Acetaminophen: Old drug, new warnings

MOST ACETAMINOPHEN IS CONJUGATED AND THEN EXCRETED IN THE URINE

Acetaminophen usually has excellent bioavailability (up to 98%), but the exact amount absorbed varies, depending on the dosage form and concomitant use of other drugs.⁸

At therapeutic doses, the elimination halflife is about 2 hours. Peak plasma concentrations are reached 30 to 60 minutes after the dose is taken,¹ but taking acetaminophen with opioids, anticholinergic drugs, or even food may delay the time to peak concentration by delaying gastric emptying.⁸

NAPQI is a toxic metabolite

Under normal circumstances, a small amount of acetaminophen undergoes hepatic metabolism by a different pathway, ie, by CYP450 enzymes, primarily CYP2E1 and to a lesser extent CYP1A2, CYP2A6, and CYP3A4, forming a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Then, the sulfhydryl groups of glutathione convert NAPQI into harmless metabolites that are excreted in the urine.^1,7

Well tolerated and relatively safe

At recommended doses, acetaminophen is well tolerated, and it is considered relatively safe when used according to labeling instructions.

Rarely, patients experience an erythematous or urticarial rash or other allergic complications.¹

However, acetaminophen is a dose-dependent hepatotoxin, and excessive doses (intentional or unintentional) may lead to acute liver failure. In addition, even in therapeutic doses, acetaminophen may still cause transient liver enzyme elevations and possibly hepatotoxicity, particularly in people who are malnourished or alcoholic or are taking certain CYP450-inducing drugs.^3,6,10

HOW ACETAMINOPHEN CAN INJURE THE LIVER

Glucuronidation and sulfation, the major metabolic pathways, become saturated after an acetaminophen overdose.⁷ When this happens, more of the toxic metabolite NAPQI is formed by CYP450-mediated N-hydroxylation. When glutathione is depleted after large doses of acetaminophen or in malnourished people, the toxic metabolite accumulates, resulting in liver damage (Figure 1).⁶

The liver is damaged by two mechanisms. In one, NAPQI binds to hepatic cell macromolecules, causing dysfunction of the enzymatic systems, structural and metabolic disarray, and eventually necrotic cell death. The other mechanism is oxidative stress due to depletion of glutathione.

In children, single acetaminophen doses of 120 to 150 mg/kg of body weight have been associated with hepatotoxicity,¹¹ as have single doses of more than 150 mg/kg or a total dose of greater than 7.5 g in adults. However, the minimal dose associated with liver injury has ranged from 4 to 10 g, and in healthy volunteers even therapeutic doses of 1 g orally every 6 hours resulted in mild liver injury.¹²

Patients who are malnourished or fasting are thought to be at greater risk of acetaminophen hepatotoxicity because they may be deficient in glutathione at baseline. In addition, even at lower-than-therapeutic doses, induction of CYP450 enzymes by drugs or chronic alcohol consumption may lead to an increase in the formation of NAPQI, increasing the risk of hepatotoxicity. Examples of drugs that induce CYP450 enzymes to produce more NAPQI include the anticonvuslants phenytoin (Dilantin) and phenobarbital.

CLINICAL PRESENTATION OF ACETAMINOPHEN OVERDOSE

The diagnosis of acetaminophen overdose is often established by a thorough history. The pertinent information may be difficult to obtain, however, because the patient may be confused or stuporous at presentation, may not know that the overthe-counter products he or she has been taking contain acetaminophen, or may be embarrassed about taking too much acetaminophen.¹³

In acute intentional overdose, signs may not be apparent immediately

The symptoms of toxicity may not be apparent immediately after ingestion of an acute overdose of acetaminophen, but early recognition and treatment can prevent more severe liver damage, decreasing morbidity and the risk of death.⁹

Phase 1 of an acetaminophen overdose begins shortly after ingestion and can last for 12 to 24 hours. Patients may have signs of gastrointestinal upset, nausea, vomiting, anorexia, diaphoresis, and pallor. Although the signs and symptoms show a consistent pattern and are more pronounced after larger acute overdoses, they are not diagnostic or specific.

Phase 2 (up to 48 hours after ingestion). Patients may begin to feel better during this phase. However, the hepatic enzyme levels, the prothrombin time (PT), and the international normalized ratio (INR) may continue to rise, and right upper quadrant pain may develop. Additionally, other laboratory results may be abnormal, and renal insufficiency can occur due to acetaminophen-induced renal tubular necrosis.⁶ Most patients receive the antidote, acetylcysteine (Mycomyst, Acetadote) before or during this phase, and consequently, liver function gradually returns to normal.

Phase 3, if reached, may be marked by severe hepatic necrosis, typically 3 to 5 days after ingestion. Symptoms during this phase range from less severe (eg, nausea and general malaise) to more severe (eg, confusion and stupor). Also, at this time, liver enzyme levels can be as high as 10,000 IU/L or even higher, and lactic acidosis and coagulopathy may worsen. If death should occur, it is most likely from complications associated with fulminant hepatic failure, including cerebral edema, multiorgan-system failure, or sepsis.⁶

Phase 4. Patients who recover generally have complete recovery of liver function with no long-term sequelae..

In unintentional overdoses, patients may have low drug levels

Many patients who present with unintentional acetaminophen toxicity have been taking the drug or products that contain the drug over several days to treat an acute or chronic medical condition. They often have low or undetectable serum acetaminophen levels after 2 to 3 days of nonspecific symptoms.¹²