- 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.)
- 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
- NAC is the only FDA approved medication for APAP overdose and is highly effective at preventing hepatotoxicity when administered within 8 – 10 hours
- Delayed presentations and massive ingestion of APAP limit NAC’s therapeutic efficacy
- Hepatotoxicity may still occur despite the early use of NAC in approximately 5-6% of patients
- Fomepizole provides inhibition of additional pathways of APAP metabolism that aid in combating hepatotoxicity induced by APAP overdose
At therapeutic doses, approximately 95% of APAP is metabolized through glucuronidation and sulfation pathways to nontoxic metabolites. In adults, glucuronidation accounts for 70% of APAP metabolism and sulfation is responsible for 25%. 5 – 10% is metabolized primarily through cytochrome P450 (CYP) enzymes – mainly CYP2E1. It is this metabolism that results in the formation of the highly reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is readily detoxified by intrahepatic glutathione (GSH) to form nontoxic cysteine and mercapturic acid conjugates. In overdose, a significantly higher amount of APAP is oxidized by CYP2E1, leading to elevated levels of NAPQI, depleting intrahepatic GSH stores, leading to hepatocyte injury and death,
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. These adducts impair mitochondrial respiration and lead to the generation of mitochondrial superoxide. This ultimately leads to the phosphorylation and activation of c-jun N-terminal Kinase (JNK) in the cytosol. 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. 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.
Treatment for APAP Overdose
NAC prevents hepatic injury primarily by restoring hepatic glutathione. NAC provides cysteine, replenishing and maintaining hepatic GSH stores. It also enhances the sulfation pathway of elimination, and may directly reduce NAPQI back to APAP. In patients with ongoing hepatic insult, NAC also helps to treat systemic toxicity through non-descript mechanisms. NAC is extremely effective when administered within 8 – 10 hours; however, beyond this time, the efficacy of NAC begins to decline. Also, NAC failure has been reported in massive ingestions of APAP, even when beginning NAC within 8 hours. This has led to the need to target other molecular mechanisms in APAP toxicity.
Fomepizole, an alcohol dehydrogenase inhibitor that is an FDA approved antidote for methanol and ethylene glycol poisoning, is also a potent inhibitor of CYP2E1, the primary driver of the formation of the NAPQI metabolite.Fomepizole also binds to the ATP binding site of JNK and competitively inhibits enzyme activity. These mechanisms have led to the potential of using fomepizole as an adjunct to NAC for severe APAP toxicity. Evidence shows that the use of fomepizole is safe when treating ethylene glycol and methanol poisoning with only transient adverse reactions. In volunteer studies of mild APAP overdose, there were no adverse events reported with the use of fomepizole.
From Bench to Bedside
In a study completed in mice and primary human hepatocytes, co-administration of fomepizole with APAP completely eliminated APAP toxicity at 6 hours. Co-treatment with fomepizole also prevented JNK activation and the translocation of P-JNK to the mitochondria. In primary human hepatocytes, the presence of fomepizole completely prevented APAP induced cell death.9 Delayed treatment with fomepizole also demonstrated efficacy in another study using a murine model. Author’s concluded that the beneficial effects of fomepizole extend beyond the drug metabolism phase (i.e., inhibition of CYP2E1) and involve inhibition of JNK activation.
In another study, the effect of fomepizole on oxidative metabolism of APAP was evaluated in human volunteers who were given a supratherapeutic, but nontoxic dose, of APAP. This was a crossover trial in which each participant (n = 5) served as their own control. Treatment A consisted of 80 mg/kg of APAP versus treatment B, which was 80 mg/kg of APAP and 2 doses of fomepizole (15 mg/kg followed by 10mg/kg 12 hours later). The APAP plus fomepizole group demonstrated a decrease in oxidative metabolites versus the APAP only group.
A case report by Zell-Kanter and colleagues initially stimulated the interest in fomepizole as an adjunctive agent to NAC for massive APAP overdose. In this case, a 59 year old female presented to the emergency department with severe acidosis accompanied by an anion gap. Based on the anion gap acidosis and possible toxic alcohol ingestion, a single dose of fomepizole was administered. IV NAC was also administered due to possible APAP ingestion with the first level of APAP being reported as 1,141 mg/L and a peak level hours later as 1,193 mg/L. The patient did not receive hemodialysis. The patient’s AST and ALT increased to 3,150 U/L and 2,780 U/L respectively on day 2 of hospitalization. Transaminase levels normalized by day 4 and the patient was transferred out of the medical intensive care unit. In a letter to the editor by Yip and Heard, they stated that the patient’s favorable outcome may have been due to fomepizole, and not entirely due to therapy with IV NAC.
Additional case reports and a case series have been reported in the literature and are summarized below:
As a result of the mechanism of action, evidence in mice/human hepatocytes/volunteer studies, and case reports/case series, will fomepizole be considered a part of your arsenal when you encounter a massive APAP overdose? As always, consult your poison center when these patients present (1-800-222-1222).
- Acetaminophen overdose is a common presentation to the emergency department
- NAC is the only FDA approved agent for APAP overdose and works primarily by providing GSH stores to detoxify NAPQI
- There are instances when, despite therapy with NAC, hepatotoxicity still occurs
- Fomepizole inhibits NAPQI through CYP2E1 inhibition and prevents further hepatotoxicity through JNK inhibition
- For massive APAP overdoses, fomepizole may be considered as an adjunct to NAC to combat hepatotoxicity
- Always consult your poison control center at 1-800-222-1222 when these patients present
- Don’t Double Up on Acetaminophen. U.S. Food and Drug Administration, FDA 10 Sept. 2018. https://www.fda.gov/consumers/consumer-updates/dont-double-acetaminophen. Accessed March 11, 2021.
- Akakpo J, Ramachandran A, Jaeschke H. Novel strategies for the treatment of acetaminophen hepatotoxicity. Expert Opin Drug Metab Toxicol. 2020 Nov; 16(11): 1039 – 1050.
- Woolum J, Hays W, Patel K. Use of fomepizole, n-acetylcysteine, and hemodialysis for massive acetaminophen overdose. Am J Emerg Med. 2020; 38(3): 692.e5 – 692.e7.
- Rampon G, Wartman H, Osmon S, Scalzo A. Use of fomepizole as an adjunct in the treatment of acetaminophen overdose: a case series. Toxicol Commun. 2020; 4(1): 1 – 4.
- Jaeschke H, Akakpo J, Umbaugh D, Ramachandran A. Novel therapeutic approaches against acetaminophen-induced liver injury and acute liver failure. Toxicol Sci. 2020; 174(2): 159 – 167.
- Heard K. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008; 359: 285 – 92.
- Hodgman M, Garrard A. A review of acetaminophen poisoning. Crit Care Clin. 2012; 28: 499 –516.
- Yip L, Heard K. Potential adjunct treatment for high-risk acetaminophen overdose. Clin Toxicol (Phila). 2016; 54(5): 459.
- Akakpo J, Ramachandran A, Kandel S, et al. 4-methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes. Hum Exp Toxicol. 2018; 37(12): 1310 – 1322.
- Kang A, Padilla-Jones A, Fisher E, et al. The effect of 4-methylpyrazole on oxidative metabolism of acetaminophen in human volunteers. J Med Toxicol. 2020; 16(2): 169 – 176.
- Zell-Kanter M, Coleman P, Whiteley P, and Leikin J. A gargantuan acetaminophen level in an academic patient treated solely with intravenous N-acetylcysteine. Am J Ther. 2013; 20(1): 104 – 6.
- Shah K, Beuhler M. Fomepizole as an Adjunctive treatment in severe acetaminophen toxicity. Am J Emerg Med. 2020; 38(2): 410.e5 – 410.e6.
- Kiernan E, Fritzges J, Henry K, Katz K. A case report of massive acetaminophen poisoning treated with a novel “triple therapy”: N-acetylcysteine, 4-methylpyrazole, and hemodialysis. Case Rep Emerg Med. 2019; 1 – 4.
- Akakpo J, Ramachandran A, Duan L, et al. Delayed treatment with 4-methylpyrazole protects against acetaminophen hepatotoxicity in mice by inhibition of c-jun n-terminal kinase. Toxicol Sci. 2019; 170(1): 57 – 68.