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