Acetaminophen overdose: Science and Resources

Acetaminophen overdose: the numbers
The physiology of acetaminophen overdose
Mechanism of Action
Treating acute acetaminophen overdose
When time is liver, timing is critical
Interpreting acetaminophen assay results
Liver function tests
Discontinuing treatment
Products containing acetaminophen
Resources

Acetaminophen overdose: the numbers

In the U.S. more than 28 billion doses of medicines containing acetaminophen are purchased each year.1

  • From 1998 to 2003, acetaminophen was the leading cause of acute liver failure (ALF) in the United States, with 48% of acetaminophen-related cases (131 of 275) associated with accidental overdose
  • A 2007 CDC population-based report estimates that, nationally, there are 1,600 cases of ALF each year (all causes). Acetaminophen-related ALF was the most common etiology

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The physiology of acetaminophen overdose2

Acetaminophen Metabolism
Acetaminophen Metabolism Chart
  • Acetaminophen is metabolized through 3 different pathways:
    • 42% to 67% undergoes glucuronidation and is excreted in urine
    • 26% to 36% undergoes sulfation and is excreted in urine
    • 5% to 8% passes through the cytochrome P-450 pathway producing a potentially hepatotoxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI)
  • In normal dosing, NAPQI is conjugated with the antioxidant, glutathione, and excreted in urine

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Mechanism of Action

Overdose depletes the available glutathione and unbound NAPQI destroys liver cells.2

IV Acetadote protects liver cells in 2 ways:

  • It helps replenish glutathione
  • It binds to and removes NAPQI
IV Acetadote protects liver cells in 2 ways:

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Treating acute acetaminophen overdose

  • The maximum adult therapeutic dose of acetaminophen is 4 grams/24 hours3
  • The maximum dose for children is 90 mg/kg4
  • Acute overdose is defined as ingestion of ≥ 150 mg/kg or 7-10 grams/24 hours4
Four stages of acetaminophen overdose5
Four stages of acetaminophen overdose

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When time is liver, timing is critical

Treatment Flow Chart
  • The critical ingestion-treatment interval for maximum protection against severe hepatic injury is between 0-8 hours.
Treatment Flow Chart

*Acetaminophen levels drawn less than 4 hours post-ingestion may be misleading.
†With an extended-release preparation, an acetaminophen level drawn less than 8 hours post-ingestion may be misleading. Draw a second level at 4 to 6 hours after the initial level. If either falls above the toxicity line, acetylcysteine treatment should be initiated.
‡Acetylcysteine may be withheld until acetaminophen assay results are available as long as initiation of
treatment is not delayed beyond 8 hours post-ingestion. If more than 8 hours post-ingestion, start acetylcysteine treatment immediately.

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Interpreting acetaminophen assay results

  • Plot acetaminophen serum level and time since overdose on the Rumack-Matthew nomogram
  • Initiate treatment if the values fall in the probable and/or possible hepatotoxicity range
Plasma or Serum Acetaminophen Concentration vs Time Post Acetaminophen Ingestion6,7
Plasma or Serum Acetaminophen Concentration vs Time Post Acetaminophen Ingestion

This nomogram is not applicable for patients with Repeated Supratherapeutic Ingestion (RSI). RSI is defined as ingestion of acetaminophen at doses higher than those recommended for extended periods of time.

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Liver function tests

Liver function tests can help determine hepatic injury

Liver function tests

Other helpful tests include:

  • Bilirubin
  • INR

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Discontinuing treatment

Assess patients before discontinuing treatment

Before discontinuing Acetadote, draw acetaminophen levels and liver function tests.

If ≥ 10 µg/mL of acetaminophen or AST/ALT >1000 IU/L,

consult your local poison control center to determine if continuation of therapy with Acetadote should be considered.

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Comprehensive List of OTC and prescription products
containing acetaminophen

For the most up-to-date information please visit the National Library of Medicine.

Resources

National Poison Control Center
1-800-222-1222
http://www.nlm.nih.gov/medlineplus/ency/article/002724.htm

American Association of Poison Control Centers (AAPCC)
www.aapcc.org

CDC
http://www.nlm.nih.gov/medlineplus/ency/article/002598.htm

e-Medicine: Acetaminophen Toxicity
http://emedicine.medscape.com/article/820200-overview

Pediatric Toxicity
http://emedicine.medscape.com/article/1008683-overview

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Selected Articles

  1. Acetaminophen Poisoning. Merck Manuals Online Medical Library for Healthcare Professionals. Available at: http://www.merckmanuals.com/professional/print/sec22/ch346/ch346b.html.
  2. Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatr. 1999;135:290-295.
  3. Bizovi KE, Aks SE, Paloucek F, Gross R, Keys N, Rivas J. Late increase in acetaminophen concentration after overdose of Tylenol Extended Relief. Ann Emerg Med. 1996;28:549-551.
  4. Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Population-based surveillance for acute liver failure. Am J Gastroenterol. 2007;102:2459-2463.
  5. Heard KJ, Green JL, James LP, et al. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose. BMC Gastroenterol. 2011. Available at: http://www.biomedcentral.com/content/pdf/1471-230X-11-20.pdf. Accessed May 10, 2010.
  6. Jaeschke H, McGill MR, Williams CD, Ramachandran A. Current issues with acetaminophen hepatotoxicity-a clinically relevant model to test the efficacy of natural products. Life Sci. 2011. [Epub ahead of print]
  7. Lee W. Drug-induced hepatotoxicity. New Eng J Med. 2003; 349:474-485. Available at: http://gastro.dom.uab.edu/Fellow_Articles/fellowsreadinglisthep/drug%20hepatotoxicity.pdf
  8. Mayhew M. Acetaminophen toxicity. J Nurs Practitioners. 2007;3:186-188. Available at: http://www.medscape.com/viewarticle/557074.
  9. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876.
  10. Stumpf JL, Skyles AJ, Alaniz C, Erickson SR. Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population. J Am Pharm Assoc. 2007;47:35-41.

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Indication

Acetadote, administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen, is indicated to prevent or lessen hepatic injury.

For maximal protection against hepatic injury, administer Acetadote within 8 hours post-ingestion.

Efficacy diminishes progressively after 8 hours and treatment initiation between 15 and 24 hours post-ingestion of acetaminophen yields limited efficacy.

Important Safety Information

Acetadote is contraindicated in patients with hypersensitivity or previous anaphylactoid reactions to acetylcysteine or any components of the preparation. Serious anaphylactoid reactions, including death in a patient with asthma, have been reported in patients administered acetylcysteine intravenously.

Acetadote should be used with caution in patients with asthma, or where there is a history of bronchospasm. The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. To avoid fluid overload, the volume of diluent should be reduced as needed. If volume is not adjusted, fluid overload can occur, potentially resulting in hyponatremia, seizure, and death.

In the literature, the most frequently reported adverse reactions attributed to IV acetylcysteine administration were rash, urticaria and pruritus. The frequency of adverse reactions has been reported to be between 0.2% and 20.8%, and they most commonly occur during the initial loading dose of acetylcysteine.

View full Prescribing Information

References

  1. FDA. Drugs, Drug Safety and Risk Management Committee. Acetaminophen overdose and liver injury – background and options for reducing injury. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM164897.pdf. Accessed June 1, 2011.

  2. Background package on acetaminophen. Acetaminophen metabolism. McNeil Pharmaceuticals. Available at: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3882B1_13_McNeil-Acetaminophen.htm#_Toc18717570. Accessed May 24, 2011.

  3. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42:1364-1372.

  4. Farrell SE. Toxicity, acetaminophen: Background. E-medicine. Available at : http://emedicine.medscape.com/article/820200-overview. Accessed June 1, 2011.

  5. Acetaminophen poisoning. Merck Manual. Available at: http://www.merckmanuals.com/professional/sec21/ch326/ch326c.html. Accessed May 24, 2011. Accessed May 24, 2011.

  6. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876.

  7. Rumack BH, Peterson RC, Kock GG, et al. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141:380-385.

  8. Farrell SE. Toxicity, acetaminophen: differential diagnosis and workup. E-medicine. Available at : http://emedicine.medscape.com/article/820200-workup. Accessed May 24, 2011.

  9. Johns Hopkins POC-IT Center. Liver function. Available at: http://www.hopkins-diabetesguide.org/clinical_tests/gastrointestinal/liver_function.html?contentInstanceId=528526. Accessed May 24, 2011.

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