Acetylcysteine for acetaminophen poisoning

Abstract

A 25-year-old man presents to the emergency department with a toothache. During the evaluation, the physician determines that the patient has been taking large doses of over-the-counter acetaminophen along with an acetaminophen–hydrocodone product for the past 5 days. His daily dose of acetaminophen has been 12 g per day (maximum recommended dose, 4 g per day). He has no other medical problems and typically consumes two beers a day. The patient has no symptoms beyond his toothache, is not icteric, and has no hepatomegaly or right-upper-quadrant tenderness. His serum acetaminophen concentration 8 hours after the most recent dose is undetectable. His serum alanine aminotransferase concentration is 75 IU per liter, his serum bilirubin concentration is 1.2 mg per deciliter (20.5 μmol per liter), and his international normalized ratio (INR) is 1.1. The emergency department physician contacts the regional poison-control center, which recommends treatment with acetylcysteine.

Figures

Figure 1. The Metabolism of Acetaminophen and the Synthesis of Glutathione

The primary pathways for acetaminophen metabolism (Panel A) are glucuronidation and sulfation to nontoxic metabolites. Approximately 5% of a therapeutic dose is metabolized by cytochrome P450 2E1 to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is extremely toxic to the liver. Ordinarily, NAPQI is rapidly detoxified by interaction with glutathione to form cysteine and mercapturic acid conjugates. If glutathione is depleted, NAPQI interacts with various macromolecules, leading to hepatocyte injury and death. Glutathione is synthesized from the amino acids cysteine, glutamate, and glycine by means of the pathway shown in Panel B. Glutamate and glycine are present in abundance in hepatocytes; the availability of cysteine is the rate-limiting factor in glutathione synthesis. However, cysteine itself is not well absorbed after oral administration. Acetylcysteine, in contrast, is readily absorbed and rapidly enters cells, where it is hydrolyzed to cysteine, thus providing the limiting substrate for glutathione synthesis.

Figure 2. The Rumack–Matthew Nomogram

The Rumack–Matthew nomogram, first published in 1975, was developed to estimate the likelihood of hepatic injury due to acetaminophen toxicity for patients with a single ingestion at a known time. To use the nomogram, the patient’s plasma acetaminophen concentration and the time interval since ingestion are plotted. If the resulting point is above and to the right of the sloping line, hepatic injury is likely to result and the use of acetylcysteine is indicated. If the point is below and to the left of the line, hepatic injury is unlikely. Patients with repeated supratherapeutic ingestion, or with an unknown time of ingestion, cannot be evaluated with the use of the Rumack–Matthew nomogram.