Managing Paracetamol Overdose

Cards (58)

  • Paracetamol
    • Acetaminophen
    • N-acetyl-p-aminophenol (APAP)
  • Paracetamol is established as the standard antipyretic and analgesic for mild to moderate pain states
  • The normal body temperature is 36.5 to 37.5
  • Fever is manifested at a temperature of greater than or equal to 37.8
  • Rectal route is the closest to the body's core temperature
  • Paracetamol Timeline
    • 1893 - first clinical use by von mering
    • 1947 - extensive medical use as prescription drug
    • 1950 - commercial availability in the US
    • 1960 - became OTC
    • 1966 - discovery of hepatotoxicity as ADR
    • 1980 - became mainstay analgesic and antipyretic
    • Present - first-line drug for pain management and antipyresis
  • Paracetamol Pharmacokinetics
    Absorption: Primarily in the small intestines, minimal in the stomach
    Distribution: 1 L/kg, protein binding at 10% to 25% at therapeutic doses, 8% to 43% at toxic concentrations
    Metabolism: Hepatic (sulfation and glucuronidation), subject to first pass metabolism for oral route of administration
  • Paracetamol Pharmacokinetics
    Half-life elimination:
    • Neonates - 7 hours
    • Infants - approx. 4 hours
    • Children - 3 hours
    • Adolescents - approx. 3 hours
    • Adults - approx. 2 hours (may be affected with patients with renal insufficiency)
  • Paracetamol Pharmacokinetics
    Renal Excretion:
    • Unchanged - <5%
    • Glucuronide metabolites - 60 to 80%
    • Sulfate metabolites - 20 to 30%
    • Cysteine and mercapturic acid metabolites - approx. 8%
  • Paracetamol Pharmacokinetics
    Onset of Action:
    • Oral - less than an hour
    • IV for analgesia - 5 to 10 minutes
    • IV for antipyresis - within 30 minutes
  • Paracetamol Pharmacokinetics
    Duration of Action:
    • Oral and IV for analgesia - 4 to 6 hours
    • IV for antipyresis - more than 6 hours
  • End-organ toxicity often delayed 24 to 48 hours after acute ingestion
  • Paracetamol can cause gastroenteritis within hours and hepatotoxicity 1 to 3 days after ingestion
  • Mechanism of Paracetamol
    Paracetamol --> Conjugation: Glucuronidation --> Glucuronide moiety (non-toxic)
  • Mechanism of Paracetamol
    Paracetamol --> Conjugation: Sulfation --> Sulfate moiety (non-toxic)
  • Mechanism of Paracetamol
    Paracetamol --> Oxidation: CYP450 metabolism --> NAPQI (toxic) --> Cysteine and Mercapturic acid (non-toxic)
  • Mechanism of Paracetamol
    Glutathione --> NAPQI (toxic) --> Cysteine and Mercapturic acid (non-toxic)
  • CYP enzymes involved in metabolism
    • CYP2E1
    • CYP1A2
    • CYP2A6
    • CYP3A4
  • N-acetyl-p-benzoquinoneimine (NAPQI)
    • Has an extremely short half-life and is rapidly conjugated with glutathione
    • Renally excreted
    • In excess formation or with glutathione reduction, it covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins
  • NAPQI-protein adducts
    • Causes an ensuing cascade of oxidative damage and mitochondrial dysfunction
    • Subsequent inflammatory response propagates hepatocellular injury and death
    • Necrosis primarily occurs in the centrilobular (zone 3) region, owing to the greater production of NAPQI by these cells
  • Alcoholic liver disease or undernutrition could increase risk of toxicity (CYP450 inducers)
  • Hepatic enzyme preconditioning may increase formation of NAPQI
  • Undernutrition reduces hepatic glutathione stores
  • Maximum Daily Dose
    Children:
    • 75 mg/kg BW
    • If younger than 12 y/o or less than 50 kg --> 10-15 mg/kg every 4-6 hours and no more than 5 doses per 24-hour period
    Adults:
    • 4 g given 325-650 mg every 4-6 hours or 1 g every 6 hours
  • Toxic Dose - minimum hepatotoxic dose as a single acute ingestion

    Children:
    • 150 mg/kg BW
    Adults:
    • 7.5 to 10 g
  • Toxic Dose
    In healthy children aged 1-6 y/o, threshold may be increased to 200 mg/kg
  • Signs and Symptoms
    Ingestion
    • Phase 1 - Preclinical Toxic Effects
    • Phase 2 - Hepatic Injury
    • Phase 3 - Hepatic Failure
    • Phase 4 - Recovery Phase
    Rectal
    • Similar clinical presentation as ingestion
    Intravenous
    • Similar clinical presentation as ingestion
  • Signs and Symptoms
    Phase 1: Preclinical Toxic Effects
    • 30 minutes to 24 hours after ingestion
    • Patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise
    • Liver function tests may remain within normal limits
    • If with elevated paracetamol concentration, metabolic acidosis which may lead to comatose state
  • Signs and Symptoms
    Phase 2: Hepatic Injury
    • 24 to 48 hours after ingestion
    • Elevation of transaminase levels
    • Elevated PT, INR, and bilirubin
    • Right upper quadrant tenderness may be present
    • Some patients may report decreased urinary output (oliguria)
    • Tachycardia and hypotension indicate ongoing volume losses
  • Signs and Symptoms
    Phase 3: Hepatic Failure
    • 72 to 96 hours after ingestion
    • Moderate elevations in hepatic transaminase levels
    • Hepatic necrosis and dysfunction associated with jaundice, coagulopathy, hypoglycemia, and hepatic encepalopathy
    • May have continued nausea and vomiting, abdominal pain, and a tender hepatic cage
    • Acute renal failure in some critically ill patients
    • Death from multiple organ failure
  • Signs and Symptoms
    Phase 4: Recovery Phase
    • 4 days to 3 weeks after ingestion
    • Complete recovery and resolution of symptoms
    • Death due to complications of liver failure
  • Diagnosis
    History Taking
    • Number of tablets taken
    • What time the overdose was taken
    • Dosage form of the medicine
    • Drug-drug interactions
    • Whether alcohol was taken at the same time
    • Any suicide risk present
    Serum Paracetamol Concentration
  • Diagnosis
    If the time of acute ingestion is UNKNOWN:
    • Determine serum paracetamol concentration
    If the time of acute ingestion is KNOWN:
    • Determine serum paracetamol concentration
    • Use Rumack-Matthew nomogram to estimate likelihood of hepatotoxicity
  • Rumack-Matthew Nomogram is used to interpret plasma paracetamol values to assess hepatotoxicity risk after a single, acute ingestion
  • Nomogram tracking begins 4 hours after ingestion and ends 24 hours after ingestion
  • Diagnosis
    Recommended serum studies are as follows:
    • Liver function tests (ALT, AST), bilirubin (total and fractionated), alkaline phosphatase
    • Prothrombin time (PT) with international normalized ratio (INR)
    • Glucose
    • Renal function studies (electrolytes, BUN, creatinine)
  • Diagnosis
    • Lipase and amylase - patients with abdominal pain
    • Serum human chorionic gonadotropin - females, child-bearing age
    • Salicylate level - patients with concern of co-ingestants
    • Arterial blood gas and ammonia - clinically compromised patients
    • Urinalysis - check for hematuria and proteinuria
    • ECG - detect additional clues for co-ingestants
    • CT scan - patients with altered mental status
  • Diagnosis
    Laboratory Findings in the Phases of Hepatotoxicity
    • Phase 1 - subclinical rise in serum transaminase levels
    • Phase 2 - elevated ALT and AST levels, PT and bilirubin values; renal function abnormalities may be present
    • Phase 3 - severe hepatotoxicity as evident on serum concentrations, hepatic necrosis to be confirmed by liver biopsy
  • Management
    • Patient stabilization and resuscitation
    • Perform decontamination if within 1 to 2 hours post-ingestion --> Gastric lavage within 1 hour, Activated charcoal within 2 hours
    • Admit patients on Rumack-Matthew Nomogram for treatment with N-acetylcysteine (NAC)
  • NAC is nearly 100% hepatoprotective