Acetaminophen Hepatotoxicity

Barry H. Rumack, M.D.May 28, 2002

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Acetaminophen Metabolic Pathways

N-acetyl-p-benzoquinone imine (NAPQI) is the reactive metabolite

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Original Nomogram - 1975

• Data from 30 cases previously published plus 34 additional cases from Ward 3, Royal Infirmary of Edinburgh

• Line constructed to discriminate between peak toxic and non-toxic cases (AST > 1,000 IU/L)

•NOT originally calculated as a 4 hour half-life line but slope is T ½ 4 hours

• Initial plasma level only after >4 hours due to concerns about absorption

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1975 Original Nomogram

Hours since ingestionRumack BH and Matthew H, Acetaminophen Poisoning and Toxicity, Pediatrics 1975, 55:871-876

Ace

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APAP and GSH depletion• Hepatic necrosis observed (animals) at

approximately 70% depletion• Normal liver GSH approximately 4mmoles/L• Human extrapolation

– 4mmoles/L X 1.5L liver = 6 mmoles– 6mmoles X 70% = 4.2 mmoles

• If NAPQI is 4% of the dose then:– 4.2 mmoles = 4% X toxic dose– Dose = 4.2mmoles X 151 mg/mmole / 4% =15.9 gm

Adapted from: Mitchell et.al., Acetaminophen-Induced Hepatic Necrosis. IV. Protective Role of Glutathione Journal of Pharmacology and Experimental Therapeutics 1973;187:211-217 and published in Rumack, BH, Peterson RG, Acetaminophen Overdose: Incidence, Diagnosis and

Management in 416 patients. Pediatrics, 1978 62:898 – 903 (supplement)

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Multi-center open NAC protocol• Not controlled since prohibited from withholding treatment

• Concern re: absorption of APAP delayed due to quantity or drugs which reduced GI motility (e.g. propoxyphene)

• T ½ in toxic patients 4 – 12 hours with some to 60 hours therefore FDA wanted a safety margin = 72 hours course

• 140mg/Kg loading dose; 70mg/Kg q4h 17 doses

• APAP levels 0, 30 min, 1, 2, 4, 8, 24, 32 hours minimum

• Lab SGOT, SGPT, Alk, phos, bili, gluc, Cr, BUN 0, 8, 16, 24, 32, 48 hours minimum

• Lab pro time and other labs 0, 24, 48 hours minimum

• Constructional dyspraxia evaluated

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Study Design Nomogram - 1976

• Safety line 25% below original line added at the request of the FDA

• High risk line 100% above original line added to define risk but did not affect treatment decisions

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1976 Study design nomogram

Hours since ingestionRumack, BH, Peterson, RC, Koch, GG, Amara IA, Acetaminophen Overdose: 662 Cases with

Evaluation of Oral Acetylcysteine Treatment, Arch. Intern. Med. 1981, 141:380-385

Ace

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Risk Nomogram - 1988

• Original line, safety line and high-risk line 50% above original line.

• Original line relabeled probable-risk

• Utilized to analyze data from 2,023 cases meeting protocol requirements

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1988 Risk Nomogram

Hours since ingestionSmilkstein, MJ. Knapp, GL. Kulig, KW. Rumack, BH. Efficacy of Oral N-Acetylcysteine in the Treatment

of Acetaminophen Overdose, NEJM 1988, 319:1557 - 1562

Ace

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Outcome nomogram• Included 517 additional patients not included in the 1988 NEJM paper

• These patients did not meet protocol criteria but received the full course of NAC

• initial plasma levels were below the safety line, or

• seen after 24 hours

• These patients completed the protocol because their initial plasma levels were not available until after completion of therapy

• They were intended to serve as safety controls for NAC however, some developed hepatotoxicity

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Treatment Outcome Nomogram

Hours since ingestionRumack, BH unpublished data from 2540 cases

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Cases Toxic % vs. Treatment Delay

* p<0.05 Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH, Efficacy of Oral N-Acetylcysteine in the Treatment of Acetaminophen Overdose. NEJM, 1988;24:1557-1562

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Mean Peak AST vs. Treatment Delay

* p<0.05 Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH, Efficacy of Oral N-Acetylcysteine in the Treatment of Acetaminophen Overdose. NEJM, 1988;24:1557-1562

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Time Course of APAP Overdose

Solid line = Untreated Dotted line = NAC treated Dot – Dash line = Severe untreated

Rumack, BH, Peterson, RC, Koch, GG, Amara IA, Acetaminophen Overdose: 662 Cases with Evaluation of Oral Acetylcysteine Treatment, Arch. Intern. Med. 1981, 141:380-385

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Common Misinterpretations

• Initial acetaminophen level is not consistent with the history– What is the body burden?

– (plasma mcg/ml)(body weight)(VD ~1L) = body burden

• Half-life is not consistent with the history– Three levels best but two will allow estimate– If it is initially greater than 4 reconsider time of ingestion

• AST is not consistent with the history– Peak occurs at ~ 72 hours– If the peak is on admission reconsider the time course

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Nomenclature of CYP Enzymes• We now abbreviate them as CYP enzymes taken from the

first two letters of the word cytochrome and adding the letter p for protein.

• There are more than 500 CYP enzymes and about the same number of genes classified into 74 families of which 14 exist in mammals.

• Families are designated by CYP followed by an Arabic number such as CYP1, CYP2, etc.

• Subfamilies of enzymes are designated by capital letters such as CYP1A and CYP1B, etc.

• Individual enzymes are then classified by adding another Arabic number in the order in which they are identified such as CYP1A1, CYP1A2, etc

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Function of CYP Enzymes• ~ 20 enzymes, which are known to be involved in the metabolism of

xenobiotics in humans. Families CYP1 through CYP4 • There are other CYP enzymes in humans which either are involved in

the synthesis or metabolism of normally occurring endogenous substances such as cholesterol, Vitamin D, etc. Examples are CYP5, CYP7, CYP8, etc.

• Of the four we are most interested in that deal with xenobiotics the highest concentrations are usually in the liver but some smaller amounts may be located in lung, kidney, etc.

• It is now possible to look at individual enzymes and see what they do in intact humans through various marker substances.

• We now understand that just because one individual enzyme is induced does not mean that other individual enzymes will be induced.

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CYP2E1• 493 amino acids• MW 56,820• One gene on chromosome 10 with 11,413 base pairs• Metabolizes more than 75 compounds• Unique among CYP producing reactive oxygen radicals

through reduction of dioxygen• Unique among CYP in being strongly induced by ethanol• Intra-cellularly in the endoplasmic reticulum with small

amounts in the cell membrane and lysosomal vesicles• CYP2E1 primarily located in the rows of 5 cells around the

central venules• Originally called “microsomal ethanol oxidizing system”

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Mechanisms of Zonal Injury

Casarett and Doull’s Toxicology, Sixth Edition, 2001 Page 479

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Hepatic Structure

Haschek, WM, Rousseaux, CG, Handbook of Toxicologic Pathology, Academic Press 1991

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Normal Hepatic Histology

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Normal Hepatic Histology High Power

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Hepatotoxicity

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Hepatotoxicity High Power

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CYP2E1 – Induction & Inhibition I• Induction and inhibition occur at

– Transcriptional– Pre-translational– Translational– Post-translational

• Post-translational protein stabilization due to ligand binding appears to be the most important mechanism

• Acetone extends CYP2E1 degradation half-life from 7 to 35 hours by ligand stabilization

• Ethanol, acetone and isoniazid increase CYP2E1 concentration in zone 3 after induction - no recruitment

• Hypophysectomy produces recruitment in zone 2 showing transcriptional activity on the apoprotein and demonstrating repression of CYP2E1 expression by growth hormone

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CYP2E1 - Induction & Inhibition II

• Inducer and substrate: Acetone, Ethanol, Pyrazole, Isoniazid• Substrate but not an inducer: Acetaminophen,

chlorzoxazone, carbon tetrachloride• Inducer but not a substrate: Imidazole• CYP2E1 is increased in diabetes, obesity and other

nutritional states that produce acetone• Acetone may be an indirect inducer although effects of

growth hormone (repression) and glucagon and epinephrine (accelerated degradation) may be part of the process

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Differential induction and inhibition used to evaluate other enzymes re: NAPQI

• In vitro NAPQI produced by CYP1A2, CYP2E1 and CYP3A4• In vivo NAPQI produced primarily by CYP2E1 in humans• Techniques used to isolate effects:

– Omperazole (Prilosec), a potent inducer of CYP1A2, pre-treatment in volunteers did not enhance NAPQI production from acetaminophen

– Rifampin, an inducer of CYP2C9, CYP2C19, CYP1A2 and CYP3A4, pre-treatment of volunteers did not enhance NAPQI production from acetaminophen

– Disulfiram, a potent inhibitor of CYP2E1, pre-treatment in volunteers reduced NAPQI production by 69%

• Substantial differences between in vitro human and in vivo human data as well as differences with animal data

Manyike,P.T. Kharasch,E.D. Kalhorn,T.F. Slattery,J.T., Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation, Clin. Pharmacol. Ther., 2000, 67:275 - 282

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Glutathione Metabolic Pathways

White, et.al. Glutathione deficiency in human disease, J. Nutr. Biochem., 1994;5:218-226

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N-Acetylcysteine (NAC)

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Hepatic Disease Glutathione LevelsHepatitis % of Control

Toxic 2311

Viral 1761

Chronic 2161

Chronic Active 1421

Cirrhosis 1862

1081

Fatty Liver 1532

Steatosis 781

1 – Poulsen, et. al., Scand J Clinical Lab Invest 1981;41:573-576

2 – Siegers, et. al. Pharmacology Research Communications, 1982;14:61-72

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Hepatic Disease P-450 LevelsType % of Control P450

Acute Viral Hepatitis

Mild 1001

Moderate 1181

Healing 922

Fatty Liver 1022

Cirrhosis 342

1 – Schoene, et. al., Eur. J. Clin Pharm. 1972;4:65-73

2 – Gabrielle, et. al., Gastro. Clin. Biol. 1977;1:775-782

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Carbon Tetrachloride as an Example of Metabolic Conversion

Variant 7 Day LD50

Control 3.6 ml/Kg

Phenobarbital 0.5 ml/KG

Low protein 14.7 ml/Kg

Low protein + Phenobarbital

4.3 ml/Kg

Garner,R.C.; McLean,A.E., Increased susceptibility to carbon tetrachloride poisoning in the rat after pretreatment with oral phenobarbitone, Biochemical Pharmacology 1969, 18:645-650

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Phenobarbital: a pleiotropic inducer

• Phenobarbital induces both Phase I (functionalization usually on the endoplasmic reticulum such as CYP) and Phase II (biosynthetic usually cytosolic such as glutathione S-transferase) reactions

• Induces CYP2B, CYP2C and others• Does NOT induce CYP2E1• Induces UDP-glucuronosyltransferase, aldehyde

dehydrogenase, glutathione S-transferase and others• Early work looking at total P-450 or total metabolism

suggested PB increased APAP risk – now not correct

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Phenytoin: an example of development of knowledge

• 1979 Multiple anti-epileptics but found that free and conjugated acetaminophen excretion showed no difference when compared with a control group1

• 1981 Were surprised to find no difference in excretion of mercapturic acid conjugates between those taking anti-epileptics or rifampin and controls2

• The same study showed a significant increase in glucuronide conjugates in those taking anti-epileptics and rifampin compared to controls.

1 - Perucca,E.; Richens,A. Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs Br. J. Clin. Pharm 1979, 7:201-206 2 - Prescott,L.F.; Critchley,J.A.; Balali-

Mood,M.; Pentland,B. Effects of microsomal enzyme induction on paracetamol metabolism in man Br. J. Clin. Pharm 1981, 12:149-153

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Phenytoin and Acetaminophen• Overdoses in patients with mixed anti-epileptics of

acetaminophen ranged from 7.5 grams to 75 grams in the nine patients. “Patients on anticonvulsant drugs should be warned not to exceed recommended doses of paracetamol, i.e. 4g/day, even if they have severe pain.”1

• A later report from the same group showed a changed view with either anti-convulsants or ethanol producing similar mortality rates of 33% and 37%.2

• Another series with phenytoin alone compared to a control group showed a decrease in mercapturic acid but an increase in glucuronide concluding no increased risk.3

1-Bray, et. al. Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure, Hum Exp Toxicology 1992;11:265-270. 2-Makin,A.J. et al. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993) Gastroenterology

1995,109:1907-1916 3-Tomlinson,B. et al. Selective liver enzyme induction by carbamazepine and phenytoin in Chinese epileptics 1996 Eur. J. Clin. Pharm. 50:411-415

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Phenytoin and Acetaminophen 2

• Phenytoin is primarily metabolized to p-HPPH* facilitated by CYP2C9 and CYP2C19 which phenytoin induces

• P-HPPH is conjugated by glucuronide and excreted and phenytoin is a potent inducer of glucuronosyltransferase

• The metabolism of phenytoin to its glucuronide increased due to increased activity of CYP2C9/2C19 but the metabolism of acetaminophen through the toxic pathway to mercapturic acid did NOT increase because phenytoin does NOT induce CYP2E1.

• Prior phenytoin treatment is hepato-protective in acetaminophen overdose rather than being a risk factor

* 5-(4-hydroxyphenyl)-5-phenyhydantoin

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Isoniazid Induction of CYP2E1

• Isoniazid stabilizes CYP2E1

• Acetaminophen and isoniazid consumed together resulted in a 63% inhibition of NAPQI

• When isoniazid was stopped and APAP continued the formation of NAPQI was enhanced 24 hours after the last isoniazid dose but the effect is not likely to be critical.

Zand et.al., Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clinical Pharmacology Therapeutics 1993;54:142-9

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Ethanol and APAP Overdose

• An overdosage of acetaminophen in an alcoholic results in the same pattern of hepatotoxicity as in a non-alcoholic

• Degree of hepatotoxicity is not affected by alcoholism

• Severe alcoholics also take a larger dose of acetaminophen

Makin,A.J. et al. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993) Gastroenterology 1995,109:1907-1916

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Ethanol Induction of CYP2E1• Stabilization of mRNA at higher doses of

ethanol (>250mg/dL)– Enhanced de novo synthesis

• Stabilization of the CYP2E1 protein at lower doses of ethanol (< 250mg/dL)– Ligand stabilization is ligand concentration

dependent by binding to the active site• The net result is simultaneous inhibition (during

ethanol consumption) and induction of CYP2E1 by increased concentration

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Induction and Inhibition of CYP2E1 by Ethanol: A COMPUTER SIMULATION

I = Inhibitor, Ki = Inhibitory Constant, Cl(t)/Cl0 = Ratio after to before infusion

Slattery et. al. Clinical Pharmacology and Therapeutics 1996;60:241-246

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Ethanol Induction of CYP2E1• CYP2E1 was increased two-fold in human alcoholics who

were drinking1

• After 5 –10 days of abstinence from ethanol the effect disappeared

• APAP consumed during ethanol infusion reduced NAPQI 72% but NAPQI increased 24% 8 hours after the infusion stopped2

• Induction leads to a maximum 2 fold increase of NAPQI

1 - Perrot, et.al., Modulation of cytochrome P450 isozymes in human liver by ethanol and drug intake. European Journal Clinical Investigation 1989;19:549-555

2 - Thummel,K.E.; Slattery,J.T.; Ro,H.; Chien,J.Y.; Nelson,S.D.; Lown,K.E.; Watkins,P.B. Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults, Clin. Pharmacol.

Ther. 2000, 67:591-599

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APAP Ethanol and Fasting• Study of cases 72% – 94% recent fasting1

– All patients who developed severe hepatotoxicity took more than 4g/day

– 70% of patients who developed hepatotoxicity were chronic acetaminophen users consuming 4 to 10 g/day

– All patients who developed toxicity while consuming > 10g/day were alcohol users

• Study of patients restricted to 500 – 1000 calories per day showed no change in APAP metabolism2

1 - Whitcomb and Block, Association of Acetaminophen Hepatotoxicity with Fasting and Ethanol Use, JAMA 1994;272:1845-1850; 2 - Schenker, S., Speeg, K.V., Perez, A., Finch, J., the effects of food restriction in man on hepatic metabolism of acetaminophen. Clinical Nutrition 200120:145 - 150

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Acute and Chronic Ethanol and Acetaminophen

• Ingestion of ethanol and acetaminophen concomitantly in a non-alcoholic individual results in less exposure to NAPQI than if ethanol was not ingested simultaneously

• Long term administration of high dose ethanol followed by brief abstinence is a risk for enhanced toxicity of APAP in overdose but NOT at therapeutic doses.

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APAP During Ethanol Withdrawal• In 201 patients administration of

acetaminophen 4 times per day at 1 gram per dose to withdrawing alcoholics show no difference to a control1

• Evaluation of a large group of patients in an alcohol detoxification program revealed no hepatotoxicity2

1 - Kuffner, et. al. Effect of Maximal Daily Doses of Acetaminophen on the Liver of Alcoholic Patients. Arch Intern Med 2001, 161: 2247 - 2252

2 - Kenny, et. al., Routine screening for acetaminophen (APAP) toxicity of patients requesting alcohol detoxification. Journal Studies Alcohol 1999;60:139-140

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Alcoholism and high risk versus low risk patients

• Toxicity, as defined by AST and ALT was worse in patients categorized in the high risk (above the “300” line) acetaminophen overdose

• Toxicity, was no different in low risk (below the “200” line) acetaminophen overdoses whether they were alcoholics or not

• Consistent with others who have reported more acetaminophen ingested in alcoholics.

Smilkstein MJ Rumack BH, Chronic Ethanol Use and Acute Acetaminophen Overdose Toxicity; Journal of Toxicology Clinical Toxicology 1998;36: 476

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Ethanol-Acetaminophen Literature example of data issues

• 68 cases 1977 - 1993• 18/68 report 4 g/day or less but, examine the cases:

– 9/18 cases – no blood level– 2/18 cases – no blood level and no history of last dose– 4/18 cases – APAP level and timing consistent with

overdose– 3/18 cases – APAP level consistent with low dose history

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Clinical Literature of Ethanol Induction 1

• Paper reports the results of a registry. The cases are very poorly documented and do not demonstrate what they are reported to show.

• Many cases are letters with minimal information and it is impossible to look at other aspects of the case

• Focus is on a “Therapeutic misadventure” – an expression of molecular intent!

Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure Hepatology 1995; 22(3):767-773.

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Clinical Literature of Ethanol Induction 2

• Paper reviews 25 patients – 19 from the literature, 5 new• Table 1 in this study shows the details for 19 patients.

Fifteen of those patients consumed more than 4 grams in 24 hours with a range of 4.5 to 16.5 grams.

• Patient 2 reported in this study ingested 12.5 g/d of acetaminophen with a six pack of beer. It is hard to imagine he thought this was therapeutic.

• A patient quoted from the literature as 4g of APAP had a level of 63 mcg/ml in the original article on day 3 of hospitalization. This would be a higher body burden than the ingested amount and so was clearly an overdose.

Seeff, et. al. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern

Med 1986; 104(3):399-404.

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Clinical Literature of Ethanol Induction 3

Despite the case of 12.5 g/day and the inability to have any idea of the intent from the published cases the authors state, “There seems little doubt that none of the 25 patients deliberately took an overdose of acetaminophen or deliberately distorted the information regarding the amount that they consumed.”

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Clinical Literature of Ethanol Induction 4• 71 cases of which 21 were hospitalized for excessive APAP

without suicidal "intent." 5 were admitted to the hospital for excess acetaminophen ingestion; the majority had abnormal aminotransferase levels or prothrombin times that mandated their admission. These were contrasted with 50 acetaminophen overdose patients who were suicide attempts. The authors conclude that the higher morbidity and mortality in the “accidental” group who also had a higher incidence of alcohol abuse that this means alcohol is a risk factor. Walker comments that this is not acceptable because even though the suicide attempts had taken more acetaminophen (by history) the others were there because they had been selected due to showing morbidity (ALT) at presentation.

Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N. Engl. J. Med. 1997; 337(16):1112-1117. Walker, AM, Acetaminophen toxicity in an urban county

hospital [letter; comment] NEJM 338:543-545

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Therapeutic Doses of Acetaminophen in an Alcoholic

“Finally, and most importantly, there has never been a single documented instance of any degree of acute liver damage produced by therapeutic doses of paracetamol given as a challenge in any chronic alcoholic under properly controlled conditions.”

- L.F. Prescott, M.D.Prescott, L.F., Paracetamol, alcohol and the liver,

British Journal of Clinical Pharmacology, 2000;49:291-301

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Finally, in regard to Ethanol

Chronic heavy alcoholics are probably at greater risk for toxicity following overdoses of acetaminophen.

There is no evidence that therapeutic doses of acetaminophen can cause toxicity in an ethanol induced patient.

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Pediatric Pharmacokinetics - absorption

• T ½ absorption– 4.5 minutes elixir– 10.3 minutes tablet

• Peak Plasma concentrations– 30 to 60 minutes (variety of studies)– 5, 10 or 20 mg/kg dose all at 30 minutes

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Pediatric Pharmacokinetics - metabolism

• VD

– normal children 0.86 L/kg –1.0 L/Kg– Children with hepatic disease 1.34 L/Kg

• T ½– 111 to 148 minutes– 2 hours generally accepted

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Pediatric Dosing

• Standard dosing of 10 – 15 mg/Kg produces levels at or below the therapeutic range of 10 to 20 mcg/ml

• Dose produces an almost direct relationship with change in temperature– 5mg/Kg = temp drop of 0.5 Co

– 10 mg/Kg = temp drop of 1.5 Co

– 20 mg/Kg = temp drop of 2.5 Co

Windorfer, A and Vogel, C; Investigations concerning serum concentration and temperature following oral application of a new paracetamol preparation Klin. Pediatr. 1976, 188:430-434

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Pediatric Pharmacokinetics – disposition and toxicity

• Young animals have 4 times the rate of turnover of GSH as older animals

• LD50 requires much higher doses in younger animals than older

• Sulfate to glucuronide shift ages 9 – 12

• Toxic plasma levels produce toxic AST in 5.5% of pediatric cases and 29% in adults.

Rumack, BH; Acetaminophen Overdose in Young Children: Treatment and effects of alcohol and other additional ingestants in 417 cases. Am. J. Dis. Child 1984, 138:428-433

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Conclusions• Specific enzymes must be considered when

looking at induction

• Data which does not separate xenobiotics must be viewed skeptically

• Compounding factors such as GSH metabolism, nutritional status, etc. must be considered

• There is no evidence that therapeutic doses of acetaminophen can cause hepatotoxicity in either induced or non-induced patients

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The Future

Case reports must be considered just thatBe careful of early literature since it may provide

erroneous information regarding CYP enzymes, inducers and inhibitors. Rapid change in this area.

Animal work must be viewed skeptically until such time as human correlation can be made

Many studies remain to be done. With new tools available the next few years should answer many questions still outstanding.