73 Hepatotoxicity of drugs

Question 1

What are the 2 types of adverse drug relations (ADRs)? Briefly describe.

Answer 1

1. Augmented (Type A) ADRs
   - related to pharmacological actions of the drugs (e.g. extension of pharmacological actions of drugs, actions on other receptors)
2. Idiosyncratic (Type B) ARRs
   - unrelated to pharmacological actions of drugs
   - unpredictable, thus high risk
   - dose-independent

Question 2

29 which of the following statements about idiosyncratic adverse reaction is incorrect?
A unpredictable amongst population
B extension of bioactivity
C caused by chemically reactive metabolite
D involve immune mediated reaction
E interaction with macromolecules

Answer 2

B

Question 3

3 causes to liver’s susceptibility to the drug-induced injury (DILI).

Answer 3

1. 1st organ exposed to the drug, exposed to high concentration of drugs
2. Major metabolite site, exposed to high concentration of reactive metabolites
   3, Blood-liver barrier with sinusoids is readily penetrated by drugs

Question 4

In __________ ADRs, usually it is the reactive metabolites that causes the adverse reactions but not the drug itself.

Answer 4

idiosyncratic

Question 5

Which of the followings are example of covalent interactions cell damage?
A. binding to DNA > mutagenicity, carcinogenicity, tertogenicity
B. binding to proteins > produce immunogens, hypersensitivity
C. binding to cellular macromolecules, cellular necrosis
D. lipid per oxidation > alter membrane permeability
E. depletion of glutathione (GSH)
F. Generation og cytotoxic reactive oxygen species

Answer 5

A,B,C

D-F: non-covalent interactions of cell damage

Question 6

Overdose of paracetamol causing hepatoxicity.

Answer 6

Sulphatation, Glucoronidation
> saturated 
> P450 (CYP3A/2E) (induced by alcohol and drugs
> NAPBQI
> glutathione conduction, detoxification pathway
> saturated
> toxic metabolite 
> hepatoxicity

Question 7

Emergency treatment for paracetamol overdose?

Answer 7

IV injection of

• N-acetyl cysteine/
• oral glutathione to increase glutathione for detoxification

Question 8

What is cholestasis and its symptoms?

Answer 8

• Impairment of bile excretion
• Symptoms:
  reversible jaundice (reversed by stopping the offended drug)
  increase alkaline phosphatase (ALP) due to damage of hepatocytes

Question 9

Name a drug that causes cholestasis and describe its metabolic pathway. C/I?

Answer 9

Tamoxifen will cause. (SERM(
mainponint: Chlorpromazine (Typical antipsychotic)
Chlorpromazine > Chlorpromazine free radicals (toxic intermediate) >
1. hydroxylation (P450)
2. Sulphoxidation (P450) (main pathway)

*Poor sulphoxidizers are more susceptible to chlorpromazine jaundice

Question 10

What is immune-mediated hypersensitivity?

Answer 10

Reactive metabolites + proteins > allergy (stable immunogenic adducts)

Question 11

Give an example of immune-mediated hypersensitivity.

Answer 11

Halothane hepatitis (inhaled GA)

• CYP2E1 metabolize halothane into TFA (trifluroacetylchloride)
• TFA binds to hepatic protein and produces immunogenic adducts
• hepatocyte damage by killer T cells (type II hypersensitivity)

Question 12

True?
A. Cisplatin is a primary carcinogen that the drugs will cause mutation
B. Aflatoxin is a secondary carcinogen in which its metabolite will cause mutations
C. Carcinogenic effect may be promoted by virus (e.g. hepatitis), inflammation and other carcinogens (e.g. alcohol)
D. Carcinogenic effect of intervention with DNA. can be promoted by smoking

Answer 12

All of the above
C: Alcohol: co-carcinogen
D: promotor: smoking

Question 13

Give an example of HILI (Herbal-induced liver damage).

Answer 13

Pyrrolizidine alkaloids (PA).

Acute exposure: hepatic sinusoidal obstruction syndrome (HSOS)
Chronic exposure: liver tumours

Question 14

What are the symptoms of HSOS ( hepatic sinusoidal obstruction syndrome)?

Answer 14

• Hepatomegaly
• jaundice
• ascites (accumulation of fluid in peritoneum)

Question 15

Give the pathway of the PA-induced hepatotoxicity.

Answer 15

Pyrrolizidine alkaloids 
> P450
> Dehydropyrrolizidine alkaloids 
> glutathione conjugation, detoxification pathway;
saturated 
> + protein > Hepatoxicity
> + DNA > Tumorigenicity