Managing Paracetamol Overdose

• 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