PARACETAMOL

POISONING

By Group C
 • Introduction
• Pharmacology and Dosing

OVERVIEW • History, Examination & Staging

• Management
• Case discussion
“All things are poison and nothing is
without poison; only the dose makes
a thing not a poison.”

- Paracelsus, Father of Modern

Toxicology (1493-1541)
LETHAL DOSES
INTRODUCTION
• Paracetamol is the most common analgesia and anti-pyretic used
• Has an excellent safety profile when administered in therapeutic doses
• Hepatotoxicity can occur in overdose if mis-used or in at-risk populations
• Paracetamol overdose may occur intentionally and accidentally - the latter due to the high number of
combination products available over the counter. There are also frequent cases of accidental poisoning
in children
FORMULATION 
& DOSES
Oral (syrup or tablet)
Adult & Children: 15mg/kg 4-6hourly
Max 1g/day or 60mg/kg/day
Suppository
Adult: 0.5-1g 4-6hourly (Max 1g/day)

Children 20-30mg/kg (Max 4

 doses/day)
Intravenous
Adult & Children: 15mg/kg 4-6 hourly

Max 1g/day or 60mg/kg/day

https://www.mims.com/malaysia/drug/info/paracetamol?mtype=generic
 Exact mechanism is
Analgesia
not known

Anti-pyrexia Postulated to be due to

COX-2 inhibition causing
decrease synthesis of
No anti-inflammatory prostaglandin
effect

PHARMACODYNAMICS

Scarth, E. and Smith, S., 2016. Drugs in anaesthesia and

intensive care. Oxford University Press
 • Good oral & rectal absorption
• High oral bioavailability

• Low protein bound

• Large Vd
• Crosses BBB and BPB

PHARMACOKINETIC • Metabolised in liver by

3 separate pathways
S
• 90% excreted as glucuronide &
sulphate products in urine
• 10% excreted unchanged in
urine
• T1/2 2-4 hours

Scarth, E. and Smith, S., 2016. Drugs in anaesthesia and intensive care. Oxford University Press.
Mohd Zain, Z.F.A.I., Fathelrahman, A.I. and Ab Rahman, A.F., 2006. Characteristics and outcomes of paracetamol poisoning cases at a general hospital
in Northern Malaysia. Singapore medical journal, 47(2), p.134.
• Females • Tablet form
• 15 – 30 years of age

• Symptomatic at presentation

• Intentional Ingestion
• Presented within 8 hours
• Non-toxic when plotted against Rumack
Matthew normogram
• Non-toxic when using Hepato-toxic dose

Mohd Zain, Z.F.A.I., Fathelrahman, A.I. and Ab Rahman, A.F., 2006. Characteristics and outcomes of paracetamol poisoning cases at a general hospital in
Northern Malaysia. Singapore medical journal, 47(2), p.134.
 PARACETAMOL
METABOLISM
•In therapeutic amounts, acetaminophen is primarily metabolised
by the liver through sulfation (20%-46%)
and glucuronidation(40%-67%) with <5% undergoing direct renal
elimination 

• A small percentage is also oxidised by the cytochrome P-450

system to a reactive metabolite, N-acetyl-
benzoquinoneimine(NAPQI)

Tintinalli, J., 2015. Tintinallis emergency medicine A

comprehensive study guide. McGraw-Hill Education.
 PARACETAMOL
METABOLISM
• This is quickly detoxified by hepatic glutathione to a
nontoxic  acetaminophen-mercapturate compound that is renally
eliminated

• After acetaminophen overdose, hepatic metabolism

through glucuronidation and sulfation may be saturated, and a
larger proportion of acetaminophen therefore metabolised by
cytochrome P-450 to NAPQI, depleting intracellular glutathione

Tintinalli, J., 2015. Tintinallis emergency medicine A

comprehensive study guide. McGraw-Hill Education.
 PARACETAMOL
METABOLISM
• When hepatic stores of glutathione decrease to  <30% of
normal, NAPQI binds to other hepatic macromolecules, and
hepatic necrosis ensues
• Although clinical manifestations are classically delayed, hepatic
injury actually occurs early, within 12 hours of exposure

Tintinalli, J., 2015. Tintinallis emergency medicine A

comprehensive study guide. McGraw-Hill Education.
••Ingestion of large amount of PCM causes
saturation of non-NAPQI pathways and
increase NAPQI synthesis

••Excess NAPQI causes exhaustion of

glutathione and its accumulation

••NAPQI and tissue injury

•-oxidative stress 
•-enzyme inhibition
•-mitochondrial dysfunction causing
decreased ATP synthesis and Ca release

Tintinalli, J., 2015. Tintinallis emergency medicine A

comprehensive study guide. McGraw-Hill Education.
HISTORY,
EXAMINATION &
STAGING
 RISK FACTORS
HISTORY & -decreased hepatic glutathione
storage
EXAMINATION -ingestion of cytochrome p450
inducing drugs
DEMOGRAPHY

EXPOSURE HISTORY
-type of PCM preparation SYMPTOMPS & SIGNS
-time of ingestion -nausea, vomiting, abdominal pain,
-amount ingested yellowish skin & eyes
-pattern of ingestion -altered sensorium, bleeding tendencies
-co-ingestion of other substances -unstable hemodynamics
-tender hepatomegaly
 Has my patient ingested a toxic dose of
paracetamol ?
My patient is >6 years and My patient is <6 years and My patient has risk factors
has no risk factors has no risk factors
>150 mg/kg as a single dose >75 mg/kg as a single dose or
>7.5 g (or 150 mg/kg) as a or over 8 hours over 24 hours
single dose OR
OR > 150 mg/kg/day for 48
>7.5 g (or 150 mg/kg) over 24 hours
hours
OR
>6 g/day (or 150 mg/kg/day)
for 48 hours

Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education
Wallace, C., Dargan, P. and Jones, A., 2002. Paracetamol overdose: an evidence based flowchart to guide management. Emergency medicine journal: EMJ, 19(3),
p.202..
RISK FACTORS OF PARACETAMOL
POISONING

Decreased liver glutathione storage Cytochrome p450 inducing drugs

• Chronic liver disease • Chronic alcoholic ingestion

• Chronic malnutrition • Phenytoin
• Anorexia nervosa, bulimia • Carbamazepine
• HIV • Phenobarbitone
• Rifampicin

Greene, S.L., Dargan, P.I. and Jones, A.L., 2005. Acute poisoning: understanding 90% of cases in a nutshell. Postgraduate medical journal, 81(954),
pp.204-216.
 Stage 4 Stage 1 • Nausea, vomiting
• Complete resolution or
Resolution/
death Pre-clinical
death • Normal LFT
(0-24 hours)
(>96 hours)

STAGES OF PCM TOXICITY

• Nausea, vomiting
Stage 3 Stage 2 • Decrease nausea and
• Symptoms and signs of vomiting
acute liver failure Encephalopathy Hepato-toxic
(72-96 hours) (24-72 hours) • Abdominal pain
• Multiorgan failure
• Abnormal LFT
Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education.
 • FBC

• RP

NO M
SIS
• LFT

AG RI
INVESTIGATIONS

SE
A S R IT
DI NF
• Paracetamol TDM level • Coagulation profile

VE
SE
CO

SS Y
• Blood gas

• Lactate

• DXT
RULE OUT DDX
 RUMACK-MATTHEW
NORMOGRAM
• 2 lines
-line above is for toxic dose ≥200 mg/kg
-line below is for toxic dose ≥150 mg/kg (as per US FDA, to allow
for potential errors due to timing of collection and PCM assays)
• Start treatment protocol if serum PCM level exceeds inferior line
• Pre-requisites
-only for adults
-only for patients without risk factors
-only for quick release PCM (not for sustained release PCM)
-only for single ingestion
-only applicable between 4-24 hours. Not applicable if time of
ingestion unknown

Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education.
 PRESCOTT
NORMOGRAM
• 2 lines
-line above is for patients without risk factors
-line below is for patients with risk factors

• Start treatment protocol if serum PCM level exceeds line

• Pre-requisites
-only for adults
-only for quick release PCM (not for sustained release PCM)
-only for single ingestion
-only applicable between 4-16 hours. PCM level >16 hours is
extrapolated. Not applicable if time of ingestion unknown

Greene, S.L., Dargan, P.I. and Jones, A.L., 2005. Acute poisoning: understanding 90% of cases in a nutshell. Postgraduate medical journal, 81(954),
pp.204-216.
 Appropriate triage
Secure ABCD. Resuscitation and stabilization
Focused History, Examination & Investigation

Decontamination
MANAGEMENT NAC
Hemodialysis
Toxicologist consultation

Management of complication of disease and treatment

Appropriate referral and disposition
 • Consider oral charcoal ± gastric lavage if

DECONTAMINATION -patient presents within 1 hour

-ingestion of large amount
-ingestion of slow released products
-multiple substance ingestion

Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education
 N-acetyl cysteine

• Antidote of choice

N-acetyl cysteine (NAC) • Mechanism of action

-increase sulfation
-replenishes glutathione reserve
-acts as a glutathione substitute
-decrease tissue oxidative damage

• Best administered within 8 hours

Hoffman, R.S., Howland, M.A., Lewin, N.A., Nelson, L.S. and Goldfrank, L.R., 2014. Goldfrank's Toxicologic Emergencies, (ebook). McGraw Hill
• Oral dose (adult and paediatric)
-140mg/kg stat followed by
-70mg/kg every 4 hours x 17 doses

• IV dose (adult) – 3 stage infusion

-150 mg/kg in 200 ml D5 over 1 hour followed by,
• Both oral and IV route are equally effective but oral route
-50 mg/kg in 500 ml D5 over 4 hours followed by,
causes more vomiting
-100 mg/kg in 1000 ml D5 over 16 hours
• IV route is preferred for fulminant liver failure, pregnancy
• IV dose (pediatric) - 3 stage infusion
and oral intolerance (e.g. nausea and vomiting)
-150 mg/kg in 3 ml/kg D5 over 1 hour followed by,
-50 mg/kg in 7 ml/kg D5 over 4 hours followed by,
• No dose adjustments in AKI/ ALI
-100 mg/kg in 14 ml/kg D5 over 16 hours

• 2 stage infusion regime is also present for pediatric group

• Higher dose regime is available for fulminant liver failure

Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education
Wallace, C., Dargan, P. and Jones, A., 2002. Paracetamol overdose: an evidence based flowchart to guide management.  Emergency medicine journal: EMJ, 19(3),
p.202..
• Anaphylactoid reactions may occur

• Continue IV infusion in mild reaction

• Stop IV infusion in severe reaction and restart at slower rate

after treatment

• Consider switching to oral NAC if not improving

• Never withhold NAC

• Reaction is more severe in asthmatics and very low PCM

level

Heard, K.J., 2008. Acetylcysteine for acetaminophen poisoning. New England Journal of Medicine, 359(3), pp.285-292.
SCENARIOS OF PCM INGESTION

• Single dose PCM ingestion with or without risk factors

• Staggered dose PCM ingestion with or without risk factors
• Sustained release PCM over ingestion
• Massive PCM over ingestion
Time since ingestion

> 24 hours/unknown time of ingestion

• Consider decontamination if time unknown
• Take serum PCM level and start NAC empirically
-if serum PCM > 66 umol/L OR symptomatic OR ↑ AST/ALT, continue NAC
-if serum PCM < 66 umol/L OR asymptomatic OR normal AST/ALT, stop NAC
24 Accept and further workout if
Allow discharge for
SINGLE
Patients
8-24 hours withoutDOSE PCMwhoOVER
risk factors ingested INGESTION
>150 mg/kg dose
• Take serum PCM level and start NAC empirically and KIV stop if patient asymptomatic, plasma PCM
WITH
Patients OR
without
below level and WITHOUT
risk
AST/ALT
factors OR
normal RISK<150
who ingested FACTORS
mg/kg dose
Patients with risk factors who
OR ingested >75 mg/kg dose
8 OR ingested <75 mg/kg dose
Patients with risk factors who
<8 hours Amount and time of ingestion unknown
• Decontamination if < 1 hr
• Take serum PCM level 4 hours post ingestion
-if result will be available <8 hours, wait and see plasma PCM level
-if result will not be available <8 hours, start NAC and KIV stop if patient asymptomatic, plasma PCM below
level and ST/ALT normal
Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education.
 Take time of exposure as time of 1st ingestion
Accept and further workout if
If patient presents ≤8 hours
Allow of ingestion,
discharge for follow <8 hours
STAGGERED
Patients withoutDOSE PCM
algorithm
risk factors OVER
who ingested >150INGESTIONS
mg/kg dose
WITH OR risk
Patients without WITHOUT
factors OR RISK
who ingested FACTORS
<150 mg/kg dose
If patient presents
Patients with risk>8factors
hourswho
ORof ingestion,
ingested >75follow
mg/kg>8 hours
dose
algorithm
Patients with risk factors OR ingested <75 mg/kg dose
who
-repeat serum Amount
PCMand time ofserum
if initial ingestion
PCMunknown
is taken within 2
hours from last ingestion

Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education.
SUSTAINED RELEASE PCM
OVER INGESTION

Follow standard algorithm

Repeat serum PCM level after 4-6 hours if initial serum PCM
level is negative

Consider treatment if lab results abnormal

Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education.
MASSIVE PCM OVER INGESTION

• Defined as PCM ingestion ≥40 g or ≥500 mg/kg or ≥ double

the normogram line

• NAC regime
150 mg/kg over 1 hour followed by
50 mg/kg over 4 hours followed by
200 mg/kg over 16 hours

Tintinalli, J., 2015. Tintinallis emergency medicine A comprehensive study guide. McGraw-Hill Education.
 RENAL REPLACEMENT
THERAPHY

Gosselin, S., Juurlink, D.N., Kielstein, J.T., Ghannoum, M., Lavergne, V., Nolin, T.D., Hoffman, R.S. and Extrip Workgroup, 2014. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup.  Clinical toxicology, 52(8),
THANK OU.