochemical mechanisms of acetaminophen hepatotoxicity (28), there was no effective treatment for overdosage and the increasing incidence of poisoning was a cause for concern. Allegedly successful treatment with antihistamines and corticosteroids (8) was uncontrolled and had no scientific or statistical basis. Indeed. subsequent studies in animals showed that such treatment actually increased the lethality of acetaminophen without protecting against liver damage (29). A controlled trial of heparin therapy showed no benefit (30). Forced diuresis has been tried but is likewise of no value. The renal clear­ ance of acetaminophen is not pH-dependent, and even after overdosage an insignificant fraction of the dose is excreted unchanged in the urine (31). Hemodialysis was also advocated, but it did not prevent liver damage, and insignificant amounts of drug were removed. In one study, 11 of 15 patients subjected to this procedure had not absorbed enough drug to be at risk of liver damage in the first place (32). MECHANISMS OF ACETAMINOPHEN HEPATOTOXICITY The effective treatment of acetaminophen poisoning only became possible with the discovery by Mitchell and his colleagues of the metabolic activa­ tion of acetaminophen and the vital protective role played by reduced

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glutathione (33-36). These workers showed that a small fraction of a dose of the drug is converted by cytochrome P-450-dependent mixed function oxidase to an e1ectrophilic arylating metabolite that binds covalently to hepatic macromolecules, causing cell damage and necrosis. The reactive metabolite is thought to be N-acetyl-benzoquinoneimine formed by N­ hydroxylation (28, 37). It is normally rapidly inactivated by preferential conjugation with reduced glutathione and eventually excreted in the urine as cysteine and mercapturic acid conjugates of acetaminophen. After a toxic dose, hepatic glutathione is depleted; when concentrations fall below 20 to 30% of normal, the excess metabolite binds covalently to essential hepatic proteins and enzymes. Hepatic necrosis is directly related to the extent of glutathione depletion and covalent binding (27, 33-36, 38). The extent of conversion of acetaminophen to its toxic metabolite is reflected in the fraction of the dose recovered in the urine as cysteine and mercapturic acid conjugates. Highly susceptible species such as the hamster excrete much more than resistant species such as the rat (25); liver damage following overdosage of acetaminophen in man is associated with increased urinary excretion of these conjugates (26, 39).

PROTECTION AGAINST EXPERIMENTAL ACETAMINOPHEN HEPATOTOXICITY
Factors that modify hepatic microsomal enzyme activity and glutathione status greatly influence the toxicity of acetaminophen. Thus Mitchell et al showed that liver damage is increased by stimulation of hepatic microsomal enzymes with inducing agents such as phenobarbital, and decreased by inhibition with cobaltous chloride or piperonyl butoxide (28,33). Similarly, covalent binding and hepatic necrosis are increased if glutathione stores are depleted by prior administration of diethyl maleate, and decreased by glu­ tathione precursors such as cysteine (28, 36). Glutathione depletion pro­ duced by fasting and low protein or yeast diets also potentiates experimental acetaminophen hepatotoxicity (40,41). These general· principles have been amply confirmed by other workers and provide a sound basis for the treat­ ment of acetaminophen poisoning in man.

Inhibition of Metabolic Activation
Selective inhibition of the minor route of metabolism that generates the toxic metabolite of acetaminophen is an attractive possibility. However, safe effective inhibition of the metabolic activation of acetaminophen has not yet been investigated adequately in man and this approach has not been ex­ ploited clinically. Recent studies have shown that the acute toxicity of acetaminophen in animals is significantly reduced by cimetidine (42-44) and by acute administration of ethanol (45, 46). Protection was attributed

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to inhibition of the metabolic activation of acetaminophen but other mecha­ nisms have not been excluded. In the case of ethanol, this hypothesis is supported by the observation that it significantly reduces the excretion of the mercapturic acid conjugate of acetaminophen in rats (46). In man, an acute ethanol load (1.72 g/Kg over 8 hours) markedly decreases the frac­ tion of an oral dose of 20 mglKg of acetaminophen excreted as the cysteine and mercapturic acid conjugates,but oral cimetidine in divided doses total­ ling 2 g over 16 hours has no such effect

(J. A. J. H. Critchley and L. F.

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Prescott, unpublished). The protective effect of acute ethanol is of particular interest since chronic pretreatment enhances experimental acetaminophen-induced hepatotoxicity (47-50) and increases the urinary excretion of the mercaptu­ ric acid conjugate (51), presumably as a result of microsomal enzyme induction. Similarly, chronic alcoholics and patients who have previously been taking agents that induce drug metabolizing enzymes seem to be at increased risk of liver damage following acetaminophen overdosage (26, 52, 53), whereas acute ingestion of ethanol at the same time appears to offer some protection (16). However, in contrast to the findings in experimental animals, chronic heavy ethanol intake in man is not associated with in­ creased metabolic activation of acetaminophen (54). In addition, the uri­ nary excretion of the cysteine and mercapturic acid conjugates of acetaminophen is not increased in patients induced by chronic treatment with anticonvulsants or rifampicin (55). The results of animal studies in­ volving the selective induction and inhibition of acetaminophen metabolism thus cannot be extrapolated directly to man.

Sulphydryl Compounds
Glutathione itself might be considered the ideal antidote for acetaminophen poisoning. However, it is normally synthesized in situ, and because it enters cells with difficulty, glutathione is relatively ineffective even when given in very large doses (56-58). On the other hand, glutathione precursors such as cysteine, N-acetylcysteine, and methionine and other sulphur-containing compounds including cysteamine, S-adenosylmethionine, a,-mercaptopro­ pionyl-glycine, dithiocarb, propylthiouracil, and even dimethyl-sulphoxide are very effective in preventing experimental acetaminophen-induced hepatotoxicity (28,38,41,56,59-66). Most of these agents have been shown to reduce the extent of acetaminophen-induced glutathione depletion. Over the last decade cysteamine, methionine and N-acetylcysteine have been studied extensively in man and the clinical management of severe acetaminophen poisoning has been transformed. Even when administration is delayed for as long as 8 to 10 hours after ingestion they have proved remarkably effective in preventing liver damage, renal failure, and death from acetaminophen overdosage.

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Stimulation of Sulphate Conjugation
Acetaminophen is extensively metabolized, with sulphate and glucuronide conjugation accounting for about 30% and 60% respectively of a therapeu­ tic dose in man (67). However, the availability of inorganic sulphate is limited and sulphate conjugation is saturated after overdosage. Slattery & Levy (68) proposed a pharmacokinetic model based on dose-dependent saturation of both sulphate and glucuronide conjugation with increasing conversion of the drug to the toxic metabolite. Unfortunately, their model was based on the results of metabolic studies reported by Davis et al (39), which differ markedly from those observed by other workers using different analytical methods. Sulphate conjugation is undoubtedly saturated with overdosage of acetaminophen but there is no evidence of similar saturation of glucuronide conjugation in man (26). According to the above hypothesis, it was suggested that restoration of sulphate conjugation by provision of inorganic sulphate would significantly enhance the elimination of acetaminophen after overdosage and hence reduce its toxicity. In rats sodium sulphate enhanced the sulphate conjugation of acetaminophen and marginally increased its rate of elimination (69, 70) and it slightly increased the acute LD50 in mice (71). However, the protective effect was minor compared to that produced by glutathione precursors and is unlikely to be of clinical significance.

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TREATMENT OF ACETAMINOPHEN POISONING Clinical assessment of the efficacy of treatment for acetaminophen poison­ ing is beset with difficulties. There are few specialist units with an interest in drug overdosage and poisoning; placebo-controlled trials cannot now be carried out because of ethical constraints, and the great majority of patients do not absorb enough drug to be at risk of severe liver damage anyway. Toxicity depends primarily on the balance between the rates of formation of the reactive metabolite and synthesis of glutathione and is influenced by many factors including age, diet, nutritional state, fasting, and previous and concurrent intake of other drugs including ethanol (26). Not surprisingly, there is marked individual variation in susceptibility (72) with a variable threshold dose for toxicity that presumably corresponds to the point of critical depletion of hepatic glutathione (36). In man, significant liver dam­ age is very uncommon following absorption of less than 125 mglKg of acetaminophen, whereas severe liver damage occurs in some 50% of indi­ viduals absorbing 250 mg/Kg, and in virtually all absorbing 350 mglKg (26). Unfortunately, self-poisoners are notoriously unreliable historians and unknown amounts of drug may be lost by vomiting and gastric lavage. The

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dose absorbed can therefore only be determined by measurement of the plasma concentrations of acetaminophen.

Assessment of Risk
To assess the effects of any treatment it is necessary to define the risk of liver damage according to the plasma concentrations of acetaminophen in rela­ tion to the time since ingestion (10, 73-75). Severe liver damage with plasma AST or ALT activity exceeding 1000 ull occurs in about 60% of patients with plasma acetaminophen concentrations above a "treatment" line join­ ing semilog plots of 200 ILg/ml at 4 hours and 30 ILg/ml at 15 hours after ingestion. The incidence is 90% above a similar parallel line joining 300 ILglml at 4 hours and 45 ILglml at 15 hours, and such patients are at high risk. Plasma concentrations cannot be interpreted less than 4 hours after ingestion, and difficulties also arise when absorption is delayed by combined overdosage with drugs such as narcotic analgesics. The plasma acetamino­ phen half-life is directly related to the extent of liver damage (10, 31, 74) but its measurement takes time and is not practicable because treatment must be started as soon as possible. The marked individual variation in response to acetaminophen makes it virtually impossible to determine the effects of treatment unless compari­ sons are made in substantial numbers of patients, preferably those at high risk. One patient may develop liver damage with relatively low initial plasma acetaminophen concentrations while another with concentrations several times higher may escape completely. Nevertheless, there are many anecdotal accounts of "successful" treatment. The historical control data with which comparisons must be made is very limited and the much-quoted "nomogram" published by Rumack & Matthew (76) as a guide to prognosis was actually taken from the original data obtained in Edinburgh (10, 73). Further difficulties have arisen through the use of nonspecific analytical methods for the estimation of plasma acetaminophen. Those that depend on direct acid hydrolysis to p-aminopheno1 without prior extraction also include acetaminophen conjugates present in high concentrations, and may overestimate the true result by as much as 700% (77). Fortunately, cystea­ mine, methionine, and N-acetylcysteine have been dramatically effective in preventing liver damage after acetaminophen overdosage, and despite all these difficulties their value is not in doubt.

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General Measures
Gastric aspiration and lavage are normally carried out in patients admitted within 4 hours of overdosage. Activated charcoal and cholestyramine may reduce the absorption of acetaminophen if given within one hour of inges-

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tion (78, 79) but are unlikely to be useful in practice because the great majority of patients do not arrive in hospital in time for such treatment to be effective. Fluid balance should be maintained and complications such as hepatic and renal failure are managed conventionally.

Cysteamine
Mitchell et al (28) showed that cysteamine protected mice against the acute toxicity of acetaminophen even when treatment was delayed for 2 hours. Shortly thereafter we reported the first successful treatment of severe acetaminophen poisoning in man using intravenous cysteamine. Seven adults with a mean plasma acetaminophen concentration of 373 p.g/ml at 4 hours were given 3.2 g over 20 hours and treatment was started 4.5 to 10 hours after ingestion of the acetaminophen. None of the patients developed the expected severe liver damage (73). Subsequent reports confirmed the protective action of cysteamine when treatment was started within 10 to 12 hours (80-83). Thus severe liver damage was completely prevented in one series of 27 severely poisoned patients treated within 10 hours (80) and occurred in only one of 14 similar patients in another (83). Douglas et al (84) failed to appreciate the importance of early treatment and claimed that cysteamine therapy was of no advantage despite evidence to the contrary in their patients admitted within 9 hours. With the exception of one report in which plasma acetaminophen was estimated by an inappropriate method (82), treatment after 12 hours was found to be of no benefit. Although effective, cysteamine produced very unpleasant gastrointestinal and central nervous system toxicity and it was not available commercially as a phar­ maceutical formulation. Other agents were therefore investigated.

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Methionine
Methionine protects rats against acetaminophen-induced liver damage and its incorporation into analgesic tablets was proposed as a simple answer to the problems of acetaminophen overdosage (41). Intravenous and oral methionine usually prevents severe liver damage following overdosage of acetaminophen if given within 10 to 12 hours (80, 83, 85, 86). However, it seems to be less reliable than intravenous cysteamine and N-acetylcysteine (26). Thus severe liver damage occurred in 3 of 15 severely poisoned pa­ tients given 20 g of methionine intravenously within 10 hours (80) and in 7 of 96 similar patients given 10 g orally (86). In addition, 3 patients treated with oral methionine within 12 hours developed fulminant hepatic failure (12). There is some doubt concerning the safety of late treatment with methio­ nine. It may aggravate or precipitate hepatic encephalopathy and late treat­ ment or delayed absorption may therefore be hazardous in patients with

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impending severe liver damage methionine

with acute acetaminophen poisoning is increased by late treatment with

(12, 85, 89). Indeed, the mortality in mice

(61). Most patients develop nausea and vomiting within a few

hours of ingestion of a toxic dose of acetaminophen and delayed or incom­ plete absorption may contribute to the failure of oral methionine in some patients

(87). Treatment with oral methionine is simple and cheap.

N-Acetylcysteine
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Following the demonstration of its protective effects in animals sive clinical studies have confirmed the efficacy and safety of N-acetylcys­ teine in the treatment of acetaminophen poisoning (16,88-91) and it is now considered the treatment of choice. Intravenous N-acetylcysteine given within 10 hours in a dose of 300 mglKg over 20 hours prevented liver damage, renal failure, and death in patients with severe acetaminophen . poisoning liver damage in severely poisoned patients at high risk when given within

(60), exten­

(88, 89), and was completely effective in preventing even triyial

8 hours (89). An extensive nationwide multicenter study of oral N-acetyl­ cysteine is currently in progress in the USA. (16, 90). Of 662 patients referred to the coordinating center in Denver, 57 were considered to be at less effective orally than intravenously. Thus, severe liver damage

"probable risk" and received oral N-acetylcysteine within 10 hours. Despite the very large total dose of 1330 mg/Kg, N-acetylcysteine appeared to be

patients given a much smaller dose of intravenous N-acetylcysteine within

7 of the 57 patients developed (16) compared with only 1 of 62 severely poisoned

10 hours (91). Like all other agents studied in man, the protective effect of 8 to 10 hours, and it is completely ineffective after 15 to 16 hours (16, 91). Unlike
N-acetylcysteine falls off rapidly if treatment is delayed beyond methionine, late treatment with N-acetylcysteine does not increase m6rtal­ ity in experimental acetaminophen poisoning is not recommended.

(61). There is no clear evi­

dence that it aggravates hepatic failure in man, but treatment after 24 hours
N-acetylcysteine has lorig been available as a mucolytic and an intrave­ nous formulation was recently introduced in the U.K. specifically for the treatment of acetaminophen poisoning. There have been two reports of transient mild allergic reactions verse effects have been noted.

(92, 93), but otherwise no significant ad­

Other Agents
Dimercaprol and D-penicillamine appear to offer little or no protection against acetaminophen toxicity in man (80, 81, 94).

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Oral Versus Intravenous Therapy
There has been controversy over the relative merits of oral and intravenous therapy. The oral route is convenient and has the great advantage that a substantial fraction of the dose should he delivered directly to the liver. However, nausea and vomiting are consistent features of severe acetamino­ phen intoxication (89, 91) and efficacy must inevitably be compromised by incomplete or delayed absorption. Vomiting occurred in 77% of 52 severely poisoned patients in one report (9 1), and in all of 4 16 patients given oral N-acetylcysteine in another (90). It was recently claimed that vomiting occurred in only 12% of 433 patients with acetaminophen overdosage (95). However, the patients were unselected and it is probably no coincidence that only 12% were shown to be severely poisoned. Acetaminophen poison­ ing is a potentially fatal condition and the ingestion-treatment interval is critical. Severe liver damage has been attributed to failure of absorption of oral methionine (87) and this route cannot be recommended because of the very high incidence of nausea and vomiting in the very patients who need treatment most. Oral therapy is clearly contraindicated in patients who have been given emetics or activated charcoal. MECHANISMS OF PROTECTION Precursors such as cysteine, N-acetylcysteine, and methionine probably act primarily by stimulating glutathione synthesis and hence facilitating the glutathione conjugation of acetaminophen (38). Other agents such as cys­ teamine and dimethylsulphoxide also antagonise the glutathione depletion induced by acetaminophen (59, 64) and indirect stimulation of glutathione synthesis could contribute to their protective action (97). Cysteamine may also act by inhibiting the metabolic activation of acetaminophen (38, 98, 99). Oxothiazolidine carboxylic acid is converted to cysteine by 5-oxo-L­ prolinase and stimulates glutathione synthesis. It reverses acetaminophen­ induced depletion of hepatic glutathione in animals and has been proposed as an effective intracellular delivery system for cysteine in the treatment of acetaminophen overdosage (100). Cysteamine, cysteine, N-acetylcysteine, and d.-mercaptopropionylglycine have all been shown to react directly with the toxic metabolite ofacetamino­ phen to form the corresponding conjugates (99). However, this is probably not important since conjugation with glutathione is catalysed by glutath­ ione-S-transferase and takes place much more readily (38, 96). Propylthi­ ouracil is unusual in that it can substitute for glutathione as a substrate for glutathione-S-transferase, and its protective action may involve direct con­ jugation with the reactive metabolite of acetaminophen (66). Methionine,

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which does not contain an SH group, does not form an adduct directly with the acetaminophen metabolite (99) and does not prevent its covalent bind­ ing in vitro

(101). It presumably acts indirectly after conversion to homo­

cysteine and cysteine and the delay may account for its relative lack of efficacy. Other mechanisms may contribute to protection. Thus acetaminophen may be regenerated from N-acetyl-benzoquinoneimine by reducing agents such as cysteine and ascorbic acid under certain conditions (102). [Ascorbic

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acid can inhibit the covalent binding of acetaminophen to hepatic mi­ crosomes in vitro (103), and it has been reported to reduce the lethality of acetaminophen in mice (104)]. In addition, the metabolism of sulphydryl compounds to inorganic sulphate can undoubtedly promote sulphate conju­ gation as an alternative route of elimination of acetaminophen. The plasma concentrations of acetaminophen sulphate in poisoned patients are in­ creased by treatment with cysteamine and N-acetylcysteine (67) and subse­ quently there may be a delayed minor decrease in the plasma half-life of the drug (73). However, enhancement of sulphate conjugation is unlikely to be relevant to the protective effects of SUlphydryl compounds in man.

OTHER METHODS OF TREATMENT
The only other recent approach to the treatment of acetaminophen poison­ ing has been the use of charcoal hemoperfusion. The drug can be removed effectively by this technique and clearances of 70 to 200 ml/min have been reported ( l 05
.

106). However. it is inconceivable that this treatment could

be instituted early enough to remove sufficient drug to prevent the critical glutathione depletion and irreversible covalent binding that seems to occur

8 to 10 hours after ingestion of a toxic dose. The first controlled trial of early hemoperfusion showed no benefit and the average amount of acetamino­ phen removed was less than

1.5 g (107). In one anecdotal report claiming

success, cysteamine had also been given and treatment was probably not necessary in the first place because plasma acetaminophen concentrations would have been greatly overestimated by the unsuitable analytical method used

(108). It is even more difficult to accept recent claims for the benefit

of late charcoal hemoperfusion. In one report, treatment was started in 7 severely poisoned patients an average of 23 hours after the acetaminophen was taken and a mean of 2.4 g was removed. According to the elevation of plasma bilirubin and prothrombin time ration, 5 patients developed severe liver damage and one died in hepatic failure. Only 0.38 and 0.36 g of acetaminophen were removed from the two patients who did not develop severe liver damage (106). There seems to be no justification for the use of hemoperfusion in the late treatment of acetaminophen poisoning.

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SUMMARY
Acetaminophen has become a very popular over-the-counter analgesic in some countries and as a result it is used increasingly as an agent for self­ poisoning. Without treatment only a minority of patients develop severe liver damage and colleagues discovered the biochemical mechanisms of toxicity in

1 to 2% die in hepatic failure. Until Mitchell and his 1973 there

was no effective treatment. They showed that the metabolic activation of

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acetaminophen resulted in the formation of a reactive arylating intermedi­ ate, and that hepatic reduced glutathione played an essential protective role by preferential conjugation and inactivation of the metabolite. Early treat­ ment with sulphydryl compounds and glutathione precursors has been dramatically effective in preventing liver damage, renal failure, and death following acetaminophen overdosage. It seems likely that these agents act primarily by stimulating glutathione synthesis. Inhibition of the metabolic activation of acetaminophen is another potential therapeutic approach that has not yet been put to the test clinically. The clinical management of acetaminophen poisoning has been transformed and it is particularly grati­ fying to have effective treatment based on a well established biochemical mechanism of toxicity. It is likely that effective treatment will be developed for toxicity caused through similar mechanisms by other agents.
Literature Cited
1. Smith, P. K. 1958. Acetophenetidin. A Critical Bibliographic Review, p. 3. Lon­ don: Wiley. 18Opp. 2. Brodie, B. B., Axelrod, J. 1948. The es­ timation of acetanilide and its metabolic products, aniline, N-acetyl-p-amino­ phenol and p-aminol'henol (free and to­ tal conjugated) in biological fluids and tissues. 1. PharmacoL Exp. Ther. 94: 22-28 3. Brodie, B. B., Axelrod, 1. 1949. The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenetidin and its metabolites in biological material 1. PharmacoL Exp. Ther. 97:58-67 4. Eder, H. 1964. Chronic toxicity studies on phenacetin, N-acetyl-p-aminophenol (NAPA) and acetylsalicylic acid on cats. Acta PharmacoL ToxicoL 21:197204 5. Boyd, E. M., Bereczky, G. M. 1966. Liver necrosis from paracetamol. Brit. 1. PharmacoL 26:606-14 6. Davidson, D. G. D., Eastham, W. N. 1966. Acute liver necrosis following overdose of paracetamol. Brit. Med 1. 2:497-99 7. Thomson, 1. S., Prescott, L. F. 1966. Liver damage and impaired glucose tol­ erance after paracetamol overdosage. Brit. Med J. 2:506-7 8. MacLean, D., Peters, T. J., Brown, R. A. G., McCathie, M., Baines, G. F., Robertson, P. G. C. 1968. Treatment of acute paracetamol poisoning. Lancet 2:849-52 9. Proudfoot, A. T., Wright, N. 1970. Acute paracetamol poisoning. Brit. Med. J. 3:557-58 10. Prescott, L. F., Wright, N., Roscoe, P., Brown, S. S. 1971. Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1:519-22 11. Clark, R., Thompson, R. P. H., Bori­ rakchanyavat, V., Widdop, B., David­ son, A. R., et aI. 1973. Hepatic damage and death from overdose of paraceta­ mol. Lancet 1:66-69 12. Canalese, J., Gimson, A. E. S., Davis, M., Williams, R. 1981. Factors con­ tributing to mortality in paracetamol­ induced hepatic failure. Brit. Med. J. 282:199-201

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PRESCOIT & CRITCHLEY chows Arch. A Pathol AnaL Histol 370:333-44

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S. B., Burk, R. F. 1978. Acetaminophen overdoses at a County Hospital: a year's experience. South. Med. /. 71:1359--63 14. Hamlyn, A. N., Douglas, A. P., lames, O. 1978. The spectrum of paracetamol (acetaminophen) overdose: clinical and epidemiological studies. Postgrad. Med. /. 54:400-4 15. McJunkin, B., Barwick, K. W., Little, W. C., Winfield, 1. B. 1976. Fatal mas­ sive hepatic necrosis following aceta­ minophen overdose. /. Am. Med. Assoc.

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