paracetamol poisoning

1. PARACETAMOL
POISONING

2. PARACETAMOL
 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

3. 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

4. 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

5. 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

6. MECHANISM OF TOXICITY
 When the dose of paracetamol is high the glucuronide and sulfate conjugation
pathways become saturated, and increasing amounts undergo CYP-mediated
Nhydroxylation 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.
 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

8. STAGES OF INTOXICATION
 Stage 1 (time of ingestion to 24 hours) : • Patient typically has anorexia,
nausea, vomiting, and diaphoresis • Results of laboratory tests are usually
normal
 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
 Stage 3 (72 to 96 hours):• 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)

9. STAGES OF INTOXICATION
 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.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.

10. 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

11. MANAGEMENT
 Activated charcoal may be used in patients presenting within 1 hour.
 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

12. 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

13. 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

14. SUPPORTIVE MANAGMENT
 Give activated charcoal to all patients who present within 1hr post ingestion
 Give vitamin K 10mg to all cases of acute ingestion

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