Metabolism- Pharmocokinetics

Question 1

Phase I drug metabolism

Answer 1

This is when enzymes introduce reactive and polar groups into the drug substrate

Metabolism by P450 cytochrome
- Hydroxylation

This involves:

• Reduction
• Hydrolysis

Question 2

Phase II drug metabolism

Answer 2

Drug is made soluble by conjugating with charged species.

Includes these processes:

• Glucuronidation
• Acetylation
• Sulfation
• Methylation

Question 3

Pro-drug

- Examples

Answer 3

A drug or compound that is metabolised to become pharmacologically active.

Examples:

• Enalapriat from enalapril
• Morphine from codeine
• Dopamine from levodopa

Question 4

Cytochrome P450 inhibitors

- Examples

Answer 4

Inhibits Phase I metabolism of certain drugs and compounds.
- Very rapid process

Examples:

• Amiodarone
• Ciprofloxacin
• Erythro/Clarithromycin
• Metronidazole
• Fluconazole
• Isoniazid
• Acute Alcohol
• Grapefruit juice

Question 5

Amiodarone

Answer 5

Cytochrome P450 inhibitor

- arrhythmic drug

Question 6

Ciprofloxacin

Answer 6

Cytochrome P450 inhibitor

Fluoroquinolone antibiotic

Question 7

Erythromycin

Answer 7

Macrolide antibiotic

- Cytochrome P450 inhibitor

Question 8

Metronidazole

Answer 8

Antibiotic

- Cytochrome P450 inhibitor

Question 9

Fluconazole

Answer 9

Antifungal

- Cytochrome P450 inhibitor

Question 10

Isoniazid

Answer 10

Antibiotic, used to treat TB

- Cytochrome P450 inhibitor

Question 11

Cytochrome P450 inducer

• Significance
• Examples

Answer 11

Increases metabolism of drugs metabolised by cytochrome P450 and increases effect of drug metabolised.
- Slow process

Examples:
Carbamazepine
Phenytoin
Rifampicin
Chronic alcohol

Question 12

Carbamazepine

Answer 12

Na+ channel blocker used to treat epilepsy and neuropathic pain.

Induces cytochrome P450.

Question 13

Phenytoin

Answer 13

Anti-seizure drug

Inducer of cytochrome P450.

Question 14

Rifampicin

Answer 14

Antibiotic used to treat TB.

Inducer of cytochrome P450.

Question 15

Drugs metabolised by Cytochrome P450 with narrow therapeutic index

Answer 15

When these drugs interact with CYP450 inhibitors, this can have potentially adverse effects
- Increases drug toxicity rapidly.

Examples:

• Warfarin
• Aminophylline

Question 16

Genetics and drug metabolism

Answer 16

Genetic polymorphism of drug metabolising enzymes can affect drug handling.

Extensive metaboliser- Two normal, active alleles

Intermediate- One normal, one abnormal

Poor- Two abnormal

Ultrarapid- Duplication of normal alleles

Question 17

Codeine phosphate and CYP2D6 (Cytochrome P450 2D6)

Answer 17

Ultrarapid metabolisers of codeine can get opiate toxicity at low doses.

Whereas poor metabolisers do not get adequate pain relief at higher doses.

Question 18

N-acetyltransferase

Answer 18

Enzyme used in phase II reaction- acetylation.

Its activity is genetically determines.

Fast enzyme= increased risk of isoniazid hepatotoxicity

Slow= Increased risk of isoniazid neuropathy
- Also increased risk of drug-induced lupus with hydralazine.

Question 19

Saturable metabolism

- Zero order kinetics

Answer 19

When drug concentrations rise disproportionately to the dose

Seen in:

• Phenytoin
• Alcohol
• Aspirin
• Verapamil
• Methotrexate
• Fluoxetine