Commentary on Acetaminophen

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AMERICANACADEMYOF PEDIATRICS

Committeeon Drugs

Commentaryon Acetaminophen

Acetaminophen is being promoted as the preferred analgesicâ€”antipyretic, particularly for pediatric use, with suggestions that it is safer and perhaps more efficacious than aspirin. The claim that acetaminophen is less toxic than aspirin is based on a lower incidence of certain side effects and toxic manifestations observed with acetami nophen than with aspirin. Although in thera peutic doses acetaminophen does not share the adverse gastrointestinal, hemorrhagic, and acid base side effects of aspirin, it does have its own unique toxicity. When ingested in excessive quan tities, it may be more lethal than aspirin, and considerably more difficult to treat.

Available studies indicate that acetaminophen and aspirin given in equal milligram doses are equally effective in relieving pain and fever.' -2 In contrast to aspirin, acetaminophen has little anti inflammatory effect.

Animal toxicity studies, although helpful in elucidating mechanisms of toxicity, have failed to provide conclusive answers to the question of relative toxicity of acetaminophen and aspirin. Acute toxicity studies in several animal species have produced widely varying results. The degree of acetaminophen toxicity varies not only among different species' but also among different strains within the same species.4 Additional determinants of acetaminophen toxicity are the nutritional status5 of the animals and pretreatment with microsomal enzyme inducers or inhibitors6 Furthermore, it is unknown which animal species, if any, best reflect toxicity in humans.

A large number of serious acetaminophen

poisonings, including fatalities, have been reported from Great Britain during the past decade.79 Reports of acetaminophen toxicity have been less common in the United States. However, one major poison control center in the

United States recently reported 156 acetamino phen ingestions, with four fatalities, during a one year period.'0 These ingestions have been in teen agers and adults who ingested large quantities in suicide attempts. Accidental acute ingestions by

children have only rarely been reported. However, there is concern that the increased

popularity and use of acetaminophen-containing products along with the recently introduced â€œ¿adult-strength,â€•higher-dose preparations may increase the risk of toxic overdoses in children. Eighteen percent of the calls regarding acetami nophen poisoning received by the London Centre of the British National Poison Information Service during 1975 concerned children.â€• A fatal acet aminophen poisoning in a 13-year-old girl also receiving phenobarbital has recently been reported in the United States (J. T. Wilson, personal communication).

Considerable confusion exists regarding the acetaminophen versus aspirin content of many products. Patients may assume they are taking aspirin, when in fact they are taking acetamino phen. Frequently, the individual may be unaware that he/she is taking either. Approximately 300 prescription and nonprescription products which contain acetaminophen are currently marketed in the United States.'2'4 The proprietary names of most of these products in no way denote that acetaminophen is included in their formulation, although acetaminophen is listed along with other ingredients in the labeling.

CLINICALSIGNS OF ACETAMINOPHEN POISONING

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are ingested. The early, acute symptoms follow

ing ingestion of a toxic quantity of acetaminophen

are extremely variable. Furthermore, early symp toms are not accurately predictive of the possi

bility of later serious complications, particularly

hepatic necrosis. Early symptoms frequently include anorexia, nausea, vomiting, malaise, pallor, and sweating occurring within a few hours after ingestion. These symptoms persist in varying

degrees for the first one or two days. The patient's

condition may appear to improve clinically on the second or third day. Some patients may only show elevations of serum transaminase levels on

the second day or later, whereas others become frankly jaundiced by the third or fourth day. In

the latter patients, the liver function tests may

show a variety of abnormalities, and the liver may be tender and/or enlarged. If results of liver

function tests are still normal after the second day, significant liver damage is unlikely; however, if the bilirubin level exceeds 4 mg/dl within the

first five days, the liver is probably severely damaged.'Â°' â€˜¿@

With severe and progressive liver damage,

fulminant hepatic failure and hepatic encepha

lopathy may develop rapidly, with such signs as hepatic flap and fetor hepaticus; mental confu

sion and deep coma may ensue in 4 to 18 days.

Clotting disorders with associated hemorrhagic problems may also develop.â€•' Potentially fatal hypoglycemia has been reported, but it is not common.'7-'@' Renal damage with acute renal failui@ehu2ii and myocardial damage have been reported.2'

The dose ingested and the resultant plasma

levels of acetaminophen are the most reliable

early indicators of prognosis. For this reason, it is

extremely useful, when facilities are available, to

obtain an acetaminophen blood level as soon as possible after ingestion. A simple colorimetric method for determining acetaminophen blood or serum concentration which can be easily set up in any hospital laboratory has recently been de

22

There is evidence to suggest that, at certain ages, children may metabolize acetaminophen differently than adults.23 Whether or not this has any effect on potential toxicity of the drug is

unknown at the present time. However, such differences make prediction of hepatotoxicity in

children difficult to extrapolate from doses known to be hepatotoxic in adults. Hepatic damage is

likely if an adult has taken more than 15 gm as a

single dose. Although toxic doses for children are not well defined, a comparable dose for an average-sized, 2-year-old child, extrapolated on

1000 500 400 300 200 100 50 10 5

Prohaf)ie Hepatic Toxicity

ix 0 ix E C -C 0 C E ix a, â€˜¿-I 4

No Hepaic loxicily

2 4 8 12 16 20 24

Hours After Ingestion

Semilogarithmic plot of plasma acetaminophen c-oncentra tion versus time based on data from adult patients.' Patients with concentrations above the line at the corresponding times after ingestion may develop hepatic toxicity. Patients with concentrations below the line have a low probability of

developing hepatic toxicity.

the basis of body surface area, is approximately 4 gm. This is equivalent to eight 500-mg capsules, twelve 325-mg tablets, or 160 ml of 24-mg/ml syrup.

When the plasma concentration of acetamino phen in adults is more than 300 @tg/mlfour hours after ingestion, hepatic necrosis is probable; between 120 @g/ml and 300 @tg/ml, necrosis is possible; and when less than 120 @.tg/ml, it is unlikely. If the measurement is obtained 12 hours after ingestion, the comparable figures are more than 120 jig/mi, between 50 @tg/m1and 120 @tg/ ml, and less than 50 @.tg/ml,respectively'Â°'24 (Fig are).

Other warning signs of impending hepatotox icity include an acetaminophen plasma half-life of more than 4 hours, and a continued rise in

SGOT, SGPT, and bilirubin levels and prothrom

bin time beyond the third day after ingestion. Because of the potential for hepatotoxicity, the use of acetaminophen should be avoided in patients known or suspected to have acute hepa tocellular damage, such as patients suffering from Reye's syndrome.

TREATMENTOF ACETAMINOPHEN POISONING

The treatment of acute acetaminophen poison

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The hepatic toxicity of acetaminophen in rodents is related to the formation of one or more highly reactive metabolites in the liver.25 With therapeutic doses of acetaminophen, this metabo lite is formed in relatively small amounts, conju gated with glutathione, and excreted. However, the ingestion of toxic amounts of acetaminophen leads to formation of quantities of the metabolite sufficient to deplete the glutathione stores, there fore allowing free metabolites to bind covalently to cellular macromolecules and produce hepato cellular damage. This appears to occur when hepatic glutathione levels are decreased below 20% of normal.

Acetaminophen is rapidly absorbed from the gastrointestinal tract, peak levels occurring 70 to 160 minutes after ingestion.26 Therefore, the liver may be exposed to damaging quantities of the toxic metabolite before treatment can be initiated.

Although of limited value, the stomach should be emptied as soon as possible after ingestion, activated charcoal (8 to 10 gm) may be adminis tered to minimize further absorption,27 and sodium sulfate (200 mg/kg) may be given every four hours until catharsis occurs. The patient's condition should be monitored for signs of hepa totoxicity. If signs of liver damage appear, the usual medical treatment for acute hepatic failure should be instituted. Corticosteroids are of no benefit either in preventing or reversing hepatic necrosis.28 Drugs such as phenobarbital and alcohol which induce microsomal enzyme activi ty appear to potentiate acetaminophen-induced hepatotoxicity and should be avoided.28'29 Normal urinary output should be maintained. However, forced diuresis is of no benefit and may be dangerous. Acetaminophen exerts an antidiuretic effect and, in combination with overhydration, may lead to excess fluid retention. Although acetaminophen can be removed from the blood by hemodialysis10 and hemoperfusion,3' these methods have not been effective in reducing hepatotoxicity or mortality in patients.

A number of compounds have offered varying degrees of protection against acetaminophen induced hepatotoxicity in animals. Among these are glutathione, L-cysteine, acetyl-L-cysteine, L methionine, cysteamine, and vitamin E.'233 The mechanisms of action of these compounds are not well understood. Cysteine and methionine may act as glutathione precursors. Other compounds may act as alternative â€”¿SHdonors or inhibitors of enzymatic oxidation of acetaminophen to the toxic metabolite(s).

Several clinical studies indicate that hepatotox

icity can be prevented or reduced by intravenous administration of methionine or cysteamine if they are given within ten hours of an acetamino phen overdose24'34 The intravenous administra tion of these compounds is accompanied by significant adverse side effects. Both agents cause flushing, nausea, vomiting, drowsiness, and severe malaise, although the severity of these adverse effects is somewhat less with methionine. Intrave nous cysteamine hydrochloride is currently avail able only as an experimental drug. An intravenous preparation of methionine is not available in the United States and Canada at the present time.

In one recently published study,35 orally admin istered methionine was effective in decreasing mortality and hepatotoxicity caused by acetami nophen poisoning. Additional clinical trials are necessary to corroborate the results of this prelim mary study. Methionine is available in tablet form in the United States. It may be administered by nasogastric tube to comatose patients. Methio nine should not be administered after ten hours following acetaminophen ingestion or if there is clinical or biochemical evidence of hepatotoxicity because it may precipitate hepatic coma under these conditions. Doses of methionine which have been used orally are 2.5 gm every four hours to a total of 10 gm for adults,'5 and 1 gm every four hours for four doses for a 3-year-old child.â€•

Recently, orally administered N-acetylcysteine

(Mucomyst)

wasshownto provideratherdramat

ic protection against acetaminophen hepatotox icity in mice.36 This drug is readily available as a 20% solution and has been safely administered orally over a period of time to patients with cystinuria. N-acetylcysteine does not appear to share many of the adverse side effects of

methionine and cysteamine, and it has been administered to an adult patient in divided doses

up to 400 mg/kg/day for six days for treatment of

acute acetaminophen poisoning.37 Clinical trials are currently in progress to determine the safety and efficacy of this therapy.

The use of oral methionine, N-acetylcysteine, or any other of the aforementioned drugs for the treatment of acetaminophen poisoning is experi mental and should be reserved for patients who, in the judgment of the physician, are at risk for significant acetaminophen toxicity, and in whom treatment can be initiated within ten hours of ingestion.

RECOMMENDATIONS

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an alternative, particularly to patients with aspirin hypersensitivity, bleeding abnormalities,

or gastrointestinal intolerance to aspirin.

2. There is no information about chronic

acetaminophen toxicity arising from chronic use at recommended therapeutic doses.

3. The acute toxicity of acetaminophen over dose is potentially life threatening and much less amenable to therapy than salicylate overdose. Physicians must be aware of the potential for severe, irreversible, and potentially lethal hepatic toxicity resulting from acetaminophen overdose.

Parents should be educated to respect this drug as a potential poison just as they do aspirin.

4. Acetaminophen-containing products should

be dispensed in â€œ¿child-proof'containers. Prod

ucts intended for consumption by children should

be dispensed in containers with no more than a total of 2 gm of acetaminophen.

5. Physicians should make an effort to keep

abreast of new developments regarding specific therapy of acetaminophen poisoning. This is a rapidly developing area, and new information and recommendations will be forthcoming during the next few years.

6. Physicians should encourage their hospital

laboratories to make a rapid assay for acetamino

phen in blood or serum available to aid in

identifying patients at risk for developing signifi cant toxicity from an acute acetaminophen over dose.

COMMITTEE ON DRUGS

Members: Sydney Segal, M.D., Chairman; Sanford N.

Cohen, M.D.; John Freeman, M.D.; Benjamin M. Kagan, M.D.; Ralph E. Kauffman, M.D.; Albert W. Pruitt, M.D.; Lester F. Soyka, M.D.

Liaison Representatives: John C. Ballin, Ph.D.; Charlotte

Catz, M.D.; Louis Farchione, M.D.; Martha M. Freeman, M.D.; Clifford P. Goplerud, M.D.; John A. Leer, Jr., M.D.; Godfrey Oakley, M.D.; Steven Sawchuk, M.D.; C. P. Scott, M.D.

REFERENCES

1. Moertel CG, Ahmann DL, Taylor WF, Schwartau N: A comparative evaluation of marketed analgesic drugs. N Engl I Med 286:813, 1972.

2. Tarlin L, Landrigan P, Babineau R, Alpert JJ: A comparison of the antipyretic effect of acetamino phen and aspirin. Am I Dis Child 124:880, 1972.

3. Davis DC, Potter WZ, Jollow DJ, Mitchell JR: Species

differences in hepatic glutathione depletion, cova lent binding and hepatic necrosis after acetamino phen. Life Sci 14:2099, 1974.

4. Thorgeirsson 55, Felton JS, Nebert DW: Genetic differ ences in the aromatic hydrocarbon-inducible N-hydroxylation of 2-acetylaminofluorene and ace taminophen-produced hepatotoxicity in mice. Mol

Pluarmacol 11:159, 1975.

5. McLean AE, Day PA: The effect of diet on the toxicity of paracetamol and the safety of paracetamolmeth

ionine mixtures. Biochem Phar-macol 24:37, 1975.

6. Mitchell JR. Jollow DJ, Potter WZ, et al: Acetamino

phen-induced hepatic necrosis: I. Role of drug metabolism. I Pharmacol Erp Ther 187: 185, 1973. 7. James 0, Roberts SH, Douglas AP, et al: Liver damage after paracetamol overdose: Comparison of liver function tests, fasting serum bile acids, and liver histology. Lancet 2:579, 1975.

8. Proudfoot AT, Wright N: Acute paracetamol poisoning.

Br Med J 3:557, 1970.

9. Gazzard BG, Davis M, Spooner J, Williams R: Why do people use paracetamol for suicide? Br Med I 1:212, 1976.

10. RumackBH, MatthewH: Acetaminophenpoisoning and toxicity. Pediatrics 55:871, 1976.

11. Crome P, Vale JA, Volans GN, Widdop B: Toxicity of paracetamol in children. Br Med I 2:475, 1976. 12. Wilson CO. Jones TM (eds): American Drug Index.

Philadelphia, JB Lippincott Co, 1976.

13. APhA Drug Names. Washington, DC, American Phar maceutical Assoc, 1976.

14. Drug Products Information File. Washington, DC, American Society of Hospital Pharmacists, 1976. 15. Done AK: Acetaminophenâ€”Beware the sleeper. Emer

gency Med, June 1975, p 139.

16. Gazzard BG, Henderson JM, Williams R: Early changes in coagulation following a paracetamol overdose and a controlled trial of fresh frozen plasma ther apy. Gut 16:617, 1975.

17. Record CO, Chase RA, Alberti KGMM, Williams R: Disturbances in glucose metabolism in patients with liver damage due to paracetamol overdose.

Gun Sci Mo! Med 49:473, 1975.

18. Ruvalcaba RHA, Limbeck GA, Kelley VC: Acetamino phen and hypoglycemia. Am I Dfr Child 112:558, 1966.

19. Boyer TD, Rouff SL: Acetaniinophen-induced hepatic necrosis and renal failure. JAMA 218:440, 1971. 20. Brown RAG: Hepatic and renal damage with parace

tamol overdosage. J Gun Pathol 21:793, 1968. 21. Sanerkin NG: Acute myocardial necrosis in paracetamol

poisoning. Br Med I 3:478, 1971.

22. Kendal SE, Lloyd-Jones G, Smith CF: The development of a blood paracetamol kit. I mt Med Res 4(suppl):83, 1976.

23. Miller R.P, Roberts RJ, Fischer U: Acetaminophen elimination kinetics in neonates, children and adults. Gun Pharmacol Ther 19:284, 1976.

24. Prescott LF, Sutherland GR, Park J, et al: Cysteamine, methionine and penicillamine in the treatment of paracetamol poisoning. Lancet 2: 109, 1976. 25. Jollow DJ, Mitchell JR. Potter WZ, et al: Acetamino

phen-induced hepatic necrosis: II. Role of covalent

binding in-vivo. J Pharmacol Erp Ther 187:195,

1973.

26. Nimmo J, Heading RC, Tothill P. Prescott LF: Pharma cologicalmodificationof gastric emptying: Effects of propantheline and metoclopromide on parace tamol absorption. Br Med I 1:587, 1973.

27. Levy G, Houston JB: Effect of activated charcoal on acetaminophen absorption. Pediatrics 58:432, 1976.

28. Nimmo J, Dixon MF, Prescott LF: Effects of mepyra mine, promethazine and hydrocortisone on parace tamol-induced hepatic necrosis in the rat. Gun

Toxico! 6:75, 1973.

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therapy of hepatotoxicity following paracetamol overdosage. Scott Med I 18:56, 1973.

30. Farid NR, Glynn JP, Kerr DN: Hemodialysis in parace tamol self-poisoning. Lancet 2:396, 1972. 31. Gazzard BG, Wilson RA, Weston MJ, et al: Charcoal

haemoperfusion for paracetamol overdose. Br I Clin

Pharmacol 1:271, 1974.

32. Mitchell JR, Jollow DJ, Potter WZ, et al: Acetamino phen-induced hepatic necrosis: IV. Protective role of glutathione. J Pharmacol Erp Ther 187:211, 1973.

33. Penn RG: A theoretical approach to the management of paracetamol overdosage. I Int Med Res 4(suppl):98,

1976.

34. Prescott LF, Swainson CP, Forrest ARW, et al: Successful treatment of severe paracetamol over dosage with cysteamine. Lancet 1:588, 1974. 35. Crome P, Volans GN, Vale JA, et al: The use of

methionine for acute paracetamol poisoning. I Int Med Res 4(suppl): 105, 1976.

36. Piperno E, Berssenbruegge DA: Reversal of experi mental paracetamol toxicosis with N-acetylcys teine. Lancet 2:738, 1976.

37. Lyons L, Studdiford JS, Sommaripa AM: Treatment of

acetaminophen overdosage with N-acetylcysteine.

N Engl I Med 296: 174, 1977.

ZOSTERIMMUNEGLOBULINANDVARICELLA-ZOSTER

IMMUNEGLOBULIN

Since January 1972, the Center for Disease Control has provided the investigational drug zoster immune globulin (ZIG) to more than 1,000 immunodeflcient children within 72 hours of exposure to varicella (chickenpox). Preliminary data suggest that ZIG, which is prepared from the plasma of healthy donors convalescing from herpes zoster infection (shingles) or varicella, is effective in preventing or modifying varicella infection in immunodeficient patients if it is administered shortly after exposure.

Unfortunately, the supply of ZIG has been intermittent because the number of plasma donors has been insufficient to meet the increasing number of requests. In an attempt to meet this increasing demand, CDC has contracted with the Sidney Farber Cancer Institute and State Laboratory Institute of Massachusetts State Department of Public Health to provide and distribute a supply of varicella-zoster immune globulin (VZIG), prepared from pooled plasma containing high titers of varicella antibody.

VZIG is also an investigational drug, and the supply of it is likewise limited. Unnecessary use can be minimized, where feasible, by routine screening of children with immunodeficiency, leukemia, or lymphoma for VZ virus antibody.

Both ZIG and VZIG have been available at no cost as of November 1, 1977, for use in patients meeting the following criteria:

1. One of the following underlying illnesses or conditions A. Leukemia or lymphoma

B. Congenital or acquired immunodeficiency C. Receiving immunosuppressive medication D. Newly born of mother with varicella

2. One of the following types of exposure to varicella or zoster patient A. Household contact

B. Playmate contact (more than one hour of play indoors)

C. Hospital contact (in same two- to four-bed bedroom or adjacent beds in a large ward)

D. Newborn contact (newborn whose mother contracted varicell@within four days before delivery or within 48 hours after delivery)

3. Negative or unknown prior disease history 4. Age of less than 15 years

5. The request for treatment must be initiated within 72 hours of exposure

A physician who desires treatment for such a patient should contact the Division of Clinical Microbiology, Sidney Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts; telephone (617) 732-3121. Although former ZIG consultants and the Immunization Division of CDC will no longer have responsibility for distribution of ZIG, they will be available for consultation regarding alternative modes of therapy.

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1978;61;108

Pediatrics

Committee on Drugs