5.1 Toxic injury to liver

Question 1

what is intrinsic liver damage from drugs?

Answer 1

when dose is high enough, hepatotoxicity is predictable

Question 2

What is idiosyncratic liver damage from drugs?

Answer 2

hepatotoxicity results at therapeutic dose of the drug, generally a delay of 5-90 days from ingestion, often fatal if drug use is continued

Question 3

What are the 6 mechanisms of hepatocyte injury?

Answer 3

1. Disrupted Ca homeostasis
2. Disruption of actin filaments next to canaliculus, inhibition of transporters
3. Covalent bonding of drug to cytP-450
4. drug cytP-450 complex becomes stable and is packed into vesicles and exposed to the cell surface as a foreign pathogen
5. apoptosis
6. Inhibition of mitochondrial function

Question 4

What is the usual threshold for hepatic injury from paracetamol?

Answer 4

150mg/kg (>10g)

Question 5

What is the antidote for paracetamol poisoning?

Answer 5

N-acetylcysteine

Question 6

In what time frame do you need to give the antidote for paracetamol poisoning?

Answer 6

survival is 100% in 8 hours, some benefit within 24 hours and no real evidence of effect after 24 hours

Question 7

What are the three types of metabolism of paracetamol?

Answer 7

Gluconerated (phase 2)

Sulfation (phase 2)

Converted into NAPQI by P450 (2E1 and 3A4) or prostaglandin H synthase

Question 8

Under normal conditions what happens to NAPQI?

Answer 8

further metabolization with conjugation of glutathione into a glutathione conjugate which can be excreted

Question 9

What occurs in paracetamol overdose?

Answer 9

The phase 2 pathways of paracetamol metabolism become saturated leading to a build up of NAPQI. Glutathione will become depleted as teh body tried to metabolise the NAPQI. The glutathione cannot be replaced fast enough leading to a build up of NAPQI.

Question 10

How does NAPQI cause damage?

Answer 10

At least 3 mechanisms
1. uncoupling of mitochondria
2. Depletes glutathione further
Disrupts Ca homeostasis

Question 11

What are the risk factors for paracetamol induced hepatotoxicity?

Answer 11

Chronic alcoholism
Prolonged fasting (deplete glutathione)
Other medications that are inducers of p450
Enzyme inducers: ethanol, phenobarbitol, phenytoin, smoking, grapefruit juice

Question 12

What are the side effects of Isoniazid

Answer 12

Causes elevated aminotransferase lebels in 15-20% patients and severe hepatic necrosis in 1:1000

Question 13

What is Isoniazid used for?

Answer 13

TB