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By the late 1800s, both phenacetin and acetanilide were used as analgesics and antipyretics, but their acceptance was limited by significant side effects, ­including methemoglobinemia. N-Acetyl-p-aminophenol is a major metabolite of phenacetin and acetanilide and is responsible for both analgesia and ­antipyresis. N-acetyl-p-aminophenol was synthesized in 1878 and has a low risk of causing methemoglobinemia. N-Acetyl-p-aminophenol is abbreviated as APAP (N-acetyl-p-aminophenol) and is referred to as acetaminophen (N-acetyl-paraaminophenol) in the United States, Canada, Japan, and several other countries and as paracetamol (para-acetylaminophenol) in most other areas of the globe. These terms are all acronyms of the chemical name. Acetaminophen was first used clinically in the United States and the United Kingdom in the mid 1950s, but its widespread acceptance was delayed until the 1970s because of concerns of the toxicities of its precursors. Acetaminophen has since proved to be a remarkably safe medication at appropriate dosage, which has led to its popularity. Acetaminophen is available in myriad single-medication dose formulations and delivery systems and in a variety of combinations with opioids, other analgesics, sedatives, decongestants, expectorants, and antihistamines.205 The diversity and wide availability of APAP products dictate that the potential for APAP toxicity be evaluated not only after identified ingestions but also after exposure to unknown or multiple xenobiotics in settings of intentional overdose, abuse, and therapeutic misadventures.

Despite enormous experience with APAP toxicity, many controversies and challenges remain unresolved. New formulations and analogs are being introduced, including multiple extended-release and transmucosal formulations that will require reassessments of the available knowledge.129,261 To best understand the continuing evolution in the approach to APAP toxicity, it is critical to start with certain fundamental principles and then to apply these principles to both typical and atypical presentations in which APAP toxicity must be evaluated.


Acetaminophen is an analgesic and antipyretic with weak peripheral antiinflammatory and antiplatelet properties. Analgesic activity is reported at a serum [APAP] of 10 mcg/mL and antipyretic activity at 4 to 18 mcg/mL.379

Acetaminophen 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. Acetaminophen also inhibits prostaglandin H2 production but does so indirectly by reducing a heme on the peroxidase (POX) portion of the PGH2,223 and indirectly inhibiting COX activation.14,217 In this way, APAP function is highly dependent on cellular location and intracellular conditions.254 Acetaminophen strongly inhibits prostaglandin ...

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