Drug Toxicology II: Treatment and Prevention

Question 1

How many phases are there in drug development?

Answer 1

4: I, II, III, IV

Question 2

List 3 questions that are asked in Phase I of drug development

Answer 2

1. What does the body do to the drug? (pharmacokinetics)
2. What does the drug do to the body? (pharmacodynamics)
3. Does it seem safe in humans?

Question 3

What is the Ames test used for?

Answer 3

In vitro test for mutogenicity

Question 4

What happens during an Ames test

Answer 4

Salmonella bacteria are used as it can’t synthesise histidine (amino acid)

1. The salmonella bacteria are grown on histidine-containing media
2. Drug is added to plate as well as a liver enzyme = cytochrome p450 (to test for reactive metabolites) - toxified or detoxified
3. Histidine becomes depleted and only mutants which can cope without histidine can grow back

This measures the rate at which a drug induces mutations in bacteria

Question 5

What does an Ames test measure?

Answer 5

The mutation rate = the rate at which a drug induces mutations in bacteria

A high mutation rate is undesirable - potentially mutagenic and carcinogenic

Question 6

What occurs during carcinogenicity testing?

Answer 6

Chronic drug dosing, look for tumours

Question 7

What occurs during reproductive (teratogenicity) testing?

Answer 7

1. Pregnant females from 1 rodent species and 1 non-rodent species (usually rabbit)
2. Dosed with the drug at different organogenesis stages
3. Look for birth defects

Question 8

What is preliminary toxicity testing?

Answer 8

• Maximum non-toxic dose is given to 2 species for 28 days
• Animals examined post-mortem and tissue damage assessed

Question 9

Define: LD₅₀

Answer 9

The dose of drug which kills 50% of treated animals within a specified short amount of time

Measured in M

Question 10

How is LD₅₀ found?

Answer 10

Graph plotted of toxic response (%) vs Log[drug] (M)

Question 11

Define: NOAEL

Answer 11

= no observed adverse effects level

Highest concentration of drug that does not give any toxic effects

Question 12

Define: LOAEL

Answer 12

= lowest observed adverse effects level

Lowest concentration of drug that produces a toxic effect

Question 13

How is the ‘Human Equivalent Dose’ found?

Answer 13

• Extrapolation from the NOAEL value
• Using a conversion table, based on body surface area (mg/m^2)
• Apply a >10 fold safety factor

Question 14

Define: Human Equivalent Dose (HED)

Answer 14

The dose in humans anticipated to provide the same degree of effect as observed in animals at a given dose

Question 15

Define: Therapeutic index

Answer 15

LD₅₀/ED₅₀

The ratio of the dose that produces an unwanted (toxic) effect to that producing a wanted (therapeutic) effect

Question 16

How is the therapeutic index calculated?

Answer 16

LD₅₀/ED₅₀

Question 17

Define: ED₅₀

Answer 17

The median effective dose = the effective dose for 50% of people recieving the drug

Question 18

What is ED₅₀ also known as?

Answer 18

EC₅₀ = effective concentration

Question 19

How is the therapeutic index of a drug affected when the ED₅₀ and LD₅₀ concentrations are very close?

Answer 19

Narrow therapeutic index - potentially dangerous drug e.g warfarin

Question 20

How does the therapeutic window link to the therapeutic index?

Answer 20

Larger therapeutic window = larger therapeutic index

Question 21

What is therapeutic index a measure of?

Answer 21

Drug safety