Also, NAC failure has been reported in massive ingestions of APAP, even when beginning NAC within 8 hours. NAC is extremely effective when administered within 8 – 10 hours however, beyond this time, the efficacy of NAC begins to decline. In patients with ongoing hepatic insult, NAC also helps to treat systemic toxicity through non-descript mechanisms. It also enhances the sulfation pathway of elimination, and may directly reduce NAPQI back to APAP. NAC provides cysteine, replenishing and maintaining hepatic GSH stores.
NAC prevents hepatic injury primarily by restoring hepatic glutathione. Collectively, NAPQI formation via CYP2E1, depletion of GSH stores, protein adducts formation, mitochondrial dysfunction, and MPTP opening and DNA damage are responsible for necrotic cell death in the centrilobular areas of the liver.
Activated P-JNK translocates to the mitochondria, amplifying the original mitochondrial oxidant stress, resulting in the formation of peroxynitrite and associated nitrosative stress, triggering the opening of mitochondrial permeability transition pores (MPTP), releasing mitochondrial intermembrane proteins such as apoptosis-inducing factor and endonuclease G, which translocate to the nucleus and cause DNA fragmentation. This ultimately leads to the phosphorylation and activation of c-jun N-terminal Kinase (JNK) in the cytosol. These adducts impair mitochondrial respiration and lead to the generation of mitochondrial superoxide. In addition to binding to cellular proteins that lead to cell injury, NAPQI also binds to mitochondrial proteins, forming APAP-cysteine protein adducts, inducing a series of events that triggers mitochondrial oxidant stress, a component essential for the cell death mechanism. Fomepizole provides inhibition of additional pathways of APAP metabolism that aid in combating hepatotoxicity induced by APAP overdose.Hepatotoxicity may still occur despite the early use of NAC in approximately 5-6% of patients.Delayed presentations and massive ingestion of APAP limit NAC’s therapeutic efficacy.NAC is the only FDA approved medication for APAP overdose and is highly effective at preventing hepatotoxicity when administered within 8 – 10 hours.In overdose (intentional or unintentional) it may cause severe hepatotoxicity, being the most common cause of acute liver failure in the U.S., accounting for 46% of all cases which results in 300 – 500 deaths annually.APAP is an active ingredient in over 600 over-the-counter and prescription medications, is one of the most commonly used analgesic and antipyretic medications, and is a common cause of poisoning, responsible for more than 78,000 emergency department visits and 33,000 hospitalizations annually in the United States (U.S.).
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