Toxicology and ADR Flashcards
What is Haber’s rule?
C x t = k
Exposure to low concn of poisonous gas for long time often had same effect (death) as exposure to high concn for short time.
What is good about using in silico (computer) testing?
It is pretty cheap and fast.
What is the purpose of regulatory toxicology?
Ensures benefits of chemical substances intended for use by humans outweigh the risk from their use.
What are the 5 levels of selection in toxicology testing?
- Test species
- End point (response)
- Dose
- Route (oral?)
- Duration of the test
What factors affect ADME?
Species Strain Gender Age Nutritional status
What are 4 biological considerations for test species?
- It may not have the relevant target.
- May be subject to diurnal variation (timing)
- Environment (temp, humidity…)
- ADME affected by many factors
What are 4 possible end points?
- Pharmacological
- Direct toxicity (skin irritancy)
- Genotoxicity (bacterial mutagens…)
- Immunotoxicity (immune suppression, allergies)
What is ED50?
The DOSE at which 50% of the maximal response is achieved.
Is a good end point death?
Yes.
Why is it not possible to look at the response of a tissue to increasing doses?
Due to the non-reversability of many toxic end points.
What is the LD50 test?
When 50% of the animals have died from the drug.
What is a NOAEL?
A ‘no observable adverse effect level’. This is where you want to operate. This is a safe level.
How can the shape of a curve be influenced?
By endogenous (genetic polymorphisms) and exogenous (drug interactions) factors.
What is the purpose of acute toxicity tests?
To determine the effects that occur within a short period after dosing. Usually only a single dose is given, maybe via different routs.
What is the Therapeutic index?
The ratio of the doses required to produce a toxic and desired response.
TI = (LD50) / (ED50)
In 2000, which test was withdrawn due to an alternative approach required?
The LD50 test.
What are sub acute toxicity tests?
Exposing the animal to the compound for 28 - 90 days. Exposure is frequent, usually daily.
How are sub acute toxicity tests useful?
Info on target organs and the major toxic effects.
Info on toxic effects with a slow onset.
Help design chronic toxicity tests.
What is a chronic toxicity test?
Lifetime exposure to the compound.
Changes is simple measurements made (weight, food and water intake…)
Often rats and dogs are used. Drug usually administered in the food.
What is the most expensive toxicity assay?
Carcinogenecity test
Why are mechanistic studies important?
- Interpretation of descriptive toxicity data.
2. Drug development
Why are stand tests sometimes not useful?
As they may not be applicable to humans.
What % of morbidity and mortality do adverse drug reactions cause medical injury?
20%
What is CARM?
Centre for Adverse Drug Reactions Monitoring. In Otago.
What % of adverse drug reactions are a result of pharmacological responses?
80%.
What are the 2 classifications of adverse reactions?
Type I: Predictable
Type II: Not predictable
What are the 5 types of mechanistic classifications of adverse drug reactions?
Type A: (Augmented). Predicted from known pharmacology of a drug. Drug-dependent, alleviated by does reduction.
Type B: (Bizzarre). Not predicted from basic pharmacology. No simple dose-response relatioinship.
Type C: (Chemical). Reactions whose biological characteristics can be predicted in terms of chemical structure of drug or its metabolite.
Type D: (Delayed). Occur after many years of treatment, e.g. secondary tumours.
Type E: (End-of-treatment). Due to withdrawal of treatment, especially suddenly.
What are NSAIDs?
Non-steroidal anti-inflammatory drugs.
15-30% of chronic users of NSAIDs developed what adverse reaction from the drugs?
NSAID-induced gastro-duodenal ulceration.
How do NSAIDs induce GI toxicity?
By inducting lesions that interact with phosphotidyl choline and reducing the ability of the gastric mucosa to protect itself (e.g. from HCl).
Inhibition of COZ important as some prostaglandins are cytoprotective and so initial lesion results in overt damage.
How is Paracetamol toxic?
Due to the saturation of detoxification pathways. The reaction is not readily reversed.
There is so dose-dependency and predictability.
What is the toxic metabolite in Paracetamol?
Quinoneimine. This can react with sulfhydryl groups in critical cellular proteins.
Loss of intracellular calcium regulation disrupts mitochondrial function and leads to necrotic cell death.
What are the 2 sub groups in genetic polymorphisms?
Pharmacokinetic types and pharmacodynamic types.
Out of metabolism and the immune system, which is pharmacokinetic and which is pharmacodynamic?
Metabolism: Pharmacokinetic
Immune system: Pharmacodynamic
What happens when there is a lack of metabolism?
You get increased plasma concentrations of the drug and thus exaggerated responses. Could also mean enhanced toxicity due to the lack of detoxification.
What is Suxamethanoium used for? How long does it last?
Muscle relaxation during surgery. Lasts about 2-6 minutes.
Why does Suxamethonium have a short duration in the body?
It is metabolised (hydrolysed) by plasma esterases. Once cleaved, it is ineffective at the receptor.
What is 6-Mercaptopurine used for? What are the consequences of taking it?
It used for treatment of Leukaemia and can lower the body’s ability to fight off infection.
What happens to 6-Mercaptopurine in the body?
It undergoes ‘S-methylation’ and is catalysed by the enzyme thiopurine methyl transferase (TPMT).
How many people have a high TPMT activity?
About 89%
How many people completely lack TPMT and what can happen?
1/300 and are at risk of fatal haematopoietic toxicity from the accumulation of thioguanine nucleotides in blood tissue.
What is Perhexiline? What is it metabolised by?
Anti-angina drug with cationic and amphipathic properties. It is metabolised by CYP2D6 enzyme.
If perhexiline is not metabolised by CYP2D6, then what happens?
It accumulates in lysosomes resulting in hepatotoxicity and neuropathy.
What % of caucasians lack the CYP2D6 enzyme?
8%
What are the most common reactions to Penicillin?
Nausea, vomiting, hairy tongue, diarrhoea.
What are less frequent reactions to Penicillin?
Haemolytic anaemia, neuropathy, nephropathy. Usually related to high doses.
What are a few hypersensitive reactions to Penicillin?
Skin erruptions, urticaria, anaphylaxis
About how many people are truly allergic to Penicillin?
1%
What main receptor does ethanol act on?
GABAa receptors
What can happen if you drink alcohol with sedatives, hypnotics or antihistamines?
Can be too much sedation, leading to coma and death.
What type of interactions are harder to predict? Pharmacokinetic or pharmacodynamic?
Pharmacokinetic interactions. It is about which enzyme is required to get rid of the drug.
Toxicity may be increased in a pharmacokinetic interaction when…? (4 things)
- Inhibition of normal detoxification results in higher than normal plasma concentrations
- Inhibition of one pathway results in a greater clearance through the bioactivation pathway
- Inhibition of detoxification pathways or repair mechanisms
- Induction of the enzymes that catalyze bioactivation
What drug stops the metabolism of Warfarin?
Cimetidine. Therefore blood concentrations increase to toxic levels.
What metabolises Terfenadine and what is the final product?
CYP metabolises it, and it turns into fexofenadine.
What happens if Terfenadine interacts with Ketoconazole?
Ketoconazole is an inhibitor of CYP3A4, which increases plasma concentrations. Fatal interaction. It also prolongs the QT interval in the heart, so the heart did not repolarise and stopped.
What induces the enzyme that bioactivates paracetamol?
Ethanol.
