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INTRODUCTION

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HISTORY AND EPIDEMIOLOGY

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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 (APAP) is a major metabolite of phenacetin and acetanilide, and is responsible for, both analgesia and antipyresis. APAP was synthesized in 1878 and has a low risk of causing methemoglobinemia. N-acetyl-p-aminophenol 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. Both terms are abbreviations of the chemical name. APAP 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. APAP has since proved to be a remarkably safe xenobiotic at appropriate dosage, which has led to its popularity. APAP is available in a myriad of ­single-agent dose formulations and delivery systems, and in a variety of combinations with opioids, other analgesics, sedatives, decongestants, expectorants, and antihistamines.184 The diversity and wide availability of APAP products dictate that APAP toxicity be considered not only after identified ingestions but also after exposure to unknown or multiple xenobiotics in settings of intentional overdose, abuse, and therapeutic misadventures.

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Despite enormous experience with APAP toxicity, many controversies and challenges remain unresolved. New formulations and new ­analogs are being introduced, that will require reassessments of the available ­knowledge.57,113,326 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 considered.

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PHARMACOLOGY

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APAP is an analgesic and antipyretic with weak peripheral antiinflammatory and antiplatelet properties. Analgesic activity is reported at a serum [APAP] of 10 μg/mL and antipyretic activity at 4 to 18 μg/mL.345

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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 PGH2,199 and indirectly inhibiting COX activation.13,154,195 In this way, APAP function is highly dependent on cellular location and intracellular conditions.12,111,231 APAP strongly inhibits prostaglandin synthesis where concentrations of POX and arachidonic acid (“peroxide tone”) are low such as in the brain.90,101 In conditions of high peroxide tone, such as inflammatory cells (macrophages) and platelets, prostaglandin synthesis is less affected by APAP,...

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