Acetaminophen (Tylenol)

Indications

  • Fever (see Fever, [[Fever]])
  • Pain
  • xxxx

Pharmacology

  • Inhibition of Prostaglandin Synthesis in the Central Nervous System (Probable)
  • Peripheral Inhibition of Pain Impulse Generation (Probable)
  • Inhibition of Hypothalamic Heat-Regulatory Center: anti-pyretic effect

Metabolism

  • xxx
  • Acetaminophen is the primary metabolite of phenacetin: phenacetin has historically been associated with analgesic nephropathy

Development of Pyroglutamic Acidosis (see Pyroglutamic Acidosis, [[Pyroglutamic Acidosis]])

  • The acetaminophen metabolite N-acetylbenzoquinonimine reacts irreversibly with glutathione
  • Precursors accumulate as they are unable to be converted to glutathione because of depletion or inhibition of the rate-limiting enzyme glutathione synthetase
  • Therefore, in the absence of glutathione, N-acetylbenzoquinonimine forms hepatotoxic compounds

Administration

  • PO:

Dose Adjustment

  • Hepatic
  • Renal

Adverse Effects

Allergic/Immunologic Adverse Effetcs

Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]])

  • Epidemiology:

Gastrointestinal/Hepatic Adverse Effects

Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]])

  • Epidemiology: questionable association

Elevation of Hepatic Transaminases with Hepatocellular Injury (see Drug-Induced Hepatotoxicity, [[Drug-Induced Hepatotoxicity]])

  • xxxx

Hematologic Adverse Effects

Doubtful Risk of Hemolysis in Patient with G6PD Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency, [[Glucose-6-Phosphate Dehydrogenase Deficiency]] and Hemolytic Anemia, [[Hemolytic Anemia]])

  • xxxx

Renal Adverse Effects

Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])

  • xxxx

Anion Gap Metabolic Acidosis (AGMA) (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]])

  • Epidemiology: associated with chronic acetaminophen ingestion in malnourished females
  • Physiology: associated with pyroglutamic acidosis (an organic acidosis), associated with pyroglutamic aciduria (5-oxoprolinuria) (see Pyroglutamic Acidosis, [[Pyroglutamic Acidosis]])

Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])

  • Epidemiology: data suggesting that chronic acetaminophen (paracetamol) use may result in chronic kidney disease is suggestive, but not conclusive [MEDLINE]

Toxicologic Adverse Effects

Methemoglobinemia (see Methemoglobinemia, [[Methemoglobinemia]])

  • xxxx

Other Adverse Effects

  • xxxxx

Acetaminophen Intoxication

Epidemiology

  • Acetaminophen overdose (intentional and unintentional) is a leading cause of acute liver failure in the United States

Physiology

  • A single dose of >10-15 g can cause acute liver failure in an adult
  • The degree of liver damage caused by acetaminophen can be effectively ameliorated in the vast majority of cases when N-acetylcysteine is given (PO or IV) within 4-8 hrs post-ingestion

Diagnosis

  • Acetaminophen Level: post-ingestion level should be used with Rumack-Matthew nomogram

Clinical

Treatment

General Treatment of Acetaminophen Intoxication

  • Oral Activated Charcoal (see Activated Charcoal, [[Activated Charcoal]]): oral activated charcoal after gastric lavage is also indicated up to 4 hrs after ingestion, but is not helpful later
  • Hemodialysis: not indicated for treatment of acetaminophen toxicity, but may be required if acute renal failure develops
  • N-Acetylcysteine (Mucomyst, Acetadote, Fluimucil, Parvolex) (see N-Acetylcysteine, [[N-Acetylcysteine]])
    • Indications: while N-acetylcysteine should still be administered to any person with hepatic dysfunction after an acetaminophen overdose (regardless of time from ingestion), starting therapy after 24 hrs is much less likely to prevent progression of liver failure and mortality is significantly higher in this late-treatment group
    • Mechanism: sulfhydryl donor
    • Administration
      • PO (Mucomyst): 140 mg/kg PO x 1 dose, then 70 mg/kg PO q4hrs x 17 doses
      • IV (Acetadote)
    • Efficacy of Prolonged Administration
      • In a small, prospective study, IV N-acetylcysteine demonstrated improved outcomes in patients who had acetaminophen-related liver failure when N-acetylcysteine was continued until clinical improvement and an INR <2 was achieved
      • A retrospective trial also demonstrated the benefit of prolonged N-acetylcysteine infusion

Treatment of Fulminant Hepatic Failure

  • Treatment of Cerebral Edema (see Increased Intracranial Pressure, [[Increased Intracranial Pressure]]): leading cause of death within the first week after acetaminophen-related fulminant hepatic failure
    • Intracranial Pressure (ICP) Monitoring
    • Therapies to ameliorate cerebral edema have not been demonstrated to improve outcome, independent of liver transplantation
  • Treatment of Renal Failure: hemodialysis may be required
  • Liver Transplantation: transfer to a liver transplantation center is recommended prior to onset of hepatic encephalopathy
    • Intentional ingestion is not considered an absolute contraindication for hepatic transplantation

Prognosis

  • Risk Factors for Poor Outcome (in absence of hepatic transplantation): degree of transaminase elevation and timing of fall in transaminases do not predict outcome
    • Delay in Starting N-Acetylcysteine: later than 24 hrs post-ingestion
    • Metabolic Acidosis
    • Grade III/IV Hepatic Encephalopathy
    • Acute Renal Failure
    • Rising INR
    • Hypoglycemia: usually late

References

  • Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:439-445 [MEDLINE]
  • Anaphylactic shock induced by paracetamol. Eur J Clin Pharmacol. 1990;38(4):389 [MEDLINE]
  • Intravenous acetylcysteine in paracetamol-induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991;26:1026-29 [MEDLINE]
  • Paracetamol anaphylaxis. Clin Exp Allergy. 1992;22(9):831 [MEDLINE]
  • A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology. 1995;109:1907-1916 [MEDLINE]
  • Acetaminophen and adverse chronic renal outcomes: an appraisal of the epidemiologic evidence. Am J Kidney Dis. 1996;28(1 Suppl 1):S14 [MEDLINE]
  • Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:947-954 [MEDLINE]
  • Acetaminophen-induced anion gap metabolic acidosis and 5-oxoprolinuria (pyroglutamic aciduria) acquired in hospital. Am J Kidney Dis. 2005 Jul;46(1):143-6 [MEDLINE]
  • Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin J Am Soc Nephrol. 2006 May;1(3):441-7. Epub 2006 Apr 19 [MEDLINE]
  • Acetaminophen hepatotoxicity. Clin Liver Dis. 2007;11:525-548 [MEDLINE]
  • Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008;359:285-92 [MEDLINE]