A. If N-acetylcysteine is started more than 2 hours post-ingestion, the risk of hepatic failure begins to increase.
B. If N-acetylcysteine is started more than 4 hours post-ingestion, the risk of hepatic failure begins to increase.
C. If N-acetylcysteine is started more than 6 hours post-ingestion, the risk of hepatic failure begins to increase.
D. If N-acetylcysteine is started more than 8 hours post-ingestion, the risk of hepatic failure begins to increase.
E. The risk of hepatic failure is dependent on the amount of ingestion, not the time before antidotal therapy is started.
Following ingestion, acetaminophen is rapidly absorbed from the gastrointestinal tract. It has a relatively low volume of distribution (0.8-1.0 L/kg) and is 25% protein-bound. The half-life of acetaminophen is approximately 1.5-2.5 hours, although it can be slightly prolonged at supratherapeutic concentrations.
Following ingestion, approximately 4% of the ingested acetaminophen is excreted unchanged in the urine, while the remainder is metabolized in the liver. In adults, 45-55% of acetaminophen is glucuronidated, while 20-30% is sulfonated. In pediatric patients, however, sulfation is the primary pathway, and glucuronidation is a minor component. The remainder of acetaminophen is metabolized via the cytochrome P450 isoenzyme CYP2E1 to form a substance called N-acetyl-para-benzoquinoneimine (NAPQI). Normally, the body's endogenous glutathione supplies are able to bind to and reduce NAPQI, resulting in renal excretion in the form of cysteine or mercaptopuric acid conjugates. In the setting of overdose, however, the NAPQI production exceeds the body's endogenous glutathione supply, and hepatotoxicity can result.
Acetaminophen's toxicity is due to the metabolism to NAPQI by the cytochrome P450 isoenzyme CYP2E1. Thus, any xenobiotic that induces the P450 isoenzyme CYP2E1 can theoretically increase the risk for acetaminophen-induced hepatotoxicity. Perhaps one of the best-studied agents for inducing CYP2E1 is ethanol. Thus, chronic ethanol consumption leads to increased CYP2E1 activity and, in theory, subsequently increases the risk of hepatotoxicity (see Special Populations below). In contrast, the co-ingestion of ethanol with acetaminophen may result in inhibition of the microsomal oxidation of acetaminophen, thereby providing some degree of protection from acetaminophen-induced hepatotoxicity during acute intoxication. The strongest risk factor for developing hepatotoxicity, however, is the time from a toxic ingestion until the antidote, N-acetylcysteine, is administered. The risk of hepatotoxicity if N-acetylcysteine is started within the first eight hours of the overdose is exceedingly low, while the risk increases substantially with delays longer than eight hours.
Answer: D
