Chapter A3: N-Acetylcysteine

INTRODUCTION

N-Acetylcysteine (NAC) is the cornerstone of therapy for patients with potentially lethal acetaminophen (APAP) overdoses. If administered early, NAC can prevent APAP-induced hepatotoxicity. If administered after the onset of hepatotoxicity, NAC improves outcomes and decreases mortality. ­N-Acetylcysteine appears to also limit hepatotoxicity from other xenobiotics that result in glutathione (GSH) 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. Finally, NAC is routinely useful in the management of adults with fulminant hepatic failure caused by nontoxicologic etiologies.^{20,36,64,76,82,84,96,145,149,165}

HISTORY

Shortly after the first case of APAP hepatotoxicity was reported, Mitchell et al described the protective effect of GSH.⁹⁴ Prescott¹⁰⁶ 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.¹⁰² Several groups^106,110,118 performed human research with PO and IV NAC in the 1970s. The US Food and Drug Administration (FDA) approved NAC for PO use in 1985, for IV use in 2004; an effervescent tablet was approved for PO use in 2016.

PHARMACOLOGY

Chemistry

N-Acetylcysteine is a thiol-containing (R-SH) compound that increases intracellular cysteine concentrations by deacetylating into cysteine as well as causing release of intracellular protein- and membrane-bound cysteine.¹⁷⁵ The amino acids cysteine, glycine, and glutamate are used to synthesize GSH, the primary intracellular antioxidant.

Related Xenobiotics

Cysteamine, methionine, and NAC, which are all GSH 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.^{109,136,156,157}

Both liposomal NAC and NAC amide have been studied in animals and are being developed with the intent of increasing intracellular delivery of NAC and decreasing adverse effects.^8,73,153 N-Acetylcysteine amide is an NAC molecule with the carboxyl group replaced by an amide.

Mechanism of Action

N-Acetylcysteine 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.

N-Acetylcysteine effectively prevents APAP-induced hepatotoxicity if it ...