Paracetamol overdose

1. Collective Review Keerati Supsaman

2. Overview Absorption, Metabolism, Distribution, Excretion. Mechanism of action Pharmacology01 Hepatotoxicity, Nephrotoxicity, Neurological toxic, Metabolic acidosis. Toxicokinetic02 Diagnosis criteria, Diagnosis testing, Investigation. Diagnosis, Risk stratification03 Stage, physical examination Sign and symptom04 Resuscitation, GI Decontamination, Antidote, Elimination Treatment05 Criteria, Liver transplant Prognosis06

3. 1948 Discovery of Paracetamol 1878 Two France Doctors. Wrong medication for anti-parasite. From Naphthalene-> Acetanilide. Decrease body temperature Side effect: Methemoglobinemia. Germany doctor: Phenacetin. Analgesic nephropathy 1948 Found N-acetyl-P-aminophenol Co-Metabolite of Acetanilide and Phenacetin .

4. Pharmacokinetics ABOSORPTION What do we need to know about Paracetamol? DISTRIBUTION METABOLISM EXCRETION

5. Pharmacokinetics ABOSORPTION • Good GI absorption: Oral Bioavailability 60-98% • Main absorption at Small intestine • Depend on gastric emptying time • ↑Gastric emptying time ↓Absorption rate • Example: Opioid • 3 Main types • Immediate-release : 30-45 mins in adult and 30 mins in ped syrups • Extended-release : in 1-2 h and within 4 h • Rectal route in pediatric : 107 mins to 5 hours

6. Pharmacokinetics DISTRIBUTION • Mainly in bloodstream • Volume of distribution(Vd) = 1 L/Kg • Protein binding ↓~10-30%

7. Pharmacokinetics METABOLISM: Liver • 3 Group • Non-toxic metabolite 90% • Toxic metabolite 5% • Unchanged 5% Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. (2016). Journal of Clinical and Translational Hepatology, 4(2). doi: 10.14218/jcth.2015.00052

8. Pharmacokinetics EXCREATION • Renal clearance 0.16-0.2 mL/min/kg • Unchanged form metabolite <5% • Biliary excretion 2.6 % • Hemodialysis

9. Paracetamol: Mechanism of action A central serotonergic mechanism Prostaglandin H2 Synthetase inhibition Inhibit COX–3 Indirect activation of CB1 receptors Inhibit L-arginine/Nitric oxide pathway

10. Paracetamol: Mechanism of action A central serotonergic mechanism https://nba.uth.tmc.edu/neuroscience/m/s2/chapter08.html

11. Paracetamol: Mechanism of action Prostaglandin H2 Synthetase inhibition http://tmedweb.tulane.edu/phar mwiki/doku.php/acetaminophen

12. Paracetamol: Mechanism of action Prostaglandin H2 Synthetase inhibition http://tmedweb.tulane.edu/phar mwiki/doku.php/acetaminophen

13. Paracetamol: Mechanism of action Inhibit COX–3

14. Paracetamol: Mechanism of action Indirect activation of CB1 receptors

15. Paracetamol: Mechanism of action Indirect activation of CB1 receptors

16. Paracetamol: Mechanism of action Inhibit L-arginine/Nitric oxide pathway

17. Toxicokinetic Hepatic injury, Kidney injury, CNS injury, Metabolic acidosis NAPQI

18. Pharmacokinetics METABOLISM: Liver • 3 Group • Non-toxic metabolite 90% • Toxic metabolite 5% • Unchanged 5% Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. (2016). Journal of Clinical and Translational Hepatology, 4(2). doi: 10.14218/jcth.2015.00052

19. Toxicokinetic Toxic metabolite NAPQI https://www.mja.com.au/system/files/issues/186_07_020407/lu b11145_fm.pdf: Accidental paracetamol poisoning

20. Toxicokinetic Hepatic injury

21. Toxicokinetic Kidney injury • ↑Renal NAPQI -> renal cell death from • Renal CYP2E1 enzyme • Renal PGH synthesis • APAP-GSH -> p-aminophenol: Nephrotoxic metabolite • prostaglandin-mediated renal medullar ischemia • Hepatic failure -> Prerenal AKI, hepatorenal syndrome

22. Toxicokinetic CNS injury • Unknown mechanism • Hypothesis • Decrease CNS glutathione • Serotonin, opioid effect Lactic acidosis • Unknown mechanism • Mitochondria dysfunction • Impair aerobic respiration

23. Diagnosis Diagnosis criteria, Diagnosis testing, Investigation APAP

24. Tintinali’s Goldfrank’s Australia CPG Single Dose Adult>6 yrs >10 g, > 200 mg/kg >7.5 gm >10g, >200mg/kg Child<6 yrs >200 mg/kg >150 mg/kg >200 mg/kg RSTI Adult>6 yrs >10g,>200mg/kg in 24 h >10g,>200mg/kg in 24h >10g,>200mg/kg in 24 h >6g, >150mg/kg in 24 h x 2days >6g, >150mg/kg in 24 h x 2days >12g, >300 mg/kg in 48 h >60mg/kg[>4g] in48 h + clinical Child<6 yrs >200 mg/kg in 8h >150 mg/kg in 24 x2 days >100 mg/kg/d in 72h Massive >= 30 g

25. Sign and symptom Early recognition and treatment of patient with Paracetamol poisoning are essential.

26. Risk stratification Pediatrics Normal child Risk ⇣ • Sulfation > adult • Elixer Prep Add propyleneglycol ⇣ NAPQI Prolong use in chronic illness GSH↓Risk↑ Geriatrics Paracetamol metabolism is Age-dependent ↑Age ,Risk↑ Pregnancy Cross placenta Fetal undeveloped CYP enzyme 1st trimester : Abortion 2nd trimester: fetal Demise Alcoholism CYP2E1↑, GSH↓ Risk↑ in RSTI Normal Risk in acute over dose Or normal dose Acute alcohol ingestion

28. Amount of NAPQI, Glutathione Metabolite measure CYP2E1 activity Enzyme Activity mRNA122, HMGB-1 Biomarker Rumack –Matthew normogram Serum paracetamol level Diagnosis Testing

29. • Unknown, Uncertain time of ingestion • Duration > 24 h • Prior treat with NAC • Modified-release paracetamol • Intravenous paracetamol • RSTI Limitation of nomogram Rumack-matthew nomogram

31. Acetaminophen-Aminotransferase multiplication product [APxAT] < 1500 mg.IU/L 1500-10000 mg.IU/L No need treatment. Low risk - Use AST or ALT which is higher - If no paracetamol level use 5 instead Possible > 10,000 mg.IU/L Probable Paracetamol level x AST/ALT

32. Australia& New Zealand guideline 2019 Investigation

33. Treatment Resuscitation, GI decontamination, Specific antidote, H/D Acetylcysteine

34. Treatment Resuscitation Primary survey Usually normal01 02 Decontamination If conscious change beware hypoglycemia DTX Before Mx No role of NG lavage : rapid absorption Activated charcoal more benefit

35. 02 Decontamination No role of NG lavage : rapid absorption Activated charcoal more benefit Activated charcoal: 50 g in an adult Awake and cooperative patients! • Within 2 hours of ingesting a toxic dose. • Within 4 hours of ingesting 1. ≥ 30 g of immediate- release paracetamol 2. toxic dose of modified-release paracetamol. (Large dose: may be indicated up to 24 hours) • Not indicated in children < 6 years!

36. Treatment Resuscitation Primary survey Usually normal01 02 03 Decontamination Enhance Elimination If conscious change beware hypoglycemia DTX Before Mx No role of NG lavage : rapid absorption Activated charcoal more benefit Hemodialysis Plasma exchange Liver dialysis

37. 03 Enhance Elimination Hemodialysis Plasma exchange Liver dialysis Hemodialysis Plasma exchange Liver dialysis Low Vd: Both Intermittent, continuous CVVHD able to Eliminate drug Indication: • Paracetamol level > 500 • Slow clearance in normal treatment Must increase dose NAC during HD • improve coagulopathy, • minimal eliminate plasma paracetamol level • Not enough study • MARS,SPAD • Use in prior to Transplant • Maintain hemodynamic • Improve encephalopathy

38. 04 Specific Antidote Mechanism of action • Improve hepatic sulfation -> decrease serum paracetamol • Precursor of glutathione synthesis • Act as glutathione • antioxidant ,decrease free radical • increase oxygen delivery to mitochondria, increase ATP N-acetylcysteine(NAC)

39. 04 Specific Antidote 2 Routes • Oral route: 72 hours regimen • 140 mg/kg(loading dose) • then 70 mg/kg q 4 hours x 17 dose • Total 1330 mg /kg • Dilute in to 5% and mixed with soft drink • Repeat dose if vomit within 1 hour • IV Route N-acetylcysteine(NAC)

40. 04 Specific Antidote N-acetylcysteine(NAC) Three-Bag regimen Two-Bag regimen NAC (mg/kg) 5%DW (mL) Duration IV drip in NAC (mg/kg) 5% glucose or NSS (mL) Duration IV drip in Initial 150 mg/kg 200 mL 15-60 mins 200 mg/kg (Max 22g) 500 mL (เด็ก 7 mL/kg) 4 h Second 50 mg/kg 500 mL 4 h 100 mg/kg (Max 11g) 1000 mL (เด็ก 14 mL/kg) 16 h Third 100 mg/kg 1000 mL 16 h Dosing should be based on actual body weight rounded up to the nearest 10 kg, with a ceiling weight of 110 kg. Same efficacy: Decrease in side effect such as non-IgE mediated anaphylactic reaction or anaphylactoid

41. 04 Specific Antidote N-acetylcysteine(NAC) each ampule containing a 20% solution. (i.e. 200 mg acetylcysteine per 1 mL)

42. Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand - March 2020

43. New guideline Acute ingestion Immediate-Release Modified- Release RSTI Massive ingestion Unknown time Multiple ingestion Massive ingestion. Major changes in management in the guidelines: • Two-bag acetylcysteine infusion regimen • Massive overdose with double the nomogram line should increased dose of acetylcysteine. • All potentially toxic modified release should receive a full course of acetylcysteine.

44. Acute immediate release paracetamol ingestion management flow chart

47. 04 Specific Antidote Multiple or staggered immediate release paracetamol ingestions • multiple or staggered paracetamol ingestions over more than 2 hours for the purpose of deliberate self-harm • be treated as per acute immediate release • If the first paracetamol concentration was measured within 2 hours of the last ingested paracetamol dose, repeated after 2 hours to ensure there is no ongoing absorption Specific situation

48. 04 Specific Antidote Unknow time of ingestion If the time of ingestion is unknown, or clinician is not confident of the history of ingestion it is safest to treat the patient as a delayed presentation. recommendation is to follow the > 8 hours scenario in Massive ingestion >= 30 g If the concentration is double nomogram line Increase second bag regimen If triple nomogram: Consult toxicologist Specific situation

49. 04 Specific Antidote Cessation of Acetylcysteine if all the following criteria have been met: • ALT or AST are decreasing • INR < 2.0 • Patient clinically well N-acetylcysteine(NAC)

50. Acute ingestion modified release paracetamol management flow chart

52. 04 Specific Antidote Cessation of Acetylcysteine if all the following criteria have been met: • ALT or AST are decreasing • INR < 2.0 • Patient clinically well AND For modified-release ingestions and those with an initial paracetamol concentration greater than double the nomogram line: paracetamol concentration < 10 mg/L (66 μmol/L) N-acetylcysteine(NAC)

53. Repeated supratherapeutic ingestion (RSTI) management flow chart

54. Repeated supratherapeutic ingestion (RSTI) management flow chart

55. 04 Specific Antidote Pediatric (< 6 years) liquid paracetamol ingestion • Activated charcoal is not indicated in this group as liquid preparations have rapid absorption. • measured at least 2 hours post-ingestion • If the 2 (to 4) hour concentration is below 150 mg/L (1000 μmol/L), acetylcysteine is not required. • If the 2-hour paracetamol concentration is greater than 150 mg/L repeated 4 hours post-ingestion and acetylcysteine commenced if this is ≥ 150 mg/L (1000 μmol/L). Specific situation

56. 04 Specific Antidote Intravenous paracetamol medication errors A clinical toxicologist or Poisons Information Centre should be contacted regarding these cases. Specific situation

57. The King’s college criteria For paracetamol toxicity The patient who met this criteria has survival rate <20% Immediate transplant must be perform. • Arterial pH <7.3 or Lactate> 3.0 After adequate fluid resuscitate Or all of the following • Creatinine >= 3.3 mg/dL • INR>6.5 or PTT > 100 sec • Hepatic encephalopathy grade III, IV Liver transplant King’s college criteria O r g a n d o n a t i o n

58. STOP TREATMENT WHEN MET THE CRITERIA Consult psychiatrist in Suicidal case AS SHOWN IN PREVIOUS SLIDE GOLDFRANK’S CRITERIA • Serum paracetamol cannot detected • AST with in normal limit. . D I S P O S I T I O N AFTER TREATMENT D I S C H R A G E H O M E

59. Prognosis KCC, APACHE, MELD, Score Acetylcysteine

60. Prognosis tool MOST SPECIFICITY IN Mortality are KCC, APACHEII> 12,SOFA>12 คะแนน Sensitivity % Specificity % PPV NPV King’s college criteria 47 83 0.70 0.65 Acute physiology and chronic health evaluation II(>12) 67 76 0.69 0.75 Sequential organ failure Assessment (>12) 67 80 0.74 0.74 Model for end stage liver disease (>32) 89 25 0.49 0.77 Lactate (>3.3) 91 52 0.69 0.83

61. Thank you

Paracetamol overdose

Paracetamol overdose

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