Excerpt from Toxicity, Acetaminophen
Synonyms, Key Words, and Related Terms: paracetamol, N-acetyl-p-aminophenol, APAP
Toxicity, Acetaminophen
Background: Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world; it is contained in more than 100 products. As such, acetaminophen is one of the most common pharmaceuticals associated with both intentional and accidental poisoning.
Acetaminophen-induced hepatotoxicity is well recognized. Acetaminophen also is known as paracetamol and N-acetyl-p-aminophenol (APAP). It is found in the United States as 325-mg and 500-mg immediate-release tablets and as a 650-mg extended-release preparation. Various children's chewable, suspension, and elixir formulations of acetaminophen also are available. Furthermore, acetaminophen is found as a component of combination drugs such as propoxyphene-acetaminophen (eg, Darvocet) and oxycodone-acetaminophen (eg, Percocet).
Pathophysiology: The maximum daily dose of APAP is 4 g in adults and 90 mg/kg in children. The toxic dose of APAP after a single acute ingestion is 150 mg/kg or approximately 7 g in adults, although the at-risk dose may be lower in persons with alcoholism and other susceptible individuals. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.
Acetaminophen is rapidly absorbed from the stomach and small intestine and metabolized by conjugation in the liver to nontoxic agents, which then are eliminated in the urine.
In acute overdose or when maximum daily dose is exceeded over a prolonged period, the normal pathways of metabolism become saturated. Excess APAP is then metabolized in the liver via the mixed function oxidase P450 system to a toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and removed from the system. Under conditions of excessive NAPQI formation or reduced glutathione stores, NAPQI is free to covalently bind to vital proteins and the lipid bilayer of hepatocytes; this results in hepatocellular death and subsequent centrilobular liver necrosis.
The antidote for APAP poisoning is N-acetylcysteine (NAC). NAC is theorized to work by a number of protective mechanisms. Early after overdose, NAC prevents the formation and accumulation of NAPQI. NAC increases glutathione stores, combines directly with NAPQI as a glutathione substitute, and enhances sulfate conjugation. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic and vasodilating effects, which improve microcirculatory blood flow and oxygen delivery to tissues. Vasodilating effects decrease morbidity and mortality once hepatotoxicity is well established.
NAC is most effective when administered within 8 hours of ingestion. When indicated, however, NAC should be administered regardless of time since the overdose. Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure (in the absence of acetaminophen in the serum).