Paracetamol

Question 1

What is the toxic dose of paracetamol?

Answer 1

100-150mg/kg

7-10g

Question 2

What is the mechanism of action of paracetamol?

Answer 2

Reversible inhibits COX in the CNS - it is inactivated peripherally, ie it inhibits the perception of pain.

Question 3

What are the four main pathways of paracetamol?

Which pathway leads to the production of NAPQI?

Answer 3

1. Glucuronidation - ~50%
2. Sulfation - ~30%
3. CYP pathway CYP2E1 - ~5-10%
4. Direct renal clearance - ~10%

The CYP pathway produces NAPQI.

Question 4

What is the toxic metabolite in paracetamol toxicity?

How is it produced?

Answer 4

NAPQI - N-acetyl p-benzoquinone imine

Paracetamol is oxidised by CYP2E1 into NAPQI

Question 5

How is NAPQI normally detoxified in the body?

Answer 5

Glutathione combines with NAPQI to detoxify it so it can be excreted in the urine.

Question 6

Outline the process by which paracetamol overdose leads to liver damage.

Answer 6

1. Glucuronidation and sulfation pathways are saturated
2. CYP pathway is overloaded -> inc’d NAPQI production
3. Glutathione combines with NAPQI until it is depleted
4. NAPQI now builds up in the blood stream
5. NAPQI is toxic to hepatocytes
6. Centrilobular necrosis and/or parenchymal necrosis of the liver

Question 7

List the four stages of paracetemol toxicity.

Answer 7

1. ASYMPTOMATIC/PRE-INJURY: <24hrs - may be symptomatic, abdo pain, N+V, diaphoretic, pallor, hypotension - NAPQI building up
2. LIVER INJURY: 24-72hrs - abdo pain, LFTs start to rise - INR is first to rise - may improve clinically despite worsening biochemical status NB all those who are going to develop hepatotoxicity will show biochemical signs by 36hrs
3. MAXIMAL LIVER INJURY: 72-96hrs - fulminant liver failure
4. RECOVERY OR DEATH: >96hrs -

Question 8

Outline the pattern of liver enzyme rise in paracetamol toxicity.

Answer 8

INR is the first enzyme to rise

AST rises earlier than ALT

AST falls faster then ALT

Question 9

What timeframe should NAC treatment be utilised within?

Answer 9

<8hrs post single ingestion - no harm in delaying to 8hrs post

Question 10

What is the time to peak paracetamol level?

Answer 10

4hrs - paracetamol should be completely absorbed within 4hrs

Question 11

What is the antidote of paracetamol toxicity?

Answer 11

N-acetyl cystine

Question 12

Name four ways that NAC protects the liver in glutathione overdose.

Answer 12

1. Decreases free NAPQI by:
   
   1. conjugating with NAPQI directly
   2. replenishing glutathione
2. Increases alternate routes esp’ly sulfation
3. Non-specific anti-inflammatory effects on the liver -> free radical scavenger

Question 13

List the important toxic dose levels for paracetamol (mg/kg).

Answer 13

1. <150mg/kg - unlikley to cause toxicity
2. >250mg/kg likely to cause toxicity
3. >350mg/kg -> all will develop severe hepatotoxicity

Question 14

What are the clinical and biochemical signs of paracetamol toxicity?

Answer 14

• Clinical:
  
  • N+V
  • Abdo pain
  • Diaphoresis
  • Pallor
  • Lethargy/malaise
  • Jaundice
  • Oliguria
  • Hepatomegaly
  • (R)UQ pain
  • Hypovolaemia
  • Confusion - hepatic encephalopathy
  • May be asymptomatic
• Biochemical
  
  • Markedly raised AST and ALT
  • Raised INR/coagulopathy - elevated PT
  • Hyperbilirubinaemia
  • Hypoglycaemia
  • Elevated ammonia
  • Renal failure

Question 15

List the differential diagnoses for paracetamol toxicity.

Answer 15

• Alcoholic hepatotoxicity
• Other drug or poison induced hepatotoxicity
• Reye’s disease (post-flu or varicella +/- aspirin use)
• Viral hepatitis
• Hepatobiliary disease
• Ischaemic hepatitis

Question 16

What are the two causes of ARF in paracetamol toxicity?

Answer 16

1. Acute tubular necrosis
2. Vascular endothelial damage -> ischaemic injury

Question 17

What is the name of the nomogram to determine risk of paracetamol toxicity?

Answer 17

The Rumack-Matthews nomogram

Question 18

What is the half-life of paracetamol?

Answer 18

4hrs - this informs the Rumack-Matthews nomogram.

Question 19

List exclusions to the use of the Rumack-Matthew nomogram.

Answer 19

• Multiple ingestions
• Ingestion >24h ago
• Unknown time of ingestion
• Iatrogenic IV overdose

Question 20

Explain the difference btw the Rumack-Matthew Line and the Treatment Line (or modified Rumack-Matthew Line).

Answer 20

The original Rumack-Matthew line (based on peak concentration of 200mg/kg and a 1/2-life of 4h) is the line above which, there is a 60% chance of hepatotoxicity.

The Treatment Line is 25% lower than this and allows for errors in quantitiative paracetamol levels, ingestion time etc.

Question 21

List the indications for NAC therapy in the repeated (chronic) paracetamol overdose patient.

Answer 21

• Ingestion of:
  
  • >7.5-10g of paracetamol in 24h, or
  • >4g in 24h AND an inc’d susceptibility to hepatotoxicity eg chronic ETOH use, fating state, use of P450-inducing drugs
  • Liver tenderness, jaundice, or unwell
  • Supratherapeutic serum paracetamol levels (>20mcg/ml) with or without ALT elevation
  • Hx of chronic overdose with raised AST/ALT regadless of paracetamol level
  • Any patient with acute, undifferentiated liver failure

Question 22

Which paracetamol overdose patients should receive AC?

Answer 22

All patients without contraindications who present <4h post ingestion of a potentially toxic dose of paracetamol should receive a single dose of AC - 1g/kg po or NG

Question 23

Outline the NAC treatment protocol.

Answer 23

1. 150mg/kg over 1hr
2. 50mg/kg over 4hr (12.5mg/kg/hr)
3. 100mg/kg over 16hr (6.25mg/kg/hr)

Equates to 300mg/kg over 24hr.