What is toxicology?
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)
What factors have an influence on toxicity?
Dose, Time(constant or multiple exposure), route of exposure, Drug target(pharmacology)
Define Haber's rule?
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.
What is the primary aim of toxicity studies?
To determine the potential for harmful effects in the intact living organism, and by extrapolation to humans.
What is the purpose of regulatory toxicology?
To ensure that the benefits of chemical substances intended for use by humans outwigh the risk from their use.
What factors should be addressed by toxicology studies?
The injury produced
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
What are the five levels of selection in toxicity testing?
Duration of test
What should be considered for toxicity testing in test species?
ADME- affected by species, gender, strain, age, nutritional status
Time of dosing-diurnal variation
Environment: temperature, humidity, photoperiod
List some of the end points(responses measured) in toxicology studies?
Pharmacological (pharmacodynamic etc)
Direct toxicity(eg skin irritancy)
Immunotoxicity( immune suppression, allergic reactions)
Death is a good end point but it is not acceptable anymore
What does a log dose response curve show?
It shows if the toxicity of the compound is because of too great a pharmacological effect( response) with a given dose.
What is a no observable adverse effect level?
It can be used as a basis of assigning "safe levels" for exposure.
Define desirable pharmacology? (Curve-pg 171)
The dose at which a suitable frequency of individuals produced the desired response without having any toxic effects.
What are the factors which influence the curve?
Endogenous(eg genetic polymorphisms)
Exogenous( Drug interactions)
These include cellular defence mechanisms(eg GSH)
Saturation of biochemical processes
What can we use populations pharmacology for?
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
What is the purpose of acute toxicity tests?
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.
The larger the number, the safer the compound.
What is the purpose of sub-acute toxicity tests?
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.
What is the purpose of chronic toxicity tests?
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
Why are mechanistic studies important ? (Look at process on pg 178 course guide)
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.
What is the incidence of ADR- adverse drug reactions?
20% of morbidity and mortality
What are adverse drug reactions due to?
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.
How do adverse drug reactions occur and what do they lead to?
Drug(then metabolised)⇒Interaction with macromolecule ⇒Alteration of macromolecule function ⇒Loss of organelle function⇒ Cell death⇒Organ failure⇒Death
What are ADR(s) classified into?
Type I- Predictable(80%)
Type II- Not predictable (20%)
What is the mechanistic classification of ADR?
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
What is an example drug of a dose dependent and predictable toxicity?
What is the ADR caused by aspirin?
Gastro-duodenal ulceration and bleeding
How do GI lesions occur with aspirin?
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.
How does metabolism play a role in adverse drug reactions?
Metabolism leads to formation of a chemically reactive species that can inhibit the biological function of a macromolecule.
What is the formation of toxic metabolites influenced by?
-Inter-individual variability in enzyme expression
How does paracetamol( another NSAID) work to create toxicity?
-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
What is used to treat paracetamol overdose?