N-acetylcysteine: 50 years since the discovery of an antidote that has changed the prognosis of acetaminophen poisoning

Abstract

Acetaminophen is one of the most widely used drugs in clinical practice due to its analgesic and antipyretic properties. However, overdose is one of the leading causes of severe acute liver failure. N-acetylcysteine, introduced as an antidote in 1974, has revolutionized the management of this intoxication by reducing hepatotoxicity and mortality associated with acetaminophen toxicity. At the end of the 19th century, acetaminophen was identified as the main active metabolite of phenacetin and acetanilide. Its therapeutic use began to gain popularity in the 1950s and later became one of the main drugs involved in suicide attempts, particularly among adolescents and young adults. Acetaminophen-induced hepatotoxicity was first described in 1966, establishing that an overdose could lead to fulminant hepatic necrosis. In 1975, Rumack and Matthew published a nomogram that allowed stratification of hepatic toxicity risk based on plasma drug levels. The mechanism of hepatotoxicity was elucidated in the early 1970s when it was discovered that acetaminophen is metabolized by cytochrome P450 into a highly reactive intermediate, N-acetyl-p-benzoquinoneimine, which is normally neutralized by hepatic glutathione. In overdose situations, glutathione depletion leads to hepatic necrosis. Based on these findings, sulfhydryl-containing agents such as cysteamine and methionine were introduced as antidotes, but N-acetylcysteine ultimately proved to be the most effective treatment. Since its introduction, N-acetylcysteine administration protocols have evolved to optimize efficacy and minimize adverse effects. Protocols such as the Scottish and Newcastle Acetylcysteine Protocol and the Two Bags regimen have simplified dosing and reduced the incidence of anaphylactoid reactions. Over the past 50 years, N-acetylcysteine has saved thousands of lives and remains the gold-standard antidotal treatment for acetaminophen poisoning.