N-acetylcysteine (NAC) is the cornerstone of therapy for patients with potentially lethal acetaminophen (APAP) overdoses. If administered early in the course of exposure, NAC can prevent APAP-induced hepatotoxicity. Administered after the onset of hepatotoxicity, NAC can improve outcome and decrease mortality. NAC also has a role in limiting hepatotoxicity caused by other xenobiotics that cause glutathione depletion and free radical formation, such as cyclopeptide-containing mushrooms, carbon tetrachloride, chloroform, pennyroyal oil, clove oil, and possibly liver failure from chronic valproic acid use.27,47,48,145 Finally, NAC is useful in the management of patients with fulminant hepatic failure caused by other nontoxicologic etiologies.17,70,76,127 Its beneficial effects are also under investigation in critically ill patients with a variety of stress-induced disorders,79,124,139 in the prevention of further renal impairment in patients with chronic renal insufficiency administered a radiographic contrast agent,46,55,71,114 and in those with hepatorenal syndrome.57 Furthermore, NAC may enhance the elimination of boron, cobalt, cadmium, chromium, gold, and methylmercury, although this evidence is limited.27,78
Shortly after the first case of APAP hepatotoxicity was reported, Mitchell and coworkers described the protective effect of glutathione.87,111 Prescott et al.99 first suggested the use of NAC for APAP poisoning in 1974. Early experiments demonstrated that NAC could prevent APAP-induced hepatotoxicity in mice and that the oral (PO) and intravenous (IV) routes were equally efficacious when treatment was initiated early after ingestion.94 Mitchell et al.,87 Prescott et al.,98,99 and Rumack and Peterson112 performed human research with PO and IV NAC in the 1970s. The United States Food and Drug Administration (FDA) approved NAC for PO use in 1985 and for IV administration in 2004.
Cysteamine, methionine, and NAC, which are all glutathione precursors or substitutes, have been used successfully to prevent hepatotoxicity, but cysteamine and methionine both produce more adverse effects than NAC, and methionine is less effective than NAC. Therefore, NAC has emerged as the preferred treatment.96,118,138
NAC has several distinct roles in the treatment of APAP poisoning. Early after ingestion and during the metabolism of APAP to N-acetyl benzoquinoneimine (NAPQI), NAC prevents toxicity by rapidly detoxifying NAPQI that has formed. After hepatotoxicity is evident, NAC decreases toxicity through several nonspecific mechanisms, including free radical scavenging, increasing oxygen delivery, antioxidant effects, and alteration of microvascular tone.
NAC effectively prevents APAP-induced hepatotoxicity if it is administered before glutathione stores are depleted to 30% of normal. This level of depletion occurs approximately 6 to 8 hours after toxic APAP ingestion.98,107,121 In this preventive role, NAC acts primarily as a precursor for the synthesis of glutathione.73 NAC is a thiol-containing compound that is deacetylated to cysteine, an amino acid that is used intracellularly. Cysteine ...