Acetaminophen (N-acetyl-para-aminophenol [APAP]) is a nonnarcotic analgesic with excellent antipyretic activity but almost no anti-inflammatory effects. It belongs to the same drug family as phenacetin and acetanilid, the coal tar or aminobenzene analgesics [1,2]. Although APAP is the active metabolite of phenacetin, unlike phenacetin it rarely, if ever, causes nephrotoxicity and does not cause methemoglobinemia and hemolytic anemia. Unlike aspirin, APAP has no barrier-breaker effect on the gastrointestinal tract and no effect on platelet function, has a high therapeutic index, and has not been implicated as a factor in Reye’s syndrome. As a result, APAP is the preferred agent
for the treatment of fever and mild to moderate pain when anti-inflammatory and antiplatelet action is not important.

Acetaminophen is an active ingredient in several hundred products, including pure APAP formulations, combinations with opioid analgesics, and numerous combination cough and cold preparations. It is also available in an extended-release (ER) formulation (which contains 325 mg of immediate-release and 325 mg of delayed-release acetaminophen per tablet) and as a suppository, but there is no commercial intravenous formulation.

Acetaminophen has a pK_a of 9.5 and is quickly and almost completely absorbed after ingestion of therapeutic doses of immediate-release formulations (10 to 15 mg per kg every 4 hours), yielding peak plasma concentrations between 5 and 20 μg per mL within 30 to 120 minutes. Clinical effects are noted within 30 minutes. Liquid preparations are absorbed slightly faster than solid formulations. Rectal absorption is similar to that of oral ingestion. The volume of distribution of APAP is 0.9 to 1.0 L per kg, and protein binding is negligible. Therapeutic plasma concentrations range from 10 to 20 μg per L, and elimination after therapeutic dosing follows first-order kinetics, with an average half-life of 2 to 4 hours [1]. Elimination is slower in neonates and young infants [3], the elderly [2], and in patients with hepatic dysfunction [4]. Clinical effects persist for 3 to 4 hours after therapeutic doses.

After overdose, peak acetaminophen levels are usually noted within 4 hours. The ingestion of very large doses and the concomitant ingestion of agents that delay gastric emptying (e.g., anticholinergics and opioids) may result in peak levels occurring later. Prolonged absorption with a late rise in the acetaminophen level has also been reported after an ER overdose [5].

The short- or long-term therapeutic use of APAP is rarely associated with adverse effects. Hypersensitivity reactions, such as urticaria, fixed drug eruption, angioedema, laryngeal edema, and anaphylaxis, are extremely rare [6]. Although high-dose APAP has been associated with chronic renal impairment [7], a cause-effect relationship has not been established.

Despite remarkable safety in appropriate doses, APAP can cause fatal hepatic necrosis after overdosage. This was first recognized in Europe more than 40 years ago and the first cases of hepatotoxicity in the United States were reported in 1975. Since that time, the incidence of APAP poisoning has increased dramatically in parallel with its increased availability and use; APAP is now the most common drug involved in exposures reported to US poison control centers, accounting for more than 140,000 calls in 2007 [8]. The incidence of occult poisoning is unknown, but based on retrospective data approximately 1 of every 70 overdose patients have a detectable acetaminophen concentration and 1 in 500 a potentially toxic APAP ingestion [9].

The metabolism of APAP explains its toxicity and the rationale for the current treatment of overdose (Fig. 118.1) (Table 118.1) [2]. After therapeutic doses, approximately 90% of APAP metabolism occurs by hepatic conjugation with sulfate or glucuronide to form inactive, nontoxic, renally eliminated metabolites. In adults, glucuronidation is the predominant route; in infants and young children, sulfation is the major pathway. Less than 5% of APAP is eliminated unchanged in the urine. The small remaining fraction (approximately 5%) undergoes oxidation by the P450 mixed-function oxidase enzyme system (CYP2E1) to yield the highly reactive, potentially toxic, electrophilic intermediate N-acetyl-para-benzoquinoneimine (NAPQI) [10]. NAPQI is quickly detoxified by reduced glutathione (GSH) to form nontoxic cysteine and mercapturic acid conjugates that are excreted in the urine.

After overdose, the amount of drug metabolized by the P450 route increases, because of a greater total drug burden and saturation of alternative enzymatic pathways [11]. As a result, GSH utilization increases. If GSH regeneration is inadequate to meet demand and becomes significantly depleted, NAPQI can persist and react with hepatocyte macromolecules, resulting in the death of hepatocytes. In animal studies, such injury occurs when GSH stores reach less than 30% of normal [12]. Hepatocyte necrosis is most pronounced in areas of highest CYP2E1 activity: the centrilobular (central venule) zones of the liver. The degree of injury can range from asymptomatic
elevations in aminotransferase levels to fulminant liver failure. Although far less common, the same process can occur in the kidney [13]. Very rarely, renal toxicity can occur in the absence of serious hepatotoxicity [14].

Pancreatitis, in some cases fulminant, can occur, and diffuse myocardial necrosis has been noted in fatal cases. Very rarely, with massive ingestions, early coma and metabolic acidosis may be seen [15]. Although uncommon, thrombocytopenia after acute overdose has also been described [16]. The mechanisms causing these atypical toxicities are unknown, and it is unclear to what extent these effects are directly due to APAP.

The precise dosage required to produce hepatotoxicity is unknown and almost certainly varies to some degree with individual differences in CYP2E1 activity, GSH stores, and capacity for GSH regeneration. Retrospective data suggest that significant toxicity is likely only after acute overdoses of greater than 250 mg per kg in adults [13], and prospective studies have suggested that toxicity is unlikely in unintentional pediatric ingestions of up to 200 mg per kg [17]. The possibility of toxicity at lower doses and skepticism regarding the accuracy of overdose histories have led to acceptance of a more conservative definition of risk, particularly in the United States. On the basis of APAP’s volume of distribution and the well-established accuracy of APAP blood levels in predicting toxicity (see later), it is currently recommended that single ingestions of greater than 140 to 150 mg per kg be considered potentially toxic.

Elevated aminotransferase concentrations have also been reported after repeated ingestions of therapeutic or slightly greater doses of APAP [18]. Individuals who have conditions associated with increased CYP2E1 activity (e.g., chronic alcoholics) or glutathione depletion such as children younger than 10 years of age [19], those with chronic malnutrition, recent fasting (due to intercurrent illness), or recent ethanol use [20] may be at increased risk for such toxicity, but the accuracy of these reports has been challenged, and their therapeutic implications remain controversial. Such individuals are likely to have low hepatic carbohydrate and sulfate stores and, hence, decreased capacity for APAP metabolism via the glucuronidation and sulfation. There is currently no valid estimation of the amount, frequency, or duration of the dosing that defines risk. It appears that after repeated doses, accumulation of APAP to concentrations associated with toxicity after acute overdose is not required and that sustained moderate elevations are sufficient to cause GSH depletion and toxicity [21]. Such observations suggest that the APAP level at which NAPQI production exceeds GSH regeneration is near, or possibly within, the therapeutic range and that GSH stores and the capacity for its regeneration are the most important factors in the development of hepatotoxicity. They also support the concept that hepatotoxicity is more dependent on the area under the curve (time vs. concentration) of APAP than the peak drug level.

Intentional acute overdose is the most common cause of toxicity and fatalities, but accidental therapeutic overdosing and the abuse of opioids with unintentional coingestion of APAP (e.g., with codeine or propoxyphene) have also been reported. Therapeutic overdoses may result from dosing calculation errors, excessive self-treatment, the use of adult formulations or extra-strength formulations when lower dosage formulations were intended, and errors involving substitution of higher-dose rectal suppositories for similar-appearing lower dosage forms.

The importance of accurately diagnosing APAP toxicity soon after overdose extends beyond the high frequency with which it is encountered and its potential for causing morbidity and mortality. Acetaminophen is unique among common toxic exposures because effective treatment requires recognition of potential poisoning and initiation of therapy when no reliable clinical signs of overdose are present. Physicians must therefore consider occult APAP ingestion and liberally obtain APAP levels on all overdose patients to avoid missing the diagnosis.

Acetaminophen hepatotoxicity can be divided into four clinical stages based on the time interval after ingestion: stage I (0 to 24 hours), the latent period; stage II (24 to 48 hours), the onset of hepatotoxicity; stage III (72 to 96 hours), maximal hepatic injury; and stage IV (4 days to 2 weeks), recovery [2,13].

During stage I, patients may be completely asymptomatic but often experience nausea, vomiting, and malaise, which may be accompanied by pallor and mild diaphoresis. There is no known correlation between presence or absence of early symptoms and the risk of hepatotoxicity. Although late in stage I very sensitive indicators of hepatic injury, such as γ-glutamyltransferase level, may be elevated, more widely used laboratory studies (e.g., aspartate aminotransferase [AST], alanine aminotransferase, prothrombin time, bilirubin) are completely normal. Early coma and metabolic acidosis have been reported in patients with massive ingestions [15], but these findings are so atypical that other causes should be suspected. They should be attributed to APAP only if the APAP concentration is extremely high and other etiologies have been excluded.

Symptoms during stage II are typical of hepatitis and include right upper-quadrant abdominal pain, nausea, fatigue, and malaise. Physical examination often reveals right upper-quadrant tenderness and hepatomegaly. The first elevation of aminotransferase levels usually occurs between 24 and 36 hours after APAP ingestion, but in the most severe cases, it can occur by 16 hours or earlier. Early in stage II, tests reflecting liver function, such as bilirubin and prothrombin time, are most often normal or only slightly elevated. Marked elevations of aminotransferase levels (greater than 1,000 IU per L) within 24 hours or bilirubin and prothrombin time within 36 hours should suggest that the time of ingestion was earlier than reported. Although unusual, in severe cases, marked liver function abnormalities may be evident by 36 to 48 hours. Complications during stage II are directly related to the degree of liver injury and may include coagulopathy, encephalopathy, acidosis, and hypoglycemia. With few exceptions, life-threatening problems are not seen earlier than 48 hours, and death in this period is distinctly rare. Renal dysfunction, manifested by rising creatinine and an active urinary sediment, may become evident during this stage but usually lags somewhat behind the hepatic injury. The blood urea nitrogen may also be elevated, but it can be normal in the presence of hepatic failure and resultant decreased urea formation.

Biochemical evidence of liver injury becomes most pronounced during stage III. With successful treatment, however, peak aminotransferase levels may sometimes occur earlier (Fig. 118.2). Most patients, even those with markedly elevated aminotransferase levels, go on to recover fully. Most deaths occur 3 to 7 days after ingestion and result from intractable metabolic disturbances, secondary complications such as cerebral edema or dysrhythmias, or exsanguination due to coagulopathy. Oliguric or anuric renal failure may result from acute tubular necrosis and is sometimes accompanied by flank pain. Some degree of renal dysfunction occurs in approximately 25% of patients with significant hepatotoxicity [15]. Even when severe, renal failure is almost always reversible.

During stage IV, if sufficient hepatocytes remain viable and the patient survives, the liver regenerates. Recovery is often complete by day 5 or 6 in patients with minimal toxicity, but those with more serious poisoning may not be clinically normal for 2 weeks or more. It is interesting that even patients with severe toxicity who survive regain normal liver function. There are no known cases of chronic or persistent liver abnormalities from APAP poisoning. In those who ultimately die, a slow decline in aminotransferase levels without clinical improvement may be seen. Declining enzyme levels merely
represent a washout of those released at the time of the initial insult, not a recovery of normal liver function. These patients can be identified by persistent or increasing marked elevations of bilirubin and prothrombin time. Although this pattern is occasionally seen in patients who recover, most survivors do not have significant or persistent bilirubin or prothrombin time elevation after aminotransferase levels fall.

Because of variations in dosing patterns and patient characteristics, the time course of toxicity in patients with repeated ingestions is not well defined. With chronic toxicity, dose–response patterns differ from those of acute overdose, but the clinical manifestations are the same.

The diagnostic evaluation consists of determining the risk of toxicity and assessing for it. The serum APAP concentration is used to predict toxicity after acute overdose. If the APAP concentration between 4 and 24 hours after ingestion falls on or above the acetaminophen treatment nomogram line (Fig. 118.3), the patient should be considered at risk for hepatotoxicity, and hence, in need of antidotal therapy (see later). Conversely, if the APAP concentration is even slightly below the nomogram line, the risk of hepatotoxicity is negligible and antidotal therapy is not necessary. The original Rumack–Matthew nomogram line, which defined the risk of toxicity based on the natural course of untreated patients [22], was actually 25% higher than the line now used in the United States. Hence, the nomogram has a 25% safety margin that allows one to be fairly rigid when using the nomogram to make treatment decisions.

There are, however, some important caveats regarding use of the nomogram. First and foremost, it applies only to single acute ingestions. Second, when there is uncertainty about the exact time of ingestion, the worst-case scenario should be assumed. For example, if the ingestion was between 4 and 6 hours earlier, the 6-hour value on the nomogram should be used. And finally, when levels are obtained 20 to 24 hours after overdose, the limit of detection of the APAP assay must also be considered. Because most hospitals use immunoassays with a detection limit of 10 μg per mL, potentially toxic APAP levels during this period will be below this limit and reported as nondetectable, which does not necessarily mean nontoxic. Again, a worst-case scenario should be assumed, and antidotal treatment should be given until the level is confirmed to be nontoxic by a more sensitive assay, or until it has been determined that the patient is asymptomatic and has no laboratory evidence of hepatotoxicity.

With rare exceptions (see later), a single APAP concentration within the time period specified by the nomogram is sufficient to plan appropriate therapy. Although it is true that the elimination half-life of APAP is related to the likelihood of toxicity, half-lives should not be relied on in making therapeutic decisions. The observations that half-lives greater than 4 hours were associated with toxicity and that toxicity was negligible if APAP half-life was less than 4 hours [23] were based on multiple APAP determinations in untreated patients over a 36-hour period. Because treatment must be started as early as possible [24] and treatment may alter APAP elimination [11], half-life determinations are not relevant to current standards of care.

There are three situations in which repeat measurements may be of value. The first is in the patient with a time of ingestion that is unknown but that was within 4 hours. In this situation, an increasing APAP level indicates ongoing absorption from a recent ingestion. To detect a rising level and define the peak value, repeat determinations must be frequent (every hour) until the level declines. This prevents underestimation of the peak value due to incomplete absorption at the time of the first level. It also may rule out toxicity by detecting a peak value less than 150 μg per mL.

The second situation in which repeating the APAP may be useful is after an overdose of an ER formula. Because of prolonged absorption, patients with nontoxic APAP levels soon after ingestion may have subsequent levels that are toxic by the nomogram [25]. The optimal time to repeat drug levels to detect such nomogram line-crossers is unknown. In one patient, a
potentially toxic APAP level did not occur until 14 hours after ingestion [5]. The manufacturer recommends obtaining a second APAP level 4 to 6 hours after the initial one [26]. Others have recommended that to avoid missing a potentially toxic level, drug levels should be measured every 2 hours from 4 to 16 hours after overdose [27].