Aspirin Pharmacology Quiz

Acute Intoxication with Analgesic Antipyretics (Salicylates and Acetaminophen)

• Salicylates (Aspirin):

  • Salicylic acid derivatives, including aspirin, amino salicylic acid, methyl salicylate, and salicylic acid, are over-the-counter (OTC) drugs.
  • Aspirin is a non-steroidal anti-inflammatory drug (NSAID) used for pain, inflammation and fever.
  • Accidental poisoning: Common in children due to mixed dose preparations and OTC topical preparations.
  • Suicidal poisoning: Common in adolescents and adults, is cheap, easily available, and painless.
  • Homicidal poisoning: Uncommon due to the bitter taste and high doses needed.
  • Toxicokinetics:
    • Rapidly absorbed from the gastrointestinal tract, reaching peak serum concentrations within 30 minutes to 4 hours.
    • Two-thirds of a therapeutic dose is absorbed within 1 hour.
    • Peak levels typically occur in 2 to 4 hours.
    • Serum concentrations may remain elevated for more than 12 hours following large ingestions or enteric capsules.
    • Salicylic acid is hydrolyzed in the intestine, liver and red blood cells, and then reversibly binds to albumin.
    • A toxic dose of aspirin is 200-300 mg/kg, with 500 mg/kg being potentially lethal.
  • Metabolism: Primarily metabolized in the liver, with conjugation with glycine to form salicyluric acid and with glucuronic acid to form salicyl acyl and phenolic glucuronides. In overdose, metabolic pathways can become saturated.
  • Excretion: Primarily excreted by the kidneys via glomerular filtration and tubular secretion.
    • Urine pH significantly affects salicylate excretion.
    • Alkalinization of urine increases ionization of salicylic acid, reducing reabsorption and enhancing excretion. Conversely, acidic urine promotes reabsorption and prolongs toxicity.
  • Mechanism of Action: Aspirin inhibits cyclooxygenase (COX-1 and COX-2) by covalent acetylation. This decreases the synthesis of thromboxane A2 (TXA2) and prostaglandins.
  • Pathophysiology:
    • Acid-base disturbances: Initial stimulation of the respiratory centre leading to respiratory alkalosis, followed by compensatory mechanisms involving the kidneys leading to metabolic acidosis. Prolonged high aspirin serum concentrations can depress the respiratory center.
    • Other disturbances: Disturbance of oxidative phosphorylation, causing hyperthermia and hypoglycemia, even without hypoglycemia; gastrointestinal effects such as nausea, vomiting, gastritis, and hemorrhage; hematological effects including hypoprothrombinemia due to platelet aggregation inhibition.
  • Grading of Toxicity: Toxicity is graded as mild, moderate, or severe, based on gastrointestinal manifestations, hypotension, hypoglycemia, hyperthermia, tachycardia, metabolic acidosis, and subconjunctival hemorrhage. Severe toxicity involves CNS psychosis, convulsions, respiratory pulmonary edema, cardiovascular failure, or renal oliguria.
  • Laboratory Investigations: Serum salicylate levels should be measured 6 hours or more after ingestion. Repeat measurements if needed to monitor absorption. Additional tests include ABG, electrolytes, blood glucose. liver function tests, coagulation profile, chest x-ray and ECG.
  • Management: Supportive care is crucial, including intravenous fluids with bicarbonate and monitoring serum pH (avoiding systemic alkalosis), addressing coma or seizure, renal, hepatic, or pulmonary involvement, and acid-base imbalance. Decontamination (gastric lavage, activated charcoal). Enhancement of elimination (alkalinization of urine, hemodialysis). Symptomatic treatment (potassium, vitamin K, sodium bicarbonate).

• Acetaminophen (Paracetamol):

  • Circumstances of Toxicity: Isolated product or in combination medications. Usually accidental, but suicidal poisoning is also common.
  • Toxicokinetics:
    • Rapidly absorbed with peak plasma concentrations within 1 hour. Complete absorption within 4 hours.
    • Metabolized in the liver primarily by conjugation into glucuronide and sulfate conjugates.
    • Small percentage is oxidized by cytochrome P450 into N-acetyl-p-benzoquinoneimine (NAPQI), a highly toxic metabolite.
    • Glutathione is used to detoxify NAPQI. In overdose, glutathione is depleted, resulting in NAPQI binding to hepatocytes, causing centrilobular necrosis. Renal injury can also occur due to NAPQI generation.
  • Mechanism of Toxicity: NAPQI, the highly reactive metabolite, causes cell damage and necrosis, primarily in the liver.
  • Clinical Picture:
    • Early stages may be asymptomatic, then nonspecific symptoms (nausea, vomiting, anorexia, malaise, diaphoresis).
    • Hepatic injury, which progresses to hepatic failure and renal failure.
    • Grading of toxicity is based on different stages.
  • Investigating Acetaminophen Toxicity: Rumack-Matthew nomogram use to assess the severity. Measured serum levels, liver function tests (AST, ALT). coagulation, blood glucose, bilirubin, renal function, acid-base status, and electrolytes.
  • Management:
    • Supportive care and treatment of complications.
    • Decontamination is not always necessary.
    • Enhancement of elimination (no evidence).
    • Antidote therapy with N-acetylcysteine (NAC).
    • Dosage and timing is critical to NAC therapy.
    • Administration of NAC is crucial within 8-hours from ingestion.

Learning Objectives

• Understand the pathophysiology of salicylate and acetaminophen overdose.
• Master the clinical presentation of salicylate and acetaminophen toxicity.
• Be aware of the antidote and its administration timing.
• Be aware of the management of salicylate and acetaminophen toxicity.