Drug Metabolism

Question 1

Define pharmacodynamics

Answer 1

What a drug does to the body

Question 2

Define pharmacokinetics

Answer 2

What the body does to the drug

Question 3

What does pharmacokinetics essentially cover?

Answer 3

Absorption, Distribution, Metabolism and Elimination of a drug (ADME)

Question 4

What usually occurs in phase I?

Answer 4

A reactive group is exposed or added to make them more unstable - reactive intermediate.

Question 5

What are the most common chemical reactions in phase 1?

Answer 5

Redox and hydrolysis

Question 6

What does phase I require?

Answer 6

Cytochrome P450 (CYP) system and NADPH

Question 7

What occurs in phase II?

Answer 7

Intermediate from phase I is conjugated with a polar molecule to form a water-soluble molecule. (conjugation)

Question 8

What is the most common conjugate of phase II?

Answer 8

Glucoronic acid. Can also be conjugated with sulphate ions and glutathione

Question 9

What does phase II metabolism require?

Answer 9

Specific enzymes and uridine disphosphate glucuronic acid (UDGPA)

Question 10

What is the first pass effect?

Answer 10

Substances absorbed from the ileum are extensively metabolised during the first pass through the liver

Question 11

Why is CYP important?

Answer 11

Isoform CYP3 A4 is most important - accounting for ~55% of drug metabolism. NADPH is a cofactor for CYP

Question 12

What is an actylator?

Answer 12

Someone who lacks the main enzyme for acetylation reaction in phase II

Question 13

Give some examples of enzyme inducers

Answer 13

Ethanol, nicotine and barbiturates

Question 14

How is paracetamol metabolised at a therapeutic level?

Answer 14

Conjugates with glucuronide or sulphate in phase II

Question 15

What happens when someone overdoses on paracetamol?

Answer 15

Phase II becomes saturated and it undergoes phase I metabolism, forming NAPQI which is toxic.

Question 16

What effect does NAPQI have?

Answer 16

Toxic to hepatocytes and also undergoes phase II conjugation with glutathione which is an important anti-oxidant

Question 17

What is the major site of alcohol metabolism?

Answer 17

Liver

Question 18

Write out the breakdown of alcohol

Answer 18

Alcohol —> acetaldehyde (alcohol dehydrogenase)
Acetaldehyde —> acetate (aldehyde dehydrogenase)
Complete oxidation requires NAD+ and forms NADH

Question 19

How can excess alcohol lead to liver damage?

Answer 19

Aldehyde dehyd. has a low Km so keeps acetaldehyde to a minimum. Prolonged consumption can lead to a build of acetaldehyde which is toxic

Question 20

What is NAD+ used for?

Answer 20

FA oxidation, conversion of lactate to pyruvate, metabolism of glycerol

Question 21

What causes lactic acidosis?

Answer 21

Accumulation of lactate in the blood due to low NAD+

Question 22

What are the effects of high actyl~CoA

Answer 22

Fatty acid synthesis increases however it cannot be moved thus causing fatty liver. Sometimes production of ketone bodies can lead to keto-acidosis

Question 23

What can reduced liver function result in?

Answer 23

Jaundice, hyperammonaemia, serum albumin may produce oedema, increase in blood-clotting time, fatty liver

Question 24

What are the indirect effects of alcohol?

Answer 24

Vitamin and mineral deficiencies. Inadequate protein and carbohydrate uptake

Question 25

What are the direct effects of alcohol?

Answer 25

Loss of appetite, diarrhoea, impaired absorption of nutrients.

Question 26

How can you treat alcohol dependency?

Answer 26

Use disulfiram - inhibits aldehyde dehydrogenase which means the person is hung over for longer

Question 27

How is jaundice related to poor liver function?

Answer 27

Leaky plasma membrane, loss of enzymes from hepatocytes, less bilirubin taken up (hyperbilirubinaemia) leading to jaundice