Episode 203: Acetaminophen Toxicity

Dec 2, 2024

Marlis Gnirke, a toxicologist and assistant professor at NYU Bellevue, dives deep into the complexities of acetaminophen toxicity. She highlights the surprising presence of acetaminophen in various over-the-counter products, leading to unintentional overdoses. Gnirke discusses the formation of the toxic metabolite NAPQI and its devastating effects on the liver. The conversation also touches on the pivotal role of N-acetylcysteine (NAC) as an antidote and introduces the Rumack-Matthew Nomogram for effective treatment planning.

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ADVICE

Hidden Acetaminophen

Ask patients about acetaminophen intake specifically, not just Tylenol.
Acetaminophen is present in many OTC and prescription medications, increasing unintentional overdose risk.

INSIGHT

Acetaminophen Metabolism and Toxicity

Acetaminophen overdose saturates normal metabolic pathways, leading to increased NAPQI, a toxic metabolite.
Excessive NAPQI depletes glutathione, causing liver cell death, especially in zone 3.

INSIGHT

Clinical Stages of Toxicity

Acetaminophen toxicity progresses in four stages, with early stages often asymptomatic.
Check acetaminophen levels early, even in asymptomatic patients, due to the potential for silent progression.

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We sit down with one of our toxicologists to discuss acetaminophen toxicity.

Hosts:
Marlis Gnirke, MD
Brian Gilberti, MD

Download One Comment Tags: Toxicology

Show Notes

0:35 – Hidden acetaminophen toxicity in OTC products

3:24 – Pharmacokinetics and toxicokinetics

6:06 – Clinical Course

9:22 – The antidote – NAC

11:02 – The Rumack-Matthew Nomogram

17:36 – Treatment protocols

22:34 – Monitoring and Lab Work

23:23 – Considerations when treating pediatric patients

23:57 – IV APAP overdose, fomepizole

25:42 – Take Home Points

Acetaminophen vs. Tylenol:

The importance of recognizing that acetaminophen is found in many products beyond Tylenol.
Common medications containing acetaminophen, such as Excedrin, Fioricet, Percocet, Dayquil/Nyquil, and others.
The risk of unintentional overdose due to combination products.

Prevalence of Acetaminophen Toxicity:

Widespread availability and under-recognition contribute to its prevalence.
The potential for unintentional overdose when taking multiple medications containing acetaminophen.

Pharmacokinetics and Metabolism:

Normal metabolism pathways of acetaminophen and the role of glutathione.
Formation of the toxic metabolite NAPQI during overdose situations.
Saturation of safe metabolic pathways leading to hepatotoxicity.

Pathophysiology of Liver Injury:

How excessive NAPQI leads to hepatocyte death, especially in zone III of the liver.
The difference between therapeutic dosing and overdose metabolism.

Clinical Stages of Acetaminophen Toxicity:

Stage 1: Asymptomatic or nonspecific symptoms (first 24 hours).
Stage 2: Onset of hepatic injury (24-72 hours), elevated AST/ALT.
Stage 3: Maximum hepatotoxicity (72-96 hours), signs of liver failure.
Stage 4: Recovery phase, complete hepatic regeneration if survived.

Antidote – N-Acetylcysteine (NAC):

Mechanisms of NAC in replenishing glutathione and detoxifying NAPQI.
The importance of early administration, ideally within 8 hours post-ingestion.
NAC’s role even in late presenters and in fulminant hepatic failure.

The Rumack-Matthew Nomogram:

How to use the nomogram for acute overdoses to determine the need for NAC.
Limitations in chronic overdoses and late presentations.
Emphasis on obtaining accurate time of ingestion and acetaminophen levels.

Treatment Protocols:

Standard 21-hour IV NAC protocol and dosing specifics.
Managing anaphylactoid reactions associated with IV NAC.
Criteria for extending NAC therapy beyond 21 hours.

Monitoring and Laboratory Work:

Importance of trending AST/ALT, INR, creatinine, lactate, and phosphate.
Use of the King’s College Criteria for potential liver transplant evaluation.

Special Considerations:

Adjustments in pediatric patients regarding NAC dosing volumes.
Awareness of IV acetaminophen overdoses and their management.
Emerging discussions on the use of fomepizole in massive overdoses.

Take-Home Points:

Comprehensive Medication History: Always inquire about all medications taken to assess for potential acetaminophen exposure.
Early Recognition and Treatment: Due to often silent initial stages, maintain a high index of suspicion and measure acetaminophen levels promptly.
Understanding Metabolism and Toxicity: Recognize how overdose alters metabolism, leading to toxic NAPQI accumulation.
N-Acetylcysteine Efficacy: NAC is most effective when administered early but remains beneficial even in advanced stages.
Proper Use of the Nomogram: Utilize the Rumack-Matthew Nomogram appropriately for acute ingestions and consult toxicology when in doubt.
Monitoring and Continuing Care: Be vigilant in monitoring laboratory values and prepared to extend NAC therapy as needed.
Consultation and Resources: Engage with poison control centers and utilize available resources for complex cases.

Resources Mentioned

Rumack-Matthew Nomogram

Rumack-Matthew Nomogram, credit: MDCalc

King’s College Criteria

King’s College Criteria for Acetaminophen Toxicity
Use this tool to assess the need for liver transplant evaluation in cases of acetaminophen-induced hepatic failure. Includes criteria for pH, INR, creatinine, and more.

Poison Control Center (available 24/7 for consultation): 1-800-222-1222

References

Goldfrank’s Toxicologic Emergencies, 9th Edition was consulted for information on the pharmacokinetics and clinical presentation of acetaminophen toxicity.
For more details, see: Nelson, L. S., Howland, M. A., Lewin, N. A., Smith, S. W., Goldfrank, L. R., & Hoffman, R. S. (Eds.). (2011). Goldfrank’s toxicologic emergencies (9th ed.). McGraw-Hill Education.