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
Since a whole population cannot receive a single dose what can be investigated to produce a safe vs toxic doseS?
May be possible to investigate:
1) Dose required for pharmacological activty
2) Dose required for sub-lethal toxicity
3) Lethal dose
In the same population
What is therapeutic index?
The ratio of doses required to produce a desired and toxic response (LD50 / ED50)
The larger the number, the safer the compound
Is Therapeutic index still used?
Yes, but no longer the same as LD testing was removed / made unethical
What is now used in place of LD50?
No effect level
What is the no effect level and how is is tested?
- It is possible to have no effect at the extreme left of the dose/ frequency curve, so that a threshold dosage exists
- It is then possible to there to determine a “No observable effect level” which can be used as a basis of assigning safe levels for exposure.
What factors influence the shape of the dose frequency curve?
- The shape of the curve maybe influenced by endogenous (genetic polymorphisms) or exogenous (drug-drug interactions) factors
- These may include cellular defense mechanisms, reserves of biochemical functions.
- Saturation of the biochemical processes, that produces the toxicant (metabolism) may result in a Plateau for toxicity
How does dose administration affect toxicity?
- Not just the dose!
- Time (constant or multiple doses)
- Route of exposure and target
Both have a huge influence on toxicity
What is habers rule?
C x t = K
What does habers rule mean?
haber found that exposure to a low concentration of toxin for a long period of time has the same effects as high concentration for short period of time.
What is a sub acute toxicity test?
A test involving exposing an animal to a compound for 28-90 days
How does a sub acute toxicity test work?
- Exposure is usually daily
- Toxic effects have a slow onset and can be detected
- Provide information on the target organs and major toxic effects
- Measurements of compound in a tissue can be made and can be correlated with any toxic effects observed
What sort of measurements can be performed during a sub acute toxicity test?
- Clinical chemical measurements may indicate the development of any pathological conditions
- Complete necropsy including histology of all organs systems in a survivor
- Blood chemistry, urinalysis, heamotology performed on any ill animals
- Data from sub-acute toxicity studies also help in the design for chronic toxicity studies
What is a chronic toxicity test?
Lifetime exposure of animals to a compound of interest
What measurements can be made during a chronic toxicity test can be made?
- Body weight changes, food and water intake, as well as clinical measurements can be made
How are chronic toxicity studies influenced by their country?
Choice of dose, species, strain, route of exposure are influenced by the type of chemical, expected exposure, plus regulations of countries where the compound is to be marketed
What animal model is typically used in chronic toxicity studies?
- Rats and dogs are animals of choice
- for rats ~ 50 males and 50 females for doses and 100 control
- for dogs ~10 males and 10 females.
- Normally the drug given in the food, other routes if necessary can be done.
How does cost of toxicity assays vary?
Mutagenicy 15 days $2000
Carcigenicity 730 days $2million
What are the limitations of animal testing?
- Limited choice of species
- Species switching between tests
- lack of subjective ADR
- Lack of suitable models for humans
Whats the difference between invivo and invitro
Invivo = Animal Invitro = Human
how is toxicology information biologically obtained?
Biology: Toxicology tests involves exposing biological systems (proteins, cells, in vitro, in vivo) to the test substance under controlled action
How is toxicology chemically obtained?
Chemical: For existing chemicals, toxicological information may be obtained from humans and animals such as those given drugs during clinical trials, exposed at the work place or in the general environment.
