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Acetaminophen is one of the most commonly used analgesic and anti-pyretic agents. The foremost brand is Tylenol, but acetaminophen is present in more than 200 brand name analgesics.  It is available in tablet, caplet, liquid and suppository form. Absorption is rapid and therapeutic levels are obtained within 40 to 120 minutes after ingestion.  Peak levels are reached within 2 to 4 hours after ingestion. Half-life for acetaminophen elimination is 2 to 4 hours. The potentially toxic dose for an adult is only about 10 fold higher than the usual therapeutic dose of 650 to 1000 mg.  For this reason, acetaminophen is one of the most common drugs involved in accidental or intentional overdoses.

Clinically, acetaminophen overdose has 4 recognized stages:

Stage Time Symptoms
1 First 24 hours Nausea, vomiting, anorexia, diaphoresis
2 24 to 48 hours RUQ tenderness, elevated transaminases
3 Day 3 to 4 Jaundice, coagulopathy, renal failure, encephalopathy, hypoglycemia
4 Day 4 to 14 Death or recovery


Acetaminophen is a dose-related toxin. Most ingestions leading to acute liver failure exceed 10 g/day (> 150 mg/kg/day). Moderate chronic ingestion of approximately 4 g/day, usually leads to transient mild elevation of liver enzymes in healthy individuals, but can in rare cases cause acute liver failure. Chronic use of alcohol or drugs, such as barbiturates or isoniazid, increases susceptibility.

After ingestion, 52% to 57% of acetaminophen is converted by the liver to glucuronide conjugates, and 30% to 44% to sulfate conjugates. These conjugates are nontoxic, water-soluble, and rapidly excreted in the urine.

Approximately 5 to 10% of ingested acetaminophen is metabolized by the cytochrome P-450 system. P450 2E1 is the main isoenzyme involved in acetaminophen metabolism, but 1A2, 3A4, and 2A6 also contribute. P450 2E1 is the same isoenzyme responsible for ethanol metabolism and is inducible. Regular alcohol consumption can induce P450 2E1 activity and increase acetaminophen metabolism through this pathway.

Metabolism of acetaminophen through the cytochrome P450 pathway results in production of N-acetyl-p-benzoquinone imine (NAPQI), which depletes glutathione stores. When glutathione becomes depleted, NAPQI binds to intracellular proteins with sulfhydryl groups causing cellular dysfunction and hepatic necrosis.

N-Acetylcysteine (NAC) is a precursor to glutathione that increases the amount of glutathione available to bind NAPQI and prevent hepatocellular injury. The effectiveness of NAC diminishes rapidly by 12 to 24 hours after acetaminophen ingestion. 

Obtaining an accurate time of ingestion is a critical factor in accurately interpreting serum acetaminophen levels.  A single blood sample should be collected at least 4 hours after ingestion to ensure that the absorptive phase is complete.  The result is then plotted on a Rumack-Matthew nomogram to assess the risk of hepatotoxicity (Arch Intern Med 1981; 141:382). The upper broken line is called the “probable toxicity line” and represents the cutoff level at which 60% of patients above the line would develop severe hepatotoxicity.  The solid line below is the “possible toxicity line”; 25% of patients between this line and the probable toxicity line develop severe hepatotoxicity.  If the acetaminophen level lies above the broken line, a full course of acetylcysteine therapy is usually administered.  If the level falls below the broken line, treatment is usually not necessary or can be discontinued.  This nomogram is limited to a single acute ingestion identified within 24 hours of the overdose. Overdoses with enteric coated or sustained-released acetaminophen do not follow the Rumack nomogram. 

For children who have ingested liquid acetaminophen elixir, treatment decisions may be reliably made at hours post ingestion since absorption is so rapid.  The suggested treatment threshold at two hours is an acetaminophen plasma level of 225 ug/mL. 

If the time of ingestion is unknown, two serum levels should be drawn during an 8-hour period. If the half-life exceeds 4 hours, hepatotoxicity is likely. It may be necessary to draw a 12-hour sample to determine serum half-life in patients taking multiple drugs.  Some co-ingestants, such as alcohol, slow GI motility, thereby increasing both the severity and duration of acetaminophen levels.  Anticonvulsants also increase the toxicity of acetaminophen. 

Therapeutic range is;

0 - 12 years old 10 - 20 ug/mL
>12 years old 0 - 49 ug/mL


Enzyme-based, colorimetric methods for acetaminophen measurement are based on the conversion of acetaminophen to p-aminophenol and subsequent reaction with o-cresol to form a blue-colored indophenol. The formation of this compound is measured by a change in absorbance at a wavelength of 600 nm. Elevated levels of bilirubin may increase background absorbance at this wavelength and cause a falsely positive acetaminophen result.

Specimen requirement is one SST or one green top (heparin) tube of blood. 

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