Paracetamol Poisoning

Question 1

What is paracetamol metabolised to?

Answer 1

1. Paracetamol sulphate (main pathway)
2. Paracetamol glucuronide (main pathway)
3. NAPQI (N-acetyl-p-benzoquinone-imine) - only 15% of therapeutic dose goes this way - toxic (causes renal and liver failure)

Question 2

How is NAPQI (N-acetyl-p-benzoquinone-imine) broken down

Answer 2

Using Glutathione (GSH) - glutathione is an anti-oxidant so it protects against cellular damage from reactive oxygen species

Question 3

What happens to the metabolic pathway of paracetamol in an overdose?

Answer 3

Fill up normal pathway so more NAPQI (N-acetyl-p-benzoquinone-imine) made. NAPQI causes hepatic injury due to glutathione depletion and its direct oxidising and arylating effects

Question 4

Factors influencing paracetamol hepatotoxicity

Answer 4

1. dose ingested / absorbed
2. plasma paracetamol concentration
3. time to antidote administration
4. Whether the tablets were taken as a single acute event or in a staggered fashion

Question 5

Toxic dose of paracetamol ingested/absorbed

Answer 5

Relates to patient weight. >150mg/kg = serious liver damage possible

Question 6

How to know if paracetamol plasma concentration of patient is hepatotoxic

Answer 6

Plot dot on treatment nomogram (concentration-time graph). If above the line - severe liver damage possible - give antidote. NB: this is not accurate after 15 hours - after this time just give the antidote anyway

Question 7

Antidotes for paracetamol poisoning

Answer 7

Glutathione precursors - increase the potential to detoxify NAPQI. Most common antidote is IV acetylcysteine - 3 bags given over 21 hours

Question 8

Dose regime for acetylcysteine

Answer 8

1. BAG 1 - 150mg/kg in 200ml 5% glucose over 1 hour
2. BAG 2 - 50mg/kg in 500ml 5% glucose over 4 hours
3. BAG 3 - 100mg/kg in 1L 5% glucose over 16 hours

Question 9

Adverse effects of acetylcysteine

Answer 9

Common, due to high dose in bag 1, occurs immediately.
- histamine-mediated anaphylactic features (flushing, uticaria, pruritis, bronchospasm)
- rarely - angioedema, wheezing, respiratory distress, hypotension
Temporarily discontinue infusion and give antihistamine if necessary

Question 10

8 hour rule for paracetamol OD

Answer 10

If given antidote within 8 hours of OD, patient not at risk of significant liver damage.

Question 11

Staggered paracetamol OD

Answer 11

Paracetamol OD spread over more than 60 mins - nomogram is useless so all patients should be treated with acetylcysteine

Question 12

24 hour rule

Answer 12

Clinically significant hepatotoxicity is extremely unlikely in a patient who 24 hours after the most recent ingestion is:

• asymptomatic
• no paracetamol detected in plasma
• normal ALT and INR

Question 13

Clinical features of paracetamol OD on day 1

Answer 13

• asymptomatic

- N&V, abdominal pain, anorexia, pallor

Question 14

Clinical features of paracetamol OD on day 2

Answer 14

• may become symptomatic
• nausea and vomiting
• hepatic tenderness +/- generalised abdo pain
• occasionally mild jaundice

Question 15

Clinical features of paracetamol OD on days 3 -5

Answer 15

• jaundice –> liver failure and encephalopathy
• back pain + renal angle tenderness - renal failure
• DIC - liver failure
• cardiac arrhythmias –> arrest

Question 16

Biochemical and haematological abnormalities in paracetamol OD

Answer 16

Raised: AST/ALT, bilirubin, INR,
Low: clotting factors, blood sugar (impaired glycogenolysis), platelets and phosphate (renal tubular leak)
METABOLIC ACIDOSIS

Question 17

Useful biomarkers in late presenters (>24 hours later)

Answer 17

PT/INR
Creatinine
pH (metabolic acidosis)
Presence of encephalopathy 
age >50