Drugs With Hepatotoxicity

Question 1

Most common reasons for a drug to be Withdrawn from the market

Answer 1

Hepatotoxicity

Question 2

Nicole picture of a drug hepatotoxicity

Answer 2

Resembles acute viral hepatitis with jaundice, malaise, anorexia, nausea, abdominal pain

Question 3

Pathogenesis of drugs induced liver injury

Answer 3

Immune response or
direct effect on biochemistry of the cells by drugs or its metabolite

Metabolites can be free radicals which can lead to depletion of reduced glutathione or induce lipid peroxidation

Sensitization to cytokines of the liver causing cytokines induced hepatotoxicity

Immune mediated injury by altering liver proteins like cyp450

Question 4

Risk factors of drug induced hepatotoxicity

Answer 4

Chemical properties of the drug

concomitant use of drugs or alcohol (main one )

Age

genetic factors

underlying disease (main one) like HIV or HCV

Question 5

Mechanisms of drug induced liver damage

Answer 5

Direct cytotoxic effects

Interference with bilirubin Uptake excretion and conjugation

Cholestatic injury

Fatty liver

Chronic hepatitis

Question 6

Example of drugs that cause direct cytotoxic injury

Answer 6

Acetaminophen with centrilobular hepatic necrosis (10g to liver damage, 15g to fatal hepatic damage )

Halothane ( general anesthetic) mostly after more than 1 exposure

Question 7

Assessments of liver damage by acetaminophen

Answer 7

Raised serum transaminase ( AST, ALT)

Bilirubin levels mildly elevated

Question 8

Halothane hepatotoxicity syndrome

Answer 8

Fever
Myalgia
Arthralgia
Rash

Question 9

Two forms of halothane hepatic injury

Answer 9

Mild form with slightly raised serum transaminases and mild necrosis
(Direct toxicity)

Severe form with massive hepatic necrosis and death in some cases (immunological)

Question 10

Examples of drugs that interfere with bilirubin concentration

Answer 10

Rifampicin (tb treatment ) inhibits uptake and excretion -> high plasma level of conjugated and non conjugated bilirubin

Question 11

Examples of drugs with cholestatic injury

Answer 11

Chlorpromazine (tranquilizer) causes jaundice

Steroids like methyltestosterone

Question 12

Presentation of chlorpromazine induced jaundice

Answer 12

Jaundice 
Fever
 Itching
 abdominal pain 
nausea 
anorexia

Elevated serum Cholesterol and alkaline phosphatase

Question 13

Mechanism of action of chlorpromazine induced jaundice

Answer 13

Chlorpromazine acts on the bile ductules

Question 14

Drugs example that cause fatty liver

Answer 14

Tetracycline after large IV dose

Question 15

Biochemistry of fatty liver from drug hepatotoxicity

Answer 15

Moderate elevation of apartate transaminase

Bilirubin levels moderately elevated

Question 16

Drug induced clinic active hepatitis and sub acute necrosis

Answer 16

Isoniazid (tB treatment) similar to viral hepatitis
High AST and ALT
Massive necrosis
Cholestasis

Question 17

Predisposing factors for isoniazid induced hepatic damage

Answer 17

Pre-existing liver dysfunction like alcoholic Cirrhosis

Asian males (low susceptibility for black males )

Acetylator phenotype (slow or fast, fast more at risk because produce more toxic metabolite)