Acetaminophen

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

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General Principles

APAP is available worldwide as an over-the-counter analgesic and antipyretic and has become the most common pharmacologic agent involved in toxicologic fatalities.1 The recommended maximum dose for adults is 4 g/d.

Classification

  • An analgesic. Within the United States, APAP is sold under the trade name Tylenol. The most common trade name for APAP outside the United States is Paracetamol.
  • Because of its use as an analgesic and antipyretic, APAP has become a common ingredient in various cold and flu remedies. It is also used in the treatment of fevers, headaches, and acute and chronic pain.
  • APAP is often sold in combination preparations together with NSAIDs, opioid analgesics, or sedatives (e.g., Tylenol #3, Percocet, Vicodin, NyQuil, Tylenol PM).

Epidemiology

APAP is the leading cause of toxicologic fatalities per year in the United States, and APAP-induced hepatotoxicity is the most frequent cause of acute liver failure.2

Etiology

  • APAP is available as tablets, capsules, liquids, and suppositories. In addition to the more common immediate-release form, there is also an extended-release preparation (e.g., Tylenol Arthritis Pain).
  • Unintentional overdosing is more common than intentional ingestion in suicide attempts, especially in elderly patients on chronic pain regimens including several APAP-containing painkillers.3
  • All patients with presumed APAP overdose should be adequately assessed, evaluated, and treated. However, only the minority of poisoned patients require inpatient care.4

Pathophysiology

  • Absorption: APAP serum levels peak 30–60 minutes after oral ingestion; the extended-release preparations peak after 1–2 hours. Absorption is often delayed in overdose, and peak levels are usually reached after 2–8 hours. The overdose kinetics of extended-release APAP are not yet well established.
  • Overdose: The hepatic conjugation pathways become saturated in overdose. A cascade of biochemical changes occurs in the liver, and centrilobular cell necrosis results.5
    • Acetaminophen is metabolized predominantly via glucuronidation (47%–62%) and sulfation (25%–36%) by phase II metabolism in liver as nontoxic conjugate products. However, a small percentage is metabolized via oxidation (5%–8%) by the cytochrome P450 (2E1) pathway to a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is conjugated by glutathione to nontoxic cysteine and mercapturic acid conjugates.
    • In cases of acetaminophen toxicity, the phase II conjugation enzymes are saturated, and a higher fraction of acetaminophen is conjugated via oxidation to NAPQI. The conjugation of NAPQI by glutathione occurs until glutathione is depleted from hepatic reserves, after which the toxic NAPQI and other free radicals accumulate and cause damage to the hepatocytes.

Risk Factors

  • Decreased glutathione stores (fasting, malnutrition, anorexia nervosa, chronic alcoholism, febrile illness, chronic disease)
  • P450 enzyme inducers (ethanol, isoniazid [INH], phenytoin and other anticonvulsants, barbiturates, smoking)

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General Principles

APAP is available worldwide as an over-the-counter analgesic and antipyretic and has become the most common pharmacologic agent involved in toxicologic fatalities.1 The recommended maximum dose for adults is 4 g/d.

Classification

  • An analgesic. Within the United States, APAP is sold under the trade name Tylenol. The most common trade name for APAP outside the United States is Paracetamol.
  • Because of its use as an analgesic and antipyretic, APAP has become a common ingredient in various cold and flu remedies. It is also used in the treatment of fevers, headaches, and acute and chronic pain.
  • APAP is often sold in combination preparations together with NSAIDs, opioid analgesics, or sedatives (e.g., Tylenol #3, Percocet, Vicodin, NyQuil, Tylenol PM).

Epidemiology

APAP is the leading cause of toxicologic fatalities per year in the United States, and APAP-induced hepatotoxicity is the most frequent cause of acute liver failure.2

Etiology

  • APAP is available as tablets, capsules, liquids, and suppositories. In addition to the more common immediate-release form, there is also an extended-release preparation (e.g., Tylenol Arthritis Pain).
  • Unintentional overdosing is more common than intentional ingestion in suicide attempts, especially in elderly patients on chronic pain regimens including several APAP-containing painkillers.3
  • All patients with presumed APAP overdose should be adequately assessed, evaluated, and treated. However, only the minority of poisoned patients require inpatient care.4

Pathophysiology

  • Absorption: APAP serum levels peak 30–60 minutes after oral ingestion; the extended-release preparations peak after 1–2 hours. Absorption is often delayed in overdose, and peak levels are usually reached after 2–8 hours. The overdose kinetics of extended-release APAP are not yet well established.
  • Overdose: The hepatic conjugation pathways become saturated in overdose. A cascade of biochemical changes occurs in the liver, and centrilobular cell necrosis results.5
    • Acetaminophen is metabolized predominantly via glucuronidation (47%–62%) and sulfation (25%–36%) by phase II metabolism in liver as nontoxic conjugate products. However, a small percentage is metabolized via oxidation (5%–8%) by the cytochrome P450 (2E1) pathway to a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is conjugated by glutathione to nontoxic cysteine and mercapturic acid conjugates.
    • In cases of acetaminophen toxicity, the phase II conjugation enzymes are saturated, and a higher fraction of acetaminophen is conjugated via oxidation to NAPQI. The conjugation of NAPQI by glutathione occurs until glutathione is depleted from hepatic reserves, after which the toxic NAPQI and other free radicals accumulate and cause damage to the hepatocytes.

Risk Factors

  • Decreased glutathione stores (fasting, malnutrition, anorexia nervosa, chronic alcoholism, febrile illness, chronic disease)
  • P450 enzyme inducers (ethanol, isoniazid [INH], phenytoin and other anticonvulsants, barbiturates, smoking)

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