Nick Buckley: Paracetamol: More than Meets the Eye

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Buckley analyses the details and prescribes a more logical remedy for a toxic overdose.

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Nick Buckley: Paracetamol: More than Meets the Eye

  1. 1. Paracetamol poisoning Nick Buckley Professorial Medicine Unit UNSW NSW Poisons Information Centre South Asian Clinical Toxicology Research Collaboration (www.sactrc.org) March 2013
  2. 2. Paracetamol poisoning for the distracted
  3. 3. Paracetamol Toxicity 90% Conjugation P4 50 Glutathione NAPQI Free Radical
  4. 4. Paracetamol overdose – Would you like social media with that? (or acetylcysteine) A 24 yo woman takes 15 grams of paracetamol • Paracetamol level at 12 hours = 300 nmol/mL (45 mg/L) •
  5. 5. The State of the art Hypertox APAP-APP
  6. 6. Questions M According to guidelines, should she be treated with acetylcysteine? MWhere is she? MWhat year is it? M M What is the risk of hepatotoxicity and death if she is treated with acetylcysteine? What is the risk of hepatotoxicity & death if she if not?
  7. 7. What threshold for treatment? Treatment Nomograms 300 & 200 150 Prescott LF et al Lancet 1971; 519-522 m g /L 100 & 50 25 & & 10 0 5 10 Time 15 20 Rumack BH, Mathew H. Paediatrics 1975; 55:871-876 ? “The high risk line” UK circa 1995 Schmidt LE, Dalhoff K. Br J Clin Pharmacol 2001 Jan;51:87-91
  8. 8. What threshold for treatment? Treatment Nomograms 300 & 200 150 Prescott LF et al Lancet 1971; 519-522 m g /L 100 & 50 25 10 0 5 10 Time 15 20 Rumack BH, Mathew H. Paediatrics 1975; 55:871-876
  9. 9. MHRA (UK) – August 2012 Treatment Nomograms 300 200 150 mg/L 100 & 50 25 & 10 0 5 10 Time 15 20 Rumack BH, Mathew H. Paediatrics 1975; 55:871-876 MHRA UK (estimated to prevent one death in UK every 37.5 years vs using 150 line)
  10. 10. Questions M According to guidelines, should she be treated with acetylcysteine? MWhere is she? MWhat year is it? M M What is the risk of hepatotoxicity & death if she if not? What is the risk of hepatotoxicity and death if she is treated with acetylcysteine?
  11. 11. Time to acetylcysteine (hours) and hepatotoxicity (%) 30 25 20 15 10 5 0 0 to 4, 4 to 8, 8 to 12, 12 to 16, 16 to 20, 20 - 24
  12. 12. CAOS theory – Individualised risk estimates are as easy as Psi.
  13. 13. Sivilotti et al 2005
  14. 14. APAP-APP
  15. 15. Remaining ‘controversies’ in antidotes for paracetamol poisoning? • What is the role of liver transplant??? King’s College criteria for transplant in paracetamol induced liver disease Arterial pH < 7·3 after adequate fluid resuscitation. OR (all of) Grade or IV encephalopathy and Prothrombin time > 100 seconds and Serum creatinine > 300 In a 24 hour period. mol/L
  16. 16. Survival curves depending on decision to transplant with "Kings criteria" 100 Survival % Transplanted QALYs extrapolations Not transplanted 50 0 0 10 20 30 40 50 60 Years Q J Med 2008; 101:723–729
  17. 17. Other ‘first world problems’ • • • Slow release paracetamol preparations Diagnosis of occult overdose presentations with acute liver failure Very Early vs 4-8 hour NAC treatment
  18. 18. Extended release OD » MJA 2008; 188: 310-311
  19. 19. » » James LP, Letzig L, Simpson PM etal. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metabolism and Disposition. 2009: 37(8); 1779-1784. James LP, Capparelli EV, Simpson PM etal. Acetaminophen-Associated Hepatic Injury: Evaluation of Acetaminophen Protein Adducts in Children and Adolescents With Acetaminophen Overdose. Nature. 2008: 84(6); 684-690.
  20. 20. Dose-related, long-half-life
  21. 21. Given acetylcysteine is about as proven an antidote as we have – how does it work? • Antioxidant – – Direct Conversion to cysteine – • • rate limiting step in glutathione synthesis “Free radical” scavenger
  22. 22. How quickly should you scavenge free radicals?
  23. 23. Five decades of paracetamol poisoning but still more than meets the eye or iphone • New evidence still needed • • • • • No RCTs comparing different NAC regimens Early risk prediction with adducts? Duration of NAC in established hepatotoxicity? Better & earlier prediction of likely fatal outcome Decision support tools • Risk prediction
  24. 24. Questions?

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