Hepatic Drug Metabolism

Question 1

What are 2 reasons for drug metabolism?

Answer 1

1. Deactivation of pharmacological activity

2. Water soluble metabolite for excretion

Question 2

What is Vmax?

Answer 2

Drug conc. achieving max enzyme turnover

Question 3

What is Km?

Answer 3

Conc. of enzyme that makes turnover at 1/2 max rate

Question 4

Describe what happens in phase 1 metabolism

Answer 4

• Functionalism reactions - expose/create chemically reactive groups
• Phase 1 enzyme reactions: oxidation, reduction, esterification, isomerisation
• Can activate pro-drugs
• Creates more biochemically active intermediate

Question 5

Describe what happens in phase 2 metabolism

Answer 5

Drug activated + made water soluble by replacing chemically active regions with sugar/sulphate group

Question 6

What is Cytochrome P450?

Answer 6

• Phase 1 enzyme
• Responsible for oxidative modification
• High conc. in Liver
• Induced through pregane-x-receptor mechanism when drug present
• Catalytic site = haem

drug + O2 -> CYP450 -> metabolite + H2O

Question 7

What are UGT enzymes?

Answer 7

• Phase 2 enzymes
• bolt on water soluble glucuronide which deactivates drug
• adds glucuronic acid to bilirubin = production of water soluble conjugated bilirubin

Question 8

What causes Gilberts & Crigler najjar syndrome?

Answer 8

Mutated/deleted UGT1A4 = build up of unconjugated bilirubin > JAUNDICE

Question 9

What effects do mutations in gene coding for CYP and UGT have?

Answer 9

Radically change ability to metabolise drug

Genotype + phenotype screening identifies mutation > avoid certain drugs > reduces ADR’s

Question 10

What is enzyme induction/inhibition?

Answer 10

Certain drugs can induce or inhibit enzymes that metabolise it

Question 11

Give an example of enzyme induction

Answer 11

St Johns Wort can induce CYP3A4 which metabolises COCP to low sub-therapeutic Liver

Question 12

Give an example of enzyme inhibition

Answer 12

Erythromycin occupies CYP3A4 preventing metabolism of COCP = increased potential ADR’s + can be toxic

Question 13

What is enterophepatic cycling?

Answer 13

Some drug metabolites excreted into GI can be reactivated by gut enzymes/flora = extended half life

Question 14

How is paracetamol overdose managed?

Answer 14

Rapidly replenishing hepatic glutathione with infusions of IV n-acetyl cysteine to reduce hepatotoxicity of NAPBQI

Question 15

Summarise the normal paracetamol metabolic pathway

Answer 15

Majority directly glucuronidated by UGT + excreted

Tiny amounts of NAPBQI generated through CYP = rapidly deactivated by binding to hepatic glutathione

Overall no hepatocyte damage

Question 16

Summarise the OD Paracetamol metabolic pathway

Answer 16

Glucronidation pathway rapidly saturated by toxic dose

Excess paracetamol forced down CYP pathway = UGTs saturated = excessive NAPBQI = glutathione reserves rapidly depleted

Sig. hepatocyte damage

Question 17

What does prothrombin time (INR) to measure?

Answer 17

• Clotting factors in Liver = shorter half life than albumin so more sensitive indicator os acute liver damage
• PTT + jaundice = hepatic jaundice

Question 18

What does gamma glutamyl transpeptidase measure?

Answer 18

• Enzyme found only in Liver

- Released into blood during cholestasis or hepatcellular disease

Question 19

What does albumin measure?

Answer 19

• Chronic conditions = decreased albumin production

- Hepatic jaundice

Question 20

What does AST:ALT ratio measure?

Answer 20

• Increased ratio (>ALP) suggests hepatic jaundice

- AST & ALT also produced by muscles so high ratio may be due to muscle inflam.

Question 21

What does ALP measure?

Answer 21

High levels suggest post hepatic jaundice -> cholestasis