Lecture 20-21- Toxicity and ADR 1+2

Question 1

What is toxicology?

Answer 1

The study of adverse effects that are detrimental to either the survival or normal functioning of the individual. (It is the main reason that a drug fails in the development process)

Question 2

What factors have an influence on toxicity?

Answer 2

Dose, Time(constant or multiple exposure), route of exposure, Drug target(pharmacology)

Question 3

Define Haber’s rule?

Answer 3

C x t = k

A low concentration of a poisonous drug over a long time will have the same effect as a high concentration of the drug over a shorter time.

Question 4

What is the primary aim of toxicity studies?

Answer 4

To determine the potential for harmful effects in the intact living organism, and by extrapolation to humans.

Question 5

What is the purpose of regulatory toxicology?

Answer 5

To ensure that the benefits of chemical substances intended for use by humans outwigh the risk from their use.

Question 6

What factors should be addressed by toxicology studies?

Answer 6

• The injury produced
• Dose-response relationship
• Mechanism of toxicity
• Factors affecting toxicity ie route of exposure, species/sex of test animal, formulation
• Development of approaches for detection of toxic responses
• Reversibility of response- spontaneous healing, antidotal treatment

Question 7

What are the five levels of selection in toxicity testing?

Answer 7

1. Test species
2. End point(response)
3. Dose
4. Route
5. Duration of test

Question 8

What should be considered for toxicity testing in test species?

Answer 8

• ADME- affected by species, gender, strain, age, nutritional status
• Relevant target
• Time of dosing-diurnal variation
• Environment: temperature, humidity, photoperiod

Question 9

List some of the end points(responses measured) in toxicology studies?

Answer 9

• Pharmacological (pharmacodynamic etc)
• Direct toxicity(eg skin irritancy)
• Genotoxicity( carcinogenicity)
• Immunotoxicity( immune suppression, allergic reactions)
• Death is a good end point but it is not acceptable anymore

Question 10

What does a log dose response curve show?

Answer 10

It shows if the toxicity of the compound is because of too great a pharmacological effect( response) with a given dose.

Question 11

What is a no observable adverse effect level?

Answer 11

It can be used as a basis of assigning “safe levels” for exposure.

Question 12

Define desirable pharmacology? (Curve-pg 171)

Answer 12

The dose at which a suitable frequency of individuals produced the desired response without having any toxic effects.

Question 13

What are the factors which influence the curve?

Answer 13

• Endogenous(eg genetic polymorphisms)
• Exogenous( Drug interactions)
• These include cellular defence mechanisms(eg GSH)
• Saturation of biochemical processes

Question 14

What can we use populations pharmacology for?

Answer 14

the 1st dose can affect the 2nd dose thus

1) can’t investigate the response of tissue to increasing doses
2) Have to use different populations to test for the effect of different dose strengths of a drug

Question 15

What is the purpose of acute toxicity tests?

Answer 15

A single dose is given to determine the effects that occur within a short period after dosing.

They have been used to determine dose-response relationships and end points such as LD50.

Therapeutic index- ratio of the doses required to produce a toxic or the desired response.

TI=LD50/ED50

The larger the number, the safer the compound.

Question 16

What is the purpose of sub-acute toxicity tests?

Answer 16

• Involve exposing the animals to the compound for 28-90 days.
• Provide information on the target organs and the major toxic effects.
• Toxic effects that have a slow onset can be detected.
• Measurement of compounds in tissues can be made and correlated with any toxic effects observed.

Question 17

What is the purpose of chronic toxicity tests?

Answer 17

• Lifetime exposure of animals to the compound.
• Changes in body weight, food, water intake as well as clinical measurements can be made.
• Often rats and dogs are used as the species of choice.
• The drug is administered with food mainly

Question 18

Why are mechanistic studies important ? (Look at process on pg 178 course guide)

Answer 18

• They may identify moieties within the structure that are pro-toxic.
• Elucidation of toxic mechanisms can lead to biochemical pathways for the design of new drugs.
• Develop techniques to antagonise the toxic effects.

Question 19

What is the incidence of ADR- adverse drug reactions?

Answer 19

20% of morbidity and mortality

Question 20

What are adverse drug reactions due to?

Answer 20

80% are a result of pharmacological processes. Therefore 20% are not.

ADR are due to the interaction of a drug with a biological target.

Interactions may be reversible or irreversible.

Question 21

How do adverse drug reactions occur and what do they lead to?

Answer 21

Drug(then metabolised)⇒Interaction with macromolecule ⇒Alteration of macromolecule function ⇒Loss of organelle function⇒ Cell death⇒Organ failure⇒Death

Question 22

What are ADR(s) classified into?

Answer 22

Type I- Predictable(80%)

Type II- Not predictable (20%)

Question 23

What is the mechanistic classification of ADR?

Answer 23

Type A- Augmented= predicted from known pharmacology of drug(dose-dependent) eg hypotension from antihypertensives

Type B- Bizarre= not predicted from pharmacology- no dose -response relationship

Type C- Chemical- reactions predicted based on the chemical structure of the drug

Type D- Delayed= occur after many years of treatment eg secondary tumours from chemotherapy

Type E- End of treatment= due to withdrawal of treatment eg seizures on stopping phenytoin

Question 24

What is an example drug of a dose dependent and predictable toxicity?

Answer 24

Aspirin

Question 25

What is the ADR caused by aspirin?

Answer 25

Gastro-duodenal ulceration and bleeding

Question 26

How do GI lesions occur with aspirin?

Answer 26

• Route of administration can cause them- route should be oral
• NSAID- Aspirin interacts with phosphotidyl choline and reduces the ability of the gastri cmucosa to protect itself from HCL⇒ GI lesions
• Inhibition of COX further causes damage as COX inhibits prostaglandin which is cytoprotective.

Question 27

How does metabolism play a role in adverse drug reactions?

Answer 27

Metabolism leads to formation of a chemically reactive species that can inhibit the biological function of a macromolecule.

Question 28

What is the formation of toxic metabolites influenced by?

Answer 28

• Dose
• Inter-individual variability in enzyme expression
• Pharmacokinetic interactions

Question 29

How does paracetamol( another NSAID) work to create toxicity?

Answer 29

• Due to saturation of detoxification pathways.
• Toxic metabolite- quinoneimine which reacts with sulfhydryl groups in proteins
• Loss of Calcium disrupts mitochondrial function and causes cell death

Question 30

What is used to treat paracetamol overdose?

Answer 30

GSH= Glucathione