N-acetylcysteine (NAC) is the cornerstone of therapy for patients with potentially lethal acetaminophen (APAP) overdoses. If administered early, NAC can then prevent APAP induced hepatotoxicity. If administered after the onset of hepatotoxicity, NAC improves outcomes and decreases mortality. NAC may also limit hepatotoxicity from other xenobiotics that result in 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.31 Finally, NAC may be useful in the management of adults with fulminant hepatic failure caused by nontoxicologic etiologies.20,75,81,84,149
Shortly after the first case of APAP hepatotoxicity was reported, Mitchell described the protective effect of glutathione.97,127 Prescott113 first suggested 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.106 Several groups96,112,113,126 performed human research with oral and IV NAC in the 1970s. The US Food and Drug Administration (FDA) approved NAC for oral use in 1985 and for IV use in 2004.
NAC is a thiol containing (R-SH) compound that is deacetylated to cysteine, an amino acid used intracellularly. The amino acids cysteine glycine and glutamate are used to synthesize glutathione.123
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.110,137,160,162
NAC has several distinct roles in the treatment of APAP poisoning. Early after ingestion when APAP is being metabolized to N-acetyl benzoquinoneimine (NAPQI), NAC prevents toxicity by rapidly detoxifying NAPQI. After hepatotoxicity is evident, NAC decreases toxicity through several nonspecific mechanisms, including free radical scavenging, increasing oxygen delivery, increased mitochondrial adenosine triphosphate (ATP) production, 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 following toxic APAP ingestion.112,120 In this preventive role, NAC acts primarily as a precursor for the synthesis of glutathione.77 The availability of cysteine is the rate-limiting step in the synthesis of glutathione, and NAC is effective in replenishing diminished supplies of both cysteine and glutathione. Additional minor mechanisms of NAC in preventing hepatotoxicity include acting as a substrate for sulfation,139 as an intracellular glutathione substitute ...