Paracetamol Poisoning ✅

Question 1

What is the most common medication taken in overdose by children in developed countries?

Answer 1

Paracetamol

Question 2

Why is paracetamol the most common drug taken in overdose?

Answer 2

Due to its wide over-the-counter availability

Question 3

Why is it hard to determine the toxic dose of paracetamol?

Answer 3

It can be very variable

Question 4

What are higher doses of paracetamol associated with?

Answer 4

Greater risk of adverse effects

Question 5

What single dose of paracetamol is considered to have a reasonable likelihood of causing toxicity?

Answer 5

200mg/kg

Question 6

Can doses lower than 200mg/kg of paracetamol cause problems?

Answer 6

Yes, lower single doses can result in significant problems, as can multiple smaller doses which cumulatively exceed this threshold taken within a 24 hour period

Question 7

What phases is paracetamol toxicity divided into?

Answer 7

• 0-24 hours
• 24-72 hours
• 72-120 hours

Question 8

What features may be present 0-24 hours after a paracetamol overdose?

Answer 8

• Nausea
• Vomiting
• Excessive sweating

Question 9

What features may be present 24-72 hours after paracetamol overdose?

Answer 9

• Right upper quadrant pain
• Liver dysfunction
• Possible renal impairment

Question 10

What features may be present 72-120 hours after paracetamol overdose?

Answer 10

• Hepatic necrosis leading to liver failure
• Renal failure
• Cerebral oedema
• Death

Question 11

What is the biochemical evidence of paracetamol-induced liver damage?

Answer 11

• Elevated blood concentrations of AST and ALT

- Prolonged prothrombin time

Question 12

What evidence of a paracetamol overdose might be found on blood gas?

Answer 12

Metabolic acidosis in severe cases

Question 13

What causes AKI in paracetamol overdose?

Answer 13

• May be primary manifestation of paracetamol toxicity

- Can occur as result of hepatorenal syndrome or multi-organ failure

Question 14

By what processes is paracetamol metabolised?

Answer 14

• Sulfation
• Glucuronidation
• Hydroxylation by CYP450

Question 15

What is formed from sulfation of paracetamol?

Answer 15

Sulfate moiety

Question 16

Is the sulfate moiety formed from paracetamol sulfation toxic?

Answer 16

No

Question 17

What is formed from the glucuronidation of paracetamol?

Answer 17

Glucuronide moiety

Question 18

Is the glucuronide moiety formed from paracetamol glucuronidation toxic?

Answer 18

No

Question 19

What is formed from the hydroxylation by paracetamol by CYP450?

Answer 19

NAPQI (N-acetyl-p-benzo-quinone imine)

Question 20

Is the NAPQI formed by the hydroxylation of paracetamol toxic?

Answer 20

Yes

Question 21

What happens to the NAPQI formed in paracetamol metabolism?

Answer 21

It is conjugated to glutathione

Question 22

What is produced from the conjugation of NAPQI to glutathione?

Answer 22

Cysteine and mercapturic acid conjugates

Question 23

Are cysteine and mercapturic acid conjugates toxic?

Answer 23

No

Question 24

What % of metabolism of therapeutic doses of paracetamol is done by sulfation and glucuronidation?

Answer 24

Over 90%

Question 25

Where does glucuronidation and sulfation of paracetamol take place?

Answer 25

In the liver

Question 26

What % of paracetamol undergoes metabolism to NAPQI at therapeutic doses?

Answer 26

Approx 5%

Question 27

Why does NAPQI not have toxic effects at therapeutic doses?

Answer 27

Because the small amount produces is easily detoxified by conjugation with glutathione

Question 28

What happens to the metabolism pathways of paracetamol in overdose?

Answer 28

The glucuronidation and sulfation pathways become saturated and a much higher proportion of paracetamol is converted to NAPQI

Question 29

What happens with the excessive amounts of NAPQI in paracetamol overdose?

Answer 29

Hepatic stores of glutathione are depleted rapidly, and NAPQI remains in its active toxic form causing acute hepatic necrosis

Question 30

What is the treatment for paracetamol overdose?

Answer 30

Administration of N-acetylcysteine (NAC)

Question 31

In what timeframe should NAC be given in paracetamol overdose?

Answer 31

Within 8 hours of ingestion

Question 32

What is the purpose of NAC in paracetamol overdose?

Answer 32

Helps limit hepatotoxicity and prevents death

Question 33

What happens to the effectiveness of NAC the longer that administration is delayed after this time?

Answer 33

It is progressively less effecrtive

Question 34

How does NAC work in paracetamol overdose?

Answer 34

Primarily by augmenting glutathione reserves, which enhances the ability to detoxify NAPQI

Question 35

How is the need for administration of NAC guided in paracetamol overdose?

Answer 35

Measurement of plasma paracetamol levels at least 4 hours after overdose, and the use of a monogram to assess risk of toxicity

Question 36

What factors put individuals at greater risk of paracetamol toxicity?

Answer 36

- Starvation/malnutrition - CYP450-inducing drugs - Neonates

Question 37

Why does starvation/malnutrition put individuals at a greater risk of paracetamol toxicity?

Answer 37

Probably as a result of depleted hepatic glutathione stores

Question 38

Give 2 examples of CYP450-inducing drugs?

Answer 38

- Carbamazepine | - Phenytoin

Question 39

How is paracetamol metabolism different in a neonate?

Answer 39

- The sulfation pathway is the primary metabolic pathway for paracetamol in the neonate because of low glucuronidation activity - The CYP450 pathway displays significantly lower activity than in later life

Question 40

What is the result of the CYP450 pathway of paracetamol metabolism showing significantly lower activity in the neonatal period than in later life?

Answer 40

May be protective

Question 41

What is used to identify patients in which liver transplantation should be considered?

Answer 41

King's College criteria

Question 42

What are the King's College criteria indicating a referral for consideration of transplant should be considered?

Answer 42

- Arterial pH <7.3 - All 3 of; - INR >6.5 - Serum creatinine >300 - Grade III/IV hepatic encephalopathy