Acetaminophen (N-acetyl-p-aminophenol [APAP]), a metabolite of phenacetin, was first used clinically in the United States in 1955.137,154,161 The well-known toxicity of phenacetin led to unfounded concerns about acetaminophen safety that delayed widespread acceptance of acetaminophen until the 1970s. Acetaminophen has since proved to be a remarkably safe drug at appropriate dosage, which has led to its popularity, as evidenced by sales of more than 90 million tablets per year.70 Acetaminophen is available alone in myriad single-agent dose formulations and delivery systems, and in a variety of combinations with opioids, other analgesics, sedatives, decongestants, expectorants, and antihistamines.161
The diversity and wide availability of acetaminophen products dictate that acetaminophen toxicity be considered not only after identified ingestions but also after exposure to unknown or multiple drugs in settings of intentional drug overdose, drug abuse, and therapeutic misadventures.
Despite enormous experience with acetaminophen toxicity, many controversies and challenges are unresolved. New formulations and new analogs will be introduced in the future, which will require reassessments of the knowledge in this area.303 To best understand the continuing evolution in approach to acetaminophen toxicity, it is critical to start with an analysis of certain fundamental principles and then to apply these principles to both typical and atypical presentations in which acetaminophen toxicity must be considered.
Acetaminophen (APAP) is an analgesic and antipyretic with weak peripheral antiinflammatory and antiplatelet properties. Analgesic activity is reported at a serum acetaminophen concentration of 10 μg/mL and antipyretic activity at 4 to 18 μg/mL.323
APAP has a unique mechanism of action among the analgesic antipyretics. Most of the nonsteroidal antiinflammatory drugs (NSAIDs) occupy the cyclooxygenase (COX) binding site on the enzyme prostaglandin H2 synthase (PGH2) and prevent arachidonic acid from physically entering the site and being converted to prostaglandin H2. APAP also inhibits prostaglandin H2 production but does so indirectly by reducing a heme on the peroxidase (POX) portion of the PGH2,177 and indirectly inhibiting COX activation.9,138,173 In this way, APAP function is highly dependent on cellular location and intracellular conditions.8,102,211 APAP strongly inhibits prostaglandin synthesis where concentrations of POX and arachidonic acid ("peroxide tone") are low, such as the brain.92 In conditions of high peroxide tone, such as inflammatory cells (macrophages) and platelets, prostaglandin synthesis is less affected by APAP.9,34,102,110,173,203,211 This explains APAP's strong central antipyretic and analgesic effect but weak peripheral antiinflammatory and antiplatelet effects. Functionally, APAP predominantly acts as a central indirect inhibitor of COX-2 enzymes,121,201,203 with some mild peripheral COX-2 inhibition164 and minimal COX-1 inhibition (see Chap. 36).53
Antipyresis and analgesia are predominantly mediated by this central indirect COX-2 inhibition and the resulting decrease in prostaglandin E2 (PGE2) synthesis.89,...