toxicology of acetaminophen

8/13/2019 Toxicology of Acetaminophen

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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

toxicology of acetaminophen

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