Metabolism

Question 1

What is drug metabolism?

Answer 1

The biochemical modification of pharmacological substances usually through the specialised enzyme systems

Question 2

How is elimination of drug achieved?

Answer 2

Elimination is achieved by excretion of unchanged drug or a metabolite from the body

Question 3

Which types of drugs are eliminated most effectively?

Answer 3

Water-soluble drugs are eliminated more efficiently than lipid-soluble drugs
Lipid-soluble drugs need to be metabolised to be eliminated effectively

Question 4

What are the aims of drug metabolism?

Answer 4

1) To make a drug more hydrophilic so it can be excreted by the kidneys
2) To inactivate the drug so it no longer produces the effect

Question 5

What is the major site of biotransformation?

Answer 5

The liver

Question 6

Name the sites of drug metabolism

Answer 6

Liver (main organ of drug metabolism)

Gastro Intestinal Tract
– Monoamine oxidase (MAO) found in wall of GIT

Plasma
Skin
Lungs
Brain

Question 7

What is first pass drug metabolism?

Answer 7

A phenomenon of whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation by means of the hepatic portal vein taking it from the GIT to the liver first, i.e. oral intake

GIT wall=MAO
Liver=cytochrome p450

Question 8

Describe the aims of each phase of drug metabolism

Answer 8

Phase 1 reactions - convert lipophilic drugs into more water soluble drugs

Phase 2 reactions - are conjugation reactions that add large endogenous molecules to drugs to make them more water soluble

Question 9

How do phase 1 reactions work?

Answer 9

Biotransform drugs by introducing or masking functional groups (-OH, -NH2, -SH)

Question 10

Give examples of phase 1 reactions

Answer 10

Oxidation
- p450 in liver, Xanthine oxidase, Monoamine oxidase

Reduction (liver = less common)
- CYP2A6 (warfarin)

Hydrolysis (plasma = less common)
- Ester and amide bonds are susceptible to hydrolysis

Question 11

What is the cytochrome p450 system?

Answer 11

A large family of enzymes found in Liver

• Heme-containing isoenzymes
• Microsomal mixed function oxidases (MFO)
• Distinct and overlapping specificities for drugs
• 74 different enzymes, 6 commonly used

Question 12

What does monoamine oxidase do?

Answer 12

Breaks down biologically active amines

Question 13

Name some of the types of phase 2 reaction

Answer 13

Glucoroidation
Sulfation
Methylation
Acetylation

Question 14

How does amount of drug effect the relationship with metabolism?

Answer 14

Low dose of drug => proportional to drug metabolism

High dose of drug => become saturated => drug metabolism no longer proportional to dose

Question 15

What are the two orders of kinetics associated with metabolism of drugs?

Answer 15

First-order: metabolism proportional to drug concentration

Zero-order: drugs metabolised at constant rate Vmax

Question 16

What is enzyme competition?

Answer 16

Also known as a pharmacokinetic drug interaction
Competition for the active site leading to a reduction in metabolism and an increased plasma concentration of the two drugs due to more than one drug being metabolised by the same isoform of the enzyme

Question 17

What is induction of metabolism?

Answer 17

Certain drugs can induce isoenzymes of the Cytochrome P450 system at the transcription level

Over 200 Drugs cause enzyme induction and can:
– Increase its own metabolism
– Increase the metabolism of other drugs
– Toxic levels of reactive metabolites can occur

Question 18

Describe inhibition of enzymes

Answer 18

• Some Drugs inhibit drug metabolism, i.e. Cytochrome P450
• Competition for the same enzyme isoform increase concentration of both drugs
• Inactivation of the enzyme can result in competitive and non-competitive inhibition of Isoenzyme

Question 19

What are pro-drugs and give an example?

Answer 19

Drugs that are in an inactive form when administered

L-dopa - converted into dopamine in CNS

Question 20

Describe reasons why drugs may be metabolised differently in different people?

Answer 20

Genetic make up