Drug Toxicology II: Treatment and Prevention Flashcards Preview

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Flashcards in Drug Toxicology II: Treatment and Prevention Deck (21):
1

How many phases are there in drug development?

4: I, II, III, IV

2

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

  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?

3

What is the Ames test used for?

In vitro test for mutogenicity

4

What happens during an Ames test

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

5

What does an Ames test measure?

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

A high mutation rate is undesirable - potentially mutagenic and carcinogenic

6

What occurs during carcinogenicity testing?

Chronic drug dosing, look for tumours

7

What occurs during reproductive (teratogenicity) testing?

  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

8

What is preliminary toxicity testing?

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

9

Define: LD50

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

Measured in M

10

How is LD50 found?

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

11

Define: NOAEL

= no observed adverse effects level

Highest concentration of drug that does not give any toxic effects

12

Define: LOAEL

= lowest observed adverse effects level

Lowest concentration of drug that produces a toxic effect

13

How is the 'Human Equivalent Dose' found?

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

14

Define: Human Equivalent Dose (HED)

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

15

Define: Therapeutic index

LD50/ED50

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

16

How is the therapeutic index calculated?

LD50/ED50

17

Define: ED50

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

18

What is ED50 also known as?

EC50 = effective concentration

19

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

Narrow therapeutic index - potentially dangerous drug e.g warfarin

20

How does the therapeutic window link to the therapeutic index?

Larger therapeutic window = larger therapeutic index

21

What is therapeutic index a measure of?

Drug safety