Transcript Acetaminophen Hepatotoxicity: an example of the metabolic

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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Acetaminophen Plasma
level, mcg/ml
1975 Original Nomogram
Hours since ingestion
Rumack BH and Matthew H, Acetaminophen Poisoning and Toxicity, Pediatrics 1975, 55:871-876
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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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Acetaminophen Plasma
Level, mcg/ml
1976 Study design nomogram
Hours since ingestion
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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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
Acetaminophen Plasma Level
1988 Risk Nomogram
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Hours since ingestion
Smilkstein, MJ. Knapp, GL. Kulig, KW. Rumack, BH. Efficacy of Oral N-Acetylcysteine in the Treatment
of Acetaminophen Overdose, NEJM 1988, 319:1557 - 1562
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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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Acetaminophen Plasma
Level, mcg/ml
Treatment Outcome Nomogram
Hours since ingestion
Rumack, 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 NAcetylcysteine 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 NAcetylcysteine 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
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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, pretreatment 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 Levels
Hepatitis
% 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 Levels
Type
% 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 antiepileptics 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.; BalaliMood,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
• T½
– 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 that
Be 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.