PARACETAMOL
POISONING
Dr Mohd Abdul Basith
FEM ,MRCEM
Specialty doctor
Epsom & St Helier University Hospital
PARACETAMOL
(ACETAMINOPHEN)
• Non-steroidal anti-inflammatory drug(NSAID)
• Has analgesic and antipyretic effects but weak anti-
inflammatory properties
• Exerts its effects through the inhibition of cyclo-
oxygenase (COX)
• COX catalyses the formation of prostaglandins (PGs) and
other mediators that are important in the processing and
signaling of pain and control of the thermoregulatory
center of the brain.
PHARMACOKINETICS
• Oral acetaminophen has excellent bioavailability
• Peak plasma concentration occur within 30 to 60 minutes
• The half-life in plasma is about 2 hours after therapeutic
doses
METABOLISM
• Metabolized in the liver by conjugation with sulfate or
glucuronate (90%), and by CYP2E1 enzymes(5%),
and the remainder is secreted unchanged in the
urine(5%)
• The CYP2E1 enzyme pathway is the basis for
acetaminophen toxicity
DOSE OF
• Therapeutic dose is 10-15PARACETAMOL
mg/kg
Toxic dose:
• More than 7.5 gm (around 15 tablets) – minimal
toxicity, severe liver toxicity if > 15gms (30 tablets)
• In adults toxic dose is 150mg/kg
• In children under 12 years toxic dose is 200mg/kg
• In the presence of chronic liver disease or malnutrition,
even 2g of PCM can be a toxic dose
MECHANISM OF TOXICITY
• When the dose of paracetamol is high
• The glucuronide and sulfate conjugation pathways
become saturated, and increasing amounts undergo
CYP-mediated N-hydroxylation to form N-acetyl-para-
benzoquinoneminine (NAPQI)
• Eliminated rapidly by conjugation with glutathione
(GSH) and then further metabolized to a mercapturic
acid and excreted into the urine
• In acetaminophen overdose, hepatocellular levels of
GSH become depleted.
CONTD…
• The highly reactive NAPQI metabolite binds
covalently to cell macromolecules, leading to
dysfunction of enzymatic systems and structural and
metabolic disarray
• Depletion of intracellular GSH renders the
hepatocytes highly susceptible to oxidative stress
and apoptosis.
• Binding covalently to cellular proteins, causes cell
death
HEPATOTOXICITY:
• In adults, hepatotoxicity may occur after ingestion of a
single dose of 10 to 15 g (150 to 250 mg/kg) of
acetaminophen
• Doses of 20 to 25 g or more are potentially fatal
High risk people:
• Conditions of CYP induction (e.g. heavy alcohol
consumption, those on anticonvulsant drugs)
• Condition of GSH depletion (e.g. fasting or malnutrition)
• With pre-existing liver disease
• Those suffering from anorexia nervosa and other eating
disorders &
• HIV infection
PHASES OF
INTOXICATION
1) Stage 1 (time of ingestion to 24 hours) :
• Patient typically has anorexia, nausea, vomiting, and
diaphoresis
• Results of laboratory tests are usually normal
2) Stage 2 (24-72 hours):
• Results of laboratory tests begin to be abnormal
• Abnormalities include increases in serum transaminases,
bilirubin and PT
• Nephrotoxicity may be evident
3) Stage 3 (72 to 96 hours): CONTD…
• Also known as hepatic stage
• Severe signs of hepatotoxicity appear
• This includes:
Plasma ALT and AST levels often >10,000 IU/L, increased
in PT or INR
Hypoglycemia
Lactic acidosis and
A total bilirubin concentration above 70umole/l (primarily
indirect)
• Death most commonly occurs in this stage, usually from
multiorgan system failure.
CONTD…
4) Stage 4 (4 days-2 weeks) :
• Is the recovery stage
• Patients who survive stage III enter a recovery phase
that usually begins by day 4 and is complete by 7
days after overdose
• However, transient renal failure may develop 5-7
days after ingestion (Back pain, proteinuria,
hematuria)
• Complete hepatic recovery may take 3-6 months.
APPROACH TO THE
PATIENT
• ABCDE
• History
• Examination
• Investigations
• Initial baseline investigations
• LFT, PT/INR, blood glucose, platelet count, electrolyte,
urine routine
• Plasma paracetamol level
• Determined after 4 hours of ingestion
MANAGEMENT
1) Activated charcoal may be used in patients presenting
within 1 hour.
2) Antidotes for paracetamol poisoning
a. N-acetylcysteine (NAC)
b. Methioinine
Act by replenishing hepatic glutathione
N-acetyl cysteine may also repair oxidation damage
caused by NAPQI
NOMOGRAM FOR
PARACETAMOL
N-ACETYLCYSTEINE
(NAC)
• IV is highly efficacious if administered within 8 hours of
the overdose
• Should not be delayed in patients presenting after 8
hours to await a paracetamol blood concentration result.
Dose:
• 150mg/kg in 200 ml 5% dextrose over 15
minutes
• Followed by 50mg/kg in 500 ml 5% dextrose
over 4 hours
• Followed by 100mg/kg in 1000 ml 5%
dextrose over 16 hours
CONTD…
• Can be stopped if the paracetamol concentration comes
below the appropriate treatment line.
• Important adverse effect is related to dose-related
histamine release
• The ‘anaphylactoid’ reaction - itching and urticaria, and in
severe cases, bronchospasm and hypotension, angio-
edema
• Managed by temporary discontinuation of acetylcysteine
and administration of a antihistamine
• Chlorpheniramine 10-20 mg i.v. in an adult may be given
METHIONINE
• An alternative antidote in paracetamol poisoning
• 2.5 g orally 4-hourly to a total of four doses
• Less effective, especially after delayed presentation
CONTD….
• If patient presents after 15 hours of ingestion
LFTs,PT, RFT measure and antidote
started
• Severe liver function abnormality Arterial blood gas
sample taken
• Liver transplantation should be considered in patient
if liver failure due to paracetamol poisoning
Summary of
management
The management of a
paracetamol overdose
ANTIDOTE REGIMENS FOR
PARACETAMOL POISONING
N -acetylcysteine (intravenously)
• 150 mg/kg over 15 min, then 50 mg/kg in 500 mL of 5% dextrose in
the next 4 hours and 100 mg/kg in 1000 mL of 5% dextrose over the
ensuing 16 hours.
• Injection Vitamin K 10 mg iv
• Total dose: 300 mg/kg over 20-25 hours.
Methionine (orally)
• 2.5 g initially, then 2.5 g 4-hourly for a further three doses.
• Total dose: 10 g methionine over 12 hours.
N -acetylcysteine (orally)
• 140 mg/kg initially, then 60 mg/kg every 4 hours for 17 additional
doses.
• Total dose: 1330 mg/kg over 72 hours
REFERENCES:
• Tintinallis Emergency Medicine, A Comprehensive
Study Guide 7th edition
• Kumar and Clark's clinical medicine, 8thedition
• Goodman & Gilman‘s pharmacological basis of
therapeutics - 11th edition
THANK
YOU
