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Acetaminophen (APAP) is a relatively safe drug, provided it is taken at the recommended therapeutic doses. As discussed in the text, at normally ingested dosages, 95% of APAP is converted by phase II enzymes into much less toxic and more water-soluble APAP-glucuronide and APAP-sulfate, both of which are eliminated in the urine (Figure 4–5). Five percent of parent APAP is converted by phase I P450 enzymes into a reactive toxic product that is conjugated by GSH, excreted in the urine, and thus detoxi-fied. However, APAP’s safety may be greatly compromised in mixed drug overdoses, ie, when ingested with other drugs such as hydrocodone, duloxetine, and carisoprodol, which compete with APAP for phase II-dependent elimination or for cellular cofactors (GSH, UDPGA, PAPS) involved in these processes. Accordingly, more APAP is diverted into its hepatotoxic reactive metabolite pathway, resulting in liver cell damage. Moreover, HCV infection could indeed have further compromised liver function including drug metabolism. APAP’s half-life is 2 hours, and therapeutic and toxic blood levels are 15 mcg/mL and > 300 mcg/mL, respectively (Chapter 3). Given that at 48 hours after inges-tion (ie, 24 half-lives later), the patient’s APAP blood level is 75 mcg/mL, it is obvious that her initial APAP levels were dangerously above the toxic range, and thus upon ED admission, her liver function tests are consistent with ongoing liver failure. She should be given N-acetylcysteine, the APAP-specific antidote (Acetadote, Mucomyst; see Chapter 58) and continuous intravenous glucose infusion to provide the precursor (glucose) for generating the UDPGA cofactor required for APAP glucuronidation, as well as the fluid to induce urine output and accelerate APAP-metabolite elimination.
Jennifer E. Hibma, PharmD, & Kathleen M. Giacomini, PhD