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