HUF 2-74 Hepatotoxicity of drugs

Question 1

Therapeutic index (TI) - safety issue

Answer 1

• TI = TD50 - ED50 (human)

TD50: toxic dose for 50% of population
ED50: effective dose for 50% of population

Question 2

No-Observed-Adverse-Effect Level (NOAEL)

Answer 2

• Laboratory animals prior to initiation of clinical trials
  => Safe clinical starting dose
• NOAEL: highest dose level without adverse effects

Question 3

Classification of adverse drug rxn (ADR)

Answer 3

1. Augmented ADR:
   - Related to principal PD action of drug
   - Extension of pharmacological effect
   - Related to dose => ↓ dose
   - Predictable
   - 70-80% of all ADR
2. Idiosyncratic ADR
   - Unrelated to principal PD action of drug
   - Diff. from pharmacological effect of drug
   - Unpredictable
   - No clear dose-response in population
   - Allergic reaction: immune mediated
   - Metabolic activation: toxic intermediates that bind to macromolecules

Drug
=> Reactive metabolite (liver metabolism)
=>
1. Tissue: cellular necrosis
2. Immune system: hypersensitivity
3. DNA: mutagenecity, carcinogenicity, teratogenicity

Question 4

ADR Situations

Answer 4

• ~50% due to antiplatelet drugs, diuretics, NSAID, anticoagulants

ADR in China:

• Antibiotics
• NSAID
• CM herbs and proprietary products

Question 5

Drug-induced liver injury (DILI)

Answer 5

• Most common cause of acute liver failure
• Withdrawal of drugs by pharmaceutical industry
• Difficult to diagnose
• Common cause: herbal hepatotoxicity (medicinal herbs and dietary supplements)
  => HILI - herb-induced liver injury

Question 6

Liver susceptibility

Answer 6

• Unique position of liver in GI tract
• Blood/liver barrier more readily penetrable by drugs
• First line defense against xenobiotics
  => Important metabolic site for drugs/compounds
  => Exposed to high conc. of drugs, reactive metabolites, toxins

Question 7

General mechanisms of cell damage

Answer 7

Non-covalent interactions

• Lipid peroxidation via chain rxn
• Cytotoxic ROS
• Depletion of glutathione (GSH)

Covalent interactions

• Binding to cellular macromolecules => cell damage
• Binding to proteins => cell damage; immunogen
• Binding to DNA => carcinogenesis, teratogenesis

Question 8

Cellular necrosis

Answer 8

• Interaction between reactive metabolites and proteins
• Direct damage caused by reactive metabolites
  1. Paracetamol induced hepatotoxicity
  2. Chlorpromazine induced cholestasis

Question 9

Paracetamol induced hepatotoxicity

Answer 9

Paracetamol
A. Sulphatation
B. Glucuronidation
C. CYP2E1 (becomes NAPBQI)
D. GSH conjugation (detoxification)
E. Cell macromolecule binding => hepatotoxicity (overdose / induced 2E1 by e.g. alcohol)

• P450: metabolic activation to reactive NAPBQI
  => Covalently bin with macromolecules
  => Hepatotoxicity
• GSH conjugation: detoxification
  => Treatment (<12h) with N-acetyl cysteine (IV) or Methionine (oral)
  => ↑ GSH availability
  => ↓ Mortality

Question 10

Chlorpromazine induced cholestasis

Answer 10

• Jaundice
• Mild; elevated serum alkaline phosphatase activity (↑ ALP)
• Disappears quickly when drug stopped or replaced by chemically unrelated antipsychotics

CPZ
=> CPZ free radicals (toxic intermediate)
=> A. P450 hydroxylation => 7-OH-CPZ
B. ***P450 sulphoxidation => CPZ S-oxide
(Individuals who are phenotypically poor sulphoxidisers - SI > 18
=> Susceptible to CPZ jaundice)

Question 11

Allergic reaction to drugs

Answer 11

- Metabolites interaction with protein
=> Stable immunogenic adduct
- Unrelated to principal action of drug
- Time course differs from main action of drugs (delayed onset / occurs only repeated overdose)
- AutoAb directly against specific CYP

1A2: Dihydralazine hepatitis
2C9: Tienilic acid hepatitis
2E1: Halothane hepatitis

Question 12

Halothane induced hepatitis

Answer 12

• Halothane metabolised to reactive metabolite: Trifluroacetylchloride (TFA)
  => Interact with hepatic protein
  => Immunogenic halothane-protein adduct
  => Destruction of hepatic cells Type II hypersensitivity involving killer T cells)
• Evidence: Ab that react with halothane-protein immunogen

Question 13

Drugs induced mutagenesis and carcinogenesis

Answer 13

1. 1° carcinogen (Cisplatin)
2. 2° carcinogen (Afatoxin) => Reactive metabolite
3. Co-carcinogen (with alcohol)
   => Alternation of DNA (mutation)
   => Oncegene expression (with promoter e.g. smoking)
   => Malignant transformation

Question 14

HILI

Answer 14

• Herbal medicine: 2nd largest cause of HILI (acute/severe)

Pyrrolizidine alkaloid (PA) induced hepatotoxicity
- Naturally occurring PA: hepatotoxic
=> Acute liver damage (HSOS: hepatic sinusoidal obstruction syndrome)
=> Liver tumour (chronic exposure)

HSOS: hepatomegaly, jaundice, ascites

PA-producing plants: herbal medicine, herbal teas, dietary supplements
PA-contaminated food: wheat, honey, vegetable, milk, meat

Riddelliine / Clivorine (PA)
=> Dehydropyrrolizidine alkaloid (CYP3A4)
=>
1. GSH conjugation: detoxification
2. Adduct formation => hepatotoxicity/tumorigenicity

*Tusanqi, Bidens pilosa (herbal tea, HM to treat appendicitis)