Toxicity/ Adverse drug reactions Ome Flashcards
What is the aim of toxicology?
To integrate itself into early drug design phase before pre-clinical toxicity testing
i.e try improve drug safety before its tested…
Whats toxicology now called?
Discovery toxicology
Whats the primary aim of most toxicology studies?
To determine the potential for harmful effects (of a drug)
How is toxicological information obtained?
Biologically and chemically
What must be tested for toxicity?
- Any chemical that humans or organisms in the environment may be exposed to must be tested for toxicity
- To ensure that the benefits of drugs outweighs the risk.
What toxicity tests must a substance undergo?
The ICH is a huge system of toxicity tests that substances must undergo.
Point is that there is a system in place for safety.
Can we predict toxicity?
Toxicity may be an intrinsic property of the molecule that results from interaction with a biological system
May be possible to predict the likely disposition and metabolism from physico-chemical parameters.
In silico testing is relatively cheap and very fast.
i.e yes it can be done
What should toxicological studies address?
You must ask what you are going to look for:
Then:
- The injury produced; structural, functional, biochemical (what it does)
- Dose-response relationship (how much…)
- Mechanisms of toxicity (how so)
- Factors affecting toxicity (gender, age, route of exposure)
- Development of approaches for recognition/ detection of specific toxic responses
- Reversibility of response (spontaneous, antidote)
When testing in animals, what five levels of selection must you consider for your model?
Must consider all these factors
1) Species / strain
2) End point (response)
3) Dose
4) Route
5) Duration of the test
Most important list to learn!!!!!!
When selecting the species of model, what are some biological considerations?
- ADME is affected by many factors
- Species, Strain, Gender, age, nutritional status
- Test species may not have the relevant treatment
- Test species may be subject to diurnal variation ; Time of dosing may be important
- Environment: Temperature, humidity, photoperiod etc
What are some types of toxicity you look for in the model?
- Pharmacological (behavioral, pharamcodynamic, pharamcokinetic)
- Direct toxicity i.e skin irritant
- Genotoxicity (detect carcinogenicity)
- Immunotoxicity (immune supression)
Whats all the possible endpoints of toxicity?
Drug ingested and undergoes metabolism
- interaction with macro molecule
- This can cause the macromolecule to be recognized as foreign -> Immune response -> Organ failure -> Death
- or interact with a cell
- loss of organelle function -> Cell Death -> Organ failure -> Death
- or alter its DNA -> Lack of cell degeneration -> Organ failure -> Death or alteration of DNA can lead to cancer -> death
How do you determine the dose?
Dose response curves:
- EC50
- Can be shown on the graph the safe boundary vs toxic response (if the pharmacological response is too great)
How is populations accounted for in toxicity testing?
- Due to the many non-variability of many toxic end points, it is not possible to look at the response of a tissue to increasing dose.
- Instead the dose required to produce a desired end point is studied in a population
- Assume non-reversible until you know better
What are the purposes of acute toxicity tests?
- These are designed to determine the effects that occur within a short period after dosing.
- Single dose of compound is given, different routes (e.g oral, IV or Ip)
Used to determine LD50 (no longer used)
- Cant use a single dose for a whole population
