Acetaminophen Toxicity: Mechanisms and Management

Show Notes

Table of Contents

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.