Lecture 20

Question 1

What is the pharmacological cycle?

Answer 1

A desirable biological change is identified, then a subcellular target is identified, the structural requirements of the drugs are identified and the drug is developed and then refined in order to create further desirable biological changes

Question 2

What is the toxicological cycle?

Answer 2

An undesirable biological change is identified this is then refined to the subcellular target and the structural requirements of this target are identified, a drug can then be developed to prevent this change

Question 3

Why is concentration of a drug less relevant in toxicology than pharmacology?

Answer 3

A positive toxicology result can always be obtained if enough drug is used

Question 4

What besides the dose can lead the drug to have a toxicological effect?

Answer 4

The time of exposure, route of exposure and the target of the drug

Question 5

What is Harbers Rule?

Answer 5

C*t=k

Question 6

How does selectivity of a drug play a role in toxicology?

Answer 6

The more selective the drug the lower the concentration required for it to be toxic

Question 7

How can toxicology of a drug be tested?

Answer 7

It may be an intrinsic property of the molecule and therefore toxicology can be predicted through In silico testing or use of computer models which is cheap and fast to do once the system has been purchased

Question 8

What are the two types of tests that are trying to be developed in the field of toxicology?

Answer 8

Ones that explain the toxicity of compounds not seen in pre clinical studies and ones that predict the toxicity of novel analogues

Question 9

What are the basic principles of toxicology testing?

Answer 9

Exposure of an animal or plant to the substance under controlled conditions
Or for chemicals already in existence information can be gained through humans or animals given the drugs during clinical trials or who are exposed in the workplace or general environment

Question 10

What should toxicology studies address?

Answer 10

The injury produced
the dose response relationship
the mechanism of toxicity
factors which affect the toxic response such as route of exposure/species/sex and formulation
development of approaches for recognition/detection of specific toxic responses
Reversibility of the response (is it spontaneous os an antidote is required)

Question 11

What are the endpoints that must be investigated both in vitro and in vivo for toxicological testing?

Answer 11

Cytotoxicity
Systemic toxicity
sub-chronic toxicity
genotoxicity
irritation/intracutaneous reactivity
sensitisation

Question 12

What are the 5 levels of selection of toxicology testing?

Answer 12

Test species
End point
Dose
Route
Duration of test

Question 13

What are the biological considerations for the species in toxicology tests?

Answer 13

The ADME may be affected by species, strain, gender, age and nutritional status
The test species may not have the relevant target
Test species may be subject to diurnal variation and the timing of the dose may be important
The environment such as the temperature, humidity and photoperiod

Question 14

How is the dose studied in a toxicology study determined?

Answer 14

As toxic end points are frequently non-reversible it is not possible to simply look at increasing doses instead the dose required to produce the desired end point is studied

Question 15

What are no effect levels?

Answer 15

It is possible for a compound to have no adverse effects at the extreme left of the curve so a threshold dose exists resulting in the ability to determine a no observable effect level which can be used to assign safe levels of the drug

Question 16

What dose levels are studied in toxicology?

Answer 16

Dose required for pharmacological activity
Dose required for sub-lethal toxicity
Lethal dose
These doses are determined using the same population

Question 17

What factors can influence the shape of the dose curve?

Answer 17

Endogenous and exogenous factors including cell defence mechanisms and reserves of biochemical function
Saturation of the biochemical processes that produce the toxicant may result in a plateau for toxicity

Question 18

What is the purpose of acute toxicity tests?

Answer 18

Designed to determine the effects that occur within short period of the dose
Use only a single dose
Have been used to determine dose response relationships and LD50s

Question 19

What is the therapeutic index

Answer 19

Measure of the ratio of doses required to produce toxic and therapeutic effects, a larger number means a safer drug
calculated by LD50/ED50

Question 20

How are sub-acute toxicity levels determined?

Answer 20

Frequently exposing the animal to the compound for 28-90 days
Used to provide information on target organs and major toxic effects
toxic effects which have slow onset can be detected
Measurements of compound in tissues can be made and correlated with any toxic effects observed
chemical measurements are made to indicate the development of any pathological lesions
There is a complete necropsy including histolgoy of all survivors

Question 21

What are the roles of a chronic toxicity test?

Answer 21

Choice of dose, species, strain and route of exposure are influenced by the type of chemical and regulations in the country where it will be marketed
Animals (commonly rats and dogs) are exposed to the compound for life typically through administration with food
Changes in simple measurements such as body weight, food and water intake are taken clinical measurements may also be made at points of interest