Acetaminophen is the most common pharmaceutical involved in overdose. As reported by the American Association of Poison Control Centers Toxic Exposure Surveillance System in 2003, acetaminophen overdose accounted for 10% of more than 1.3 million pharmaceutical exposures. Of the 350,000 exposures to pharmaceutical agents that resulted in some degree of toxicity, acetaminophen was involved in 21% of these cases. Of the 2,054 deaths resulting from pharmaceutical substances, 327 (16%) were attributed to acetaminophen either singly or in combination with at least one other substance. This is in contrast to 225 deaths from all stimulants and street drugs and 213 deaths from opioids reported during that same year. Children less than 6 years old accounted for 31% of all exposures to acetaminophen, and those from 6 to 19 years old accounted for 21%. However, of the 327 deaths associated with acetaminophen, only six were in children less than 6 years of age and seven were in those aged 6 to 19 years. Of those less than 6 years old, three deaths were the result of chronic therapeutic error, the cause of one was unknown, and one was the result of malicious intent. The final child died of an unintentional ingestion of acetaminophen, diphenhydramine, and iron. Of the seven children older than 6 years who died, all were older than 14 years; five had intended suicide, one cause was unknown, and one died as a result of a chronic therapeutic error. Of the 313 adults who died of acetaminophen overdose, 17 were more than 65 years old. Nine adults died as a result of therapeutic errors with the ingestion of acetaminophen alone or in combination with other products. Of these, six were older than 65 years of age.

These data emphasize the following key points: (a) acetaminophen is by far the single most common agent resulting in the highest number of pharmaceutical exposures; (b) despite its wide therapeutic index, acetaminophen exposure results in a disproportionate share of toxicity; (c) although children less than 6 years of age are overrepresented in the number of exposures to toxicity, nonetheless little major toxicity, including death, result; (d) most exposures in individuals greater than 6 years of age are the result of intended suicide; (e) the number of deaths caused by the ingestion of acetaminophen as a result of therapeutic error is disproportionately represented by those less than 6 and greater than 65 years of age; and (f) specific antidotal therapy (i.e. N-acetylcysteine [NAC]) improves the outcome of those who have experienced significant acute exposures.

The maximum adult therapeutic dose of acetaminophen is 1 g, four times a day at 4-hour intervals. The pediatric dose is 10 to 15 mg/kg, four to five times a day (total of 75 mg/kg/day). An acute overdosage of approximately 15 g is thought to be the threshold for production of toxicity in adults. For more than 25 years, the reported threshold dose for acute ingestion in children has been 150 mg/kg. However, this dose is empiric and extrapolated from adult data. More recent investigations and consideration of pharmacokinetic features unique to children suggest raising the level to 200 mg/kg. In single-dose ingestions, children younger than 6 years ingest less drug than adolescents. In adolescents, the overdose is either a suicide attempt or a manipulative episode, and handfuls of tablets typically are consumed. It has been difficult to define a “toxic” dose in those patients with prolonged supratherapeutic dosing. In adults, it is hypothesized that repeated supratherapeutic ingestion of 10 g/day for 2 days is associated with liver injury. In children, 150 mg/kg/day for 2 or more days is believed to be the threshold level that will produce toxicity.

Acetaminophen is absorbed rapidly after an oral therapeutic dose, producing a peak plasma level between 30 and 60 minutes after ingestion. This absorption may be delayed in overdose, so peak plasma levels may not occur until 4 hours after ingestion. Approximately 94% of the drug is metabolized to the glucuronide or sulfate conjugate; 2% is excreted unchanged in the urine. Neither the conjugated forms nor the unchanged forms are hepatotoxic. The remaining 4% is metabolized through the cytochrome P-450 mixed-function oxidase system, primarily CYP2E1 and, to a much less extent, CYP3A4, to form a toxic, electrophilic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). After therapeutic dosing, any NAPQI formed is conjugated with glutathione (GSH) to produce mercapturic acid, which is excreted in the urine.

With a significant overdose, the CYP2E1 enzyme system becomes increasingly important for metabolizing acetaminophen, and large amounts of NAPQI are formed. Hepatic GSH is the primary antioxidant that conjugates and neutralizes NAPQI. Liver GSH stores can be depleted with an acute or chronic overdose. When the liver GSH stores are sufficiently depleted, usually to approximately 70% of normal, NAPQI quickly accumulates. Although short-lived, NAPQI forms adducts with more than 40 cellular components, including deoxyribonucleic acid, lipids, enzymes, and cellular organelles. Because the CYP2E1 is primarily located in centrilobular hepatocytes (i.e., those around the central vein), injury initially is confined to this region. Oxidative stress, lipid peroxidation, and mitochondrial damage all play a role in the centrilobular necrosis. A second stage of injury then occurs involving Kupffer cells, cytokine release, and various reactive oxygen species that propagates injury beyond the centrilobular areas. These substances also signal hepatocyte proliferation and regeneration. If injury is limited, and hepatic regeneration is sufficient, liver recovery can be complete.

Organ systems other than the liver can be affected immediately after overdose, including the kidney (about 5% to 10% in one series) and central nervous system. Rarely, a renal defect occurs without concomitant hepatic damage. Elevation of pancreatic enzyme levels has been reported in as many as 22% of unselected patients.

Drug induction and disease interactions have been proposed to increase vulnerability to acetaminophen. The issue in each
case is whether the acetaminophen increases the production of NAPQI or impairs defences to the reactive metabolite (e.g., reduces GSH). Liver disease including hepatitis and cirrhosis and “starvation” were thought to result in reduced GSH levels, thus increasing the risk of NAPQI formation with overdose. Subsequent studies have proven that these assumptions were not correct. Phenytoin and phenobarbital, which increase total cellular P-450, were also thought to increase the toxic effects of acetaminophen. Neither phenobarbital nor any of the barbiturates increases CYP2E1; thus, these drugs do not affect acetaminophen metabolism. Phenytoin has no effect on CYP2E1 but does induce glucuronyl transferase, so it may potentially be hepatoprotective by increasing glucuronidation. Ethanol enhancement of acetaminophen toxicity has also been misunderstood. Ethanol consumption on a long-term basis may maximally induce CYP2E1 about twofold, and there is some depletion of GSH in alcoholic patients. Long-term heavy abusers of alcohol are therefore probably at greater risk for toxicity from an overdose of acetaminophen, but not from therapeutic doses. In contrast, the acute coingestion of alcohol and acetaminophen in children and adults appears to be hepatoprotective. This is likely because the alcohol competes with acetaminophen at the CYP2E1-binding site.

As stated earlier, children younger than 6 years have different patterns of toxicity and are half as likely to develop acetaminophen plasma levels in the toxic range compared with adolescents and adults. Several mechanisms for decreased toxicity in children less than 6 years old have been postulated, including (a) higher turnover rates of GSH, resulting in more glutathione available for detoxification; (b) increased rates of sulfatization; (c) spontaneous vomiting after ingestion; and (d) increased ratio of liver to body weight, in effect providing increased ability to detoxify acetaminophen.

The manifestations of acute acetaminophen poisoning are well described, and the clinical course of acetaminophen toxicity has four stages (Table 121.1). In the first stage (i.e., first 24 hours), adult and adolescent patients develop nausea, vomiting, diaphoresis, and general malaise. Children younger than 6 years show little diaphoresis and vomit earlier. Young children often develop vomiting regardless of the acetaminophen level and may have no other symptoms unless the blood level is in the toxic range. Symptoms usually develop within 12 hours in patients with toxic levels of acetaminophen. Evidence of liver injury as reflected by elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and prolongation of prothrombin time may appear as early as 8 hours after overdose, and more than one-half of all patients with liver injury develop some elevation of these values within 24 hours. Lethargy is rarely seen during this stage. If lethargy develops, some other agent should be considered in addition to or instead of the acetaminophen. During the second stage, most patients begin to feel better. If no treatment was received or treatment was unsuccessful, the levels of AST, ALT, international normalized ratio (INR), and/or partial thromboplastin time (PTT) rise. Patients who have elevations of AST or ALT levels greater than 1,000 IU/L commonly demonstrate other evidence of liver dysfunction by 24 to 72 hours after overdose, including elevations in bilirubin.

During the third stage, from 72 to 96 hours after ingestion and as early as 48 hours, transaminase levels as high as 50,000 IU/L may be seen in patients with severe acetaminophen overdoses. Examination of the liver at this point demonstrates centrilobular necrosis. In the final stage, within 14 days of ingestion, hepatic abnormalities should return to normal. Follow-up evaluations of patients who experienced significant hepatotoxicity and survived reveal no sequelae clinically or on hepatic biopsy. Patients who ultimately die or who require liver transplantation progress to hepatic necrosis, including jaundice, coagulation defects, hepatorenal syndrome, and hepatic encephalopathy. Some degree of renal injury develops in almost 50% of patients with severe liver injury. However, renal failure is reversible if the patient survives.

Coma with metabolic acidosis is an unusual but well-documented presentation of acute severe acetominophen poisoning. There have been several reports of comatose patients presenting with metabolic acidosis and a very high acetaminophen level (greater than 800 mg/L), with very little evidence of liver injury. Prompt treatment with NAC can prevent liver injury in these patients.

After acute and subacute overdosage of acetaminophen, one must determine the need for treatment with the antidote for acetaminophen, NAC. The Rumack-Matthew nomogram uses a timed plasma acetaminophen level drawn at least 4 hours after ingestion to establish the likelihood of liver injury (Fig. 121.1). This nomogram was empirically derived from 64 patients with untreated acetaminophen poisoning at the Edinburgh poison treatment center. A line connecting a point at 200 μg/mL at 4 hours after ingestion and 50 μg/mL at 12 hours after ingestion was found to separate all patients with liver injury from those in whom liver injury did not develop. As shown in Figure 121.1,
there is a second line created 25% below the original line as the “possible hepatic toxicity” line. This modification of the nomogram was requested by the Food and Drug Administration, to allow for possible errors in either the measurement of acetaminophen plasma levels or the estimated time from ingestion. In the United States, NAC administration is begun if the acetaminophen level falls above the lower 4-hour line (i.e., 150 μg/mL). In patients who have acute ingestion of extended-release formulations of acetaminophen, it is recommended that at least two serial acetaminophen levels be performed at least 4 to 6 hours apart. The nomogram is not useful in suspected toxicity with long-term or prolonged ingestion of therapeutic doses.