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Paracetamol Poisoning

Paracetamol Poisoning. Kent R. Olson, M.D. Clinical Professor of Medicine University of California, San Francisco Medical Director, San Francisco Division California Poison Control System. Case Study:.

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Paracetamol Poisoning

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  1. Paracetamol Poisoning Kent R. Olson, M.D. Clinical Professor of Medicine University of California, San Francisco Medical Director, San Francisco Division California Poison Control System

  2. Case Study: • A 17 year old young man took “pills” and some alcohol after failing his exams. He is drunk and depressed. • BP 120/80 HR 105 • Resp 14/min Temp 37 C • His airway is patent, he is breathing normally

  3. Case, continued: • He is treated with intravenous fluids, watched until sober, given a psychiatric referral, and sent home with his family. • 3 days later he returns with jaundice. WHAT IS YOUR DIAGNOSIS?

  4. Paracetamol poisoning • Diagnosis easily missed • often overlooked in history • no characteristic early symptoms or signs

  5. Paracetamol Poisoning • Common analgesic • often found in combination products • eg, with antihistamines, codeine

  6. AcetaminophenMetabolism ~ 50% ~ 45% P450 Sulfation (non toxic) Glucuronidation (non toxic) ~ 5% NAPQI N-acetylcysteine (NAC) Glutathione + NAPQI = nontoxic product Liver cell damage

  7. Paracetamol Toxicity: • Overdose: • sulfation and glucuronidation saturated • increased production of p-450 metabolite • glutathione eventually depleted • reactive intermediate NAPQI injures cells

  8. PCM toxicity, cont. • High-risk groups: enhanced p-450 activity • chronic alcoholics • chronic use of isoniazid (INH)

  9. Pharmacokinetics • Tablets dissolve rapidly • Peak level 3-4 hours after ingestion • May be delayed in the presence of other drugs (eg, antihistamines, anticholinergics, opiates)

  10. Pharmacokinetics, cont. • Volume of Distribution approx. 1L/kg • Ingestion of 200 mg/kg ~ 200 mg/L est. blood level • Elimination half-life normally 1-3 hours • Increased to 4-6 hours or more after overdose

  11. Clinical Manifestations of Toxicity: • Early: non-specific • anorexia, vomiting

  12. Clinical toxicicity, cont. • 24-48 hrs: • onset of liver injury • AST, ALT may exceed 10,000 IU • renal injury may also occur

  13. Paracetamol Toxicity, continued: • 2-5 days: • liver & kidney injury resolve in most patients • some patients may develop fulminant liver failure • progressive rise in PT/INR, bilirubin • metabolic acidosis, hypoglycemia • encephalopathy • DEATH

  14. Rarely - massive ingestions only: • > 600 mg/kg: early onset metabolic acidosis • Not due to liver failure • Probably mitochondrial poisoning • One case of massive ingestion >1500 mg/kg • Coma • Hypotension • Acidosis

  15. Prediction of Paracetamol Toxicity: • History: • acute ingestion of >200 mg/kg or >10 gm • 20 tablets in average-sized person • chronic use of >4-6 gm/day in a high-risk group • Chronic alcohol abuse, isoniazid use

  16. Prediction of PCM toxicity, cont. • Clinical evaluation: • serum PCM level is best predictor, if available • levels associated with “probable toxicity”: • 200 mg/L at 4 hrs after acute ingestion • 100 at 8 hrs • 50 at 12 hrs

  17. Tylenol “Extended Relief” Case: Serum PCM level APAP (mg/L) Prob. Toxic Poss. Toxic hrs Note: co-ingestion of Nyquil plus up to 44 g Tylenol ER Ref: Bizovi K et al: J Toxicol Clin Toxicol 1995; 33:510

  18. Potential Pitfalls with Nomogram: • Chronic intoxication • Delayed or erratic absorption • massive ingestion • mixed ingestion with opioids, anticholinergics

  19. Very early and transient increase in the PT/INR may predict later LFT rise • Normal PT/INR at 24 hrs may have good negative predictive value

  20. Gut decontamination for PCM • NO forced emesis • Activated charcoal preferred • Gastric lavage? • only for massive ingestions (eg, > 600 mg/kg)

  21. Treatment, continued • Antidote: N-acetylcysteine (NAC) • provides SH group - binds to NAPQI • most effective if started within 8-10 hrs after ingestion • can be given PO or IV • if vomiting, use IV route or give antiemetic • Alternate medication: oral methionine

  22. Summary • Ingestion < 200 mg/kg probably not toxic • If no serum level available treat based on dose • IV acetylcysteine or oral methionine • Start antidote within 8 hours • Liver or kidney damage delayed 24-48 hrs

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