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Toxicology of Acetaminophen
William L. Enslow, DO
CPT, MC, USA
Darnall Army Community Hospital
Fort Hood, Texas
Government Services ChapterAmerican College of Emergency Physicians
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Acetaminophen
Acetaminophen = N-acetyl-p-aminophenolparacetamol = APAP
Pharmacologic use Centrally acting analgesic
antipyretic
NOT an anti-inflammatory Sources:
Multiple OTC preparations
Combinations with other analgesics
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Pharmacokinetics
Most APAP is absorbed within 2 hours
Peak plasma concentration in 4 hours
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Metabolism
Primary: Hepatic conjugation with
glucuronide or sulfate
Secondary: Oxidation by Cytochrome
P-450 enzymes to highly reactive N-
acetyl-p-benzoquinoneimine (NAPQI) Final step of deactivation of NAPQI
uses glutathione (GSH)
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NAPQI/GSH
Glutathione is a three amino-acid
peptide
Reactive portion is a sulfhydryl group
(-SH) from a cysteine moiety
-SH group reduces NAPQI to inactiveAPAP-mercaptate which is renally
excreted
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Metabolism/Clearance
Normal doses: 95% metabolized by
conjugation
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APAP Toxicity
Hepatic conjugation pathway easily
saturated in overdose
Excess APAP goes to CYT P-450
pathway
Large amounts of NAPQI is produced Limited GSH stores used to detoxify
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APAP Toxicity
When hepatic GSH stores
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Pathophysiology
Severe APAP toxicity manifests asfulminant hepatic failure
Encephalopathy
Coagulopathy
Hypoglycemia
Metabolic Acidosis
Renal failure may ensue with severeliver failure
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Mortality
Hemorrhage
ARDS Sepsis
Multiorgan failure
Cerebral edema
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Stage 1: Pre-injury Period
Nausea/vomiting
Anorexia Diaphoresis
Malaise
Patients may be asymptomatic
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Stage 2: Onset of Liver Injury
Nausea, vomiting
RUQ/epigastric pain or tenderness
Elevated AST/ALT/Bilirubin
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Stage 3: Maximum Liver Injury
Clinical picture depends on severity of
injury.
May have symptoms of hepatic failure
Continued GI symptoms
Coagulopathy
Encephalopathy
Metabolic Acidosis
Renal Failure
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Stage 4: Recovery or liver failure
2 subsets of patients
Irreversible liver failure
Reversible liver injury
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Stage 4: Reversible liver injury
Patients surviving initial liver
injury/failure complications begin to
recover
LFTs normalize in 5-7 days or more
Liver function eventually returns tonormal
Liver completely regenerates over
months
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Stage 4: Irreversible liver failure
Patients continue in clinical picture offulminant liver failure despite
treatment
Definitive treatment is liver transplant
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Diagnosis
Suspicion for toxic ingestion verifiedby Rumack-Matthew Nomogram
Use within 4 to 24 hours after ingestion
Use in acute ingestion
Measured serum [APAP] levels plottedvs time from ingestion
Concern for toxic overdose with levels>140mg/dL @ 4 hours
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Diagnosis/Management
Measure serum [APAP] in all suspectedtoxic ingestions, along with BMP, LFTs
Diagnosis of toxicity/management based onRumack-Matthew Nomogram
Measured at 4 hours
Acute Toxicity defined as >140 ug/mL Nomogram may be used from 4-24 hours
post-ingestion
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Rumack-Matthew Nomogram
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Management Goals
Minimize further absorption
Prevent/reverse NAPQI damage
Supportive care
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Minimizing Absorption
GI decontamination with activated
charcoal
Gastric lavage not indicated
AC does not interfere with other
treatment
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Preventing/reversing
NAPQI damage
N-acetyl cysteine (NAC)
Free sulfhydryl group similar to GSH
If treatment begun within 8 hrs, nearly
100% prevention of hepatotoxicity
Efficacy continues even after 8 hrspost-ingestion
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NAC
Oral or IV form:
140 mg/kg loading dose, 17 subsequent doses
of 70 mg/kg, every 4hrs after Oral form used in US
IV form used in UK and Canada.
No official studies comparing the two Many alternative treatment courses are used
within the US
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IV NAC
Indications for IV NAC Intractable vomiting
Contraindication to PO (caustic
ingestions, etc)
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Management
Actual treatment based on presentingtime from ingestion
24 hours post-ingestion
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4-24 hours post-ingestion
GI decontamination for co-ingestants
If APAP level can be obtained before 8hrs, send
If toxic-begin NAC treatment
If level will not be back before 8 hrs Presume toxicity, begin NAC
If level comes back non-toxic, can stop
NAC
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>24 hrs
GI decontamination for co-ingestants
Check APAP level, LFTs If APAP >10 ug/mL, AST/ALT increased
presume toxicity, start NAC
If pH 100, Cr >3.3, or alteredmental status presume liver failure
Refer to Liver Transplant Center
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Disposition
If patients not at risk for hepatotoxicity:
Unknown time since ingestion with:
Serum [APAP]
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Disposition
Patients receiving NAC should behospitalized for duration of treatment course
Need monitoring for possible irreversibleliver toxicity
Refer to Liver transplant for presumed liver
failure. Consult Poison Center on all cases
Consider co-ingestants in all cases