Acetaminophen (Tylenol) is a common over the counter analgesic and antipyretic.  The recommended adult dosage is 650 to 1000 mg every 4 to 6 hours with a maximum dosage of 4000 mg in 24 hours.  The recommended pediatric dosage is 15 mg/kg every 4 to 6 hours with a maximum of five doses in a 24 hour period.  In appropriate doses it is a relatively safe medication; however, excessive doses may prove fatal when ingested intentionally or accidentally.  Concomitant combination narcotic/acetaminophen and OTC acetominophen ingestion is not uncommon.  Patients should be warned not to take acetaminophen while on combination analgesics.  Also, patients who abuse alcohol or have advanced underlying liver disease may be at risk of acetaminophen’s potential for hepatotoxicity at lower dosages.  Acetaminophen undergoes hepatic metabolism into nontoxic products; however, approximately 5% of the drug is metabolized by the cytochrome P450 system and results in the production of N-acetyl-p-benzoquinoneimine which is a toxin.  Normally, any formed N-acetyl-p-benzoquinoneimine is quickly inactivated by hepatic stores of glutathione.  In situations of overdosage, underlying iver disease, or alcoholism, hepatic stores of glutathione are either overwhelmed or depleted such that N-acetyl-p-benzoquinoneimine metabolism is impaired resulting in the accumulation of this toxic product.  As N-acetyl-p-benzoquinoneimine accumulates it destroys hepatocytes resulting in liver injury.  Toxicity may also occur at normal dosages in persons on concomitant drugs that induce cytochrome P450 enzymes thus leading to increased metabolism to N-acetyl-p-benzoquinoneimine. Hepatic toxicity may occur following ingestion of greater than 7.5 grams of acetaminophen in a brief period of time (less than 8 hours).  The risk of fatality increases in dosages over 15 grams.

     Symptoms of toxicity occur in phases.  Phase I occurs for 12 to 24 hours after ingestion and includes gastrointestinal distress, nausea, vomiting, anorexia, diaphoresis, and pallor.  In phase II, phase I symptoms abate and patients improve clinically; however, liver enzymes, prothrombin time and bilirubin values will increase dramatically.  Patients in phase II may also develop right upper quadrant pain.  Symptoms of phase III (3 to 5 days following ingestion) include anorexia, nausea, malaise, abdominal pain, confusion, and stupor.  Associated symptoms of hepatic damage include jaundice, hypoglycemia, and encephalopathy.  Renal failure and cardiomyopathy may also occur during phase III.

     In order to determine the potential for hepatotoxicity following the ingestion of excessive doses, a plasma or serum acetaminophen level should be determined 4 hours after the ingestion occurred.  It is important to determine the time of ingestion as accurately as possible.  Assays drawn sooner than 4 hours postingestion can not be plotted on the overdose nomogram and therefore are of little value.  If the time of ingestion is in question, use the earliest possible ingestion time.  If an assay can not be drawn, assume the overdose is toxic.  The assay value is then plotted on the overdose nomogram against the post ingestion time in hours.  Four hour values above the Rumack-Matthew line are associated with an increased risk for hepatotoxicity.  Four hour values above the treatment line (25% below the Rumack-Matthew line) should also be treated.  Four hour values below the treatment line are associated with only a minimal risk of hepatotoxicity and do not require therapy, and if empiric therapy has already been started, it may be discontinued.

     In the immediate postingestion period (up to 4 hours), activated charcoal should be administered.  Specific therapy for acetaminophen overdose is with N-acetylcysteine (NAC).  It is important to initiate therapy within eight hours post ingestion.  Therapy is initiated with a loading dose of 140 mg/kg of NAC followed by 70 mg/kg administered orally every four hours over a 72 hour period.  If emesis occurs within one hour of administration, repeat the dose.  In patients with repeated emesis, initiate antiemetic therapy or administer NAC intravenously.  Questions regarding individual cases should be directed to the Rocky Mountain Poison and Drug Center at 1-800-525-6115.

     In patients who require NAC therapy, monitor the AST and/or ALT levels daily.  If there is an elevation noted, determine the bilirubin, prothrombin time, creatinine, BUN, glucose, electrolyte, and pH level.  If fulminant hepatic failure develops, liver transplantation may be necessary.