Acetaminophen

Acetaminophen is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles

Epidemiology

  • APAP is available worldwide as an over-the-counter analgesic and antipyretic. It is a common component of cold and flu remedies and is often sold in combination preparation together with nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, or sedatives.
  • APAP is available in multiple formulations, including tablets, extended-release tablets, capsules, liquids, suppositories. An intravenous formulation is also available.
  • In the US, APAP is the most common pharmacologic agent involved in toxicologic fatalities and the most common cause of acute liver failure.

Pathophysiology

  • APAP is a centrally active cyclooxygenase (COX) inhibitor with analgesic and antipyretic effects.
  • In therapeutic doses, APAP is primarily metabolized via phase II conjugation enzymes in the liver, which generates nontoxic conjugate products. Small amounts of APAP are metabolized by phase I enzymes (primarily cytochrome P450 2E1), producing a toxic oxidizing metabolite, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is then detoxified by glutathione.
  • In cases of APAP toxicity, the phase II conjugation enzymes are saturated, and a higher proportion of APAP is metabolized via oxidation to NAPQI. Conjugation of NAPQI by glutathione occurs until cellular glutathione is depleted, after which the toxic NAPQI and other free radicals accumulate and cause damage to the hepatocytes.
  • Toxicity may occur after a large APAP overdose or after the repeated use of supratherapeutic amounts of APAP.
  • Conditions that reduce glutathione stores (such as fasting, malnutrition, and chronic heavy alcohol use) or induce CYP 2E1 (chronic heavy alcohol use, phenytoin and other anticonvulsants, isoniazid) predispose patients to APAP toxicity.

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General Principles

Epidemiology

  • APAP is available worldwide as an over-the-counter analgesic and antipyretic. It is a common component of cold and flu remedies and is often sold in combination preparation together with nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, or sedatives.
  • APAP is available in multiple formulations, including tablets, extended-release tablets, capsules, liquids, suppositories. An intravenous formulation is also available.
  • In the US, APAP is the most common pharmacologic agent involved in toxicologic fatalities and the most common cause of acute liver failure.

Pathophysiology

  • APAP is a centrally active cyclooxygenase (COX) inhibitor with analgesic and antipyretic effects.
  • In therapeutic doses, APAP is primarily metabolized via phase II conjugation enzymes in the liver, which generates nontoxic conjugate products. Small amounts of APAP are metabolized by phase I enzymes (primarily cytochrome P450 2E1), producing a toxic oxidizing metabolite, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is then detoxified by glutathione.
  • In cases of APAP toxicity, the phase II conjugation enzymes are saturated, and a higher proportion of APAP is metabolized via oxidation to NAPQI. Conjugation of NAPQI by glutathione occurs until cellular glutathione is depleted, after which the toxic NAPQI and other free radicals accumulate and cause damage to the hepatocytes.
  • Toxicity may occur after a large APAP overdose or after the repeated use of supratherapeutic amounts of APAP.
  • Conditions that reduce glutathione stores (such as fasting, malnutrition, and chronic heavy alcohol use) or induce CYP 2E1 (chronic heavy alcohol use, phenytoin and other anticonvulsants, isoniazid) predispose patients to APAP toxicity.

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