20 & 21: Toxicity and Adverse Drug Reactions Flashcards
Toxicology is…
The study of adverse effects that are detrimental to either the survival or normal functioning of the individual
What is the top reason for failure in preclinical trials?
Toxicology (44.1%)
What is the top reason for failure in phase 1 trials?
Clinical Safety (27.9%)
What is the top reason for failure in phase 2 trials?
Efficacy (52%)
What is the top reason for failure in phase 3 trials?
Efficacy (72.5%)
What is the top reason for failure in registration trials?
Clinical Safety and Market Potential (both 30%)
What is Haber’s Rule?
C x t = k
- developed to make ammonia from hydrogen and nitrogen
- low conc for long time has similar effect to high conc for short time
What is one way that they predict toxicity?
in silico testing - which is cheap and very fast
What has to be tested for toxicity?
In most industrialised countries…
anything from drugs to additives that humans and other living organisms may be exposed to
What type of toxicology tests is there currently a lot of work into developing?
- ones that explain the toxicity of compounds that isn’t seen in preclinical trials
- ones that predict the toxicity of novel analogues
What should toxicology studies address? (6)
- The injury produced - structural, functional, biochemical
- The dose-response relationship
- Mechanism/s of toxicity
- Factors affecting the toxic response - route of exposure, species/sex, formulation etc.
- Development of approaches for recognition of toxic responses
- Reversibility of response - spontaneous (healing), antidotal (treatment)
Which toxic endpoints must be evaluated? (6)
- cytotoxicity
- systemic toxicity
- sub-chronic toxicity
- genotoxicity
- irritation/intracutaneous reactivity
- sensitisation
What are the 5 levels of selection in toxicology tests?
- Test species
- End point
- Dose
- Route
- Duration of test
Wha are some considerations in choosing a test species?
- If they contain the relevant target
- If they’re subject to diurnal variation
- Environmental factors
- The effects of species, strain, gender, age and nutritional status on ADME
What are some possible types of end points?
- Pharmacological
- Direct toxicity
- Genotoxicity
- Immunotoxicity
What are some points that should be investigated to ensure effective, safe dosage?
- dose required to produce pharmacological effect
- dose required for sub-lethal toxicity
- lethal dose
What are some factors that could influence the shape of dosage curves?
- endogenous factors (genetic polymorphisms)
- exogenous factors (drug interactions)
- saturation of biochemical processes that produe toxicant (via metabolism) may result in toxicity plateau
What are Acute Toxicity Tests for?
- determine the effects that occur within a short period after dosing
- usually only use a singular dose, possibly by different routes
=> in the past were used for dose-response relationships and LD50 determination
What is the therapeutic index?
TI = LD50 / ED50
Ratio of doses required to produce a toxic and a desired response
Larger the number, safer the compound - over 10 safe
No longer used
What do Sub Acute Toxicity Tests involve?
- involve animal exposure for 28-90 days
- frequent exposure (daily)
- information on target organs and major toxic effects
- effects with slow onset detected
- may indicate development of pathological lesions
- survivors undergo complete necroscopy
- blood chemistry, urinalysis and haematology on all ill animals
- aids in design of chronic toxicity tests
What do Chronic Toxicity Tests involve?
- involve lifetime exposure of animals to compound
- changes in weight and food/water intake and clincal measurements made
- choise of dose, species, strain, route (usually in food) are all influenced by type of chemical and regulations
- often rats and dogs
- Rats - about 50 male and female in a group, 100 control
- Dogs - about 10 male and female in a group
Why are mechanistic studies important?
- they can identify moieties in the pructure that may be toxic
- elucidation of toxic mechanisms may help characterise pathways or help in deisgn of new classes of drugs - e.g. stropine from deadly nightshade can be exploited therapeutically in the right doses
Why can human insulin not be studied in animals?
- there is no effect because it is metabolised too quickly
Why can peptides not be tested in animals?
- they are designed to target human DNA, so animal testing wouled be irrelevant
What is the chance that a patient will get an adverse drug reaction in hospital and what effects this chance?
- 1-44%
- type of hospital
- classification of ADR
- reporting method
- condition of the patient
- hospital has newer drugs than GP, and uses multiple
How many ADR are due to pharmacological responses?
80%
What are some non-pharmalogical targets that drugs or their metabolites interact with to cause ADR?
- proteins - inhibition etc. - reversible
- lipids - may dissolve in, can disrupt ion channels
- DNA - may have mutagenic/carcinogenic properties - irreversible
Aspirin toxicity is…
- dose dependent
- predictable
- relatively common
Why can NSAIDs cause GI toxicity?
- chronic COX inhibition (although not completely due to this) which only occurs through oral administration - can be avoided by bypassing the GI tract
- inhibition of COX serious as some prostaglandins are cytoprotective and initial lesion results in overt damage
- interaction with phsophotidyl choline, reducing ability of gastric mucosa to protect from HCl etc
What can the formation of toxic metabolites influenced by?
- dose
- inter-individual variability in enzyme expression/pharmacokinetic interactions
Paracetamol
- toxic due to saturation of detoxification pathways
- some dose-dependency and predictability
- toxic metabolite = a quinoneimine, can react with sulfhydryl groups in critical cellular proteins
- loss of intracellular calcium regulation disrupts mitochondrial function and leads to necrotic cell death
- risk low if taken in small doses as recommended and sparingly.
