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Flashcards in Lecture 21 Deck (18):

What is the importance of understanding toxic mechanisms?

May provide procedures for the prevention of drug toxicity through either alteration of the drug or production of an antidote
Can also help to design new classes of drugs


What is the mechanistic toxicology process?

Detect toxicity in vitro or in vivo studies
Characterise lesion
Then understand the significance of the lesion by formulating a hypothesis, testing this to define the mechanism and relate to exposure or metabolism
then define the species variation in this toxic effect and extrapolate it to humans


How common are adverse drug reactions?

May account for 20% or morbidity and mortality
1-44% chance a patient will experience and ADR during hospitalisation (depends on type of hospital, reporting method and classification of ADR)


What is CARM?

The Centre of Adverse reactions monitoring, based at otago collects and evaluates spontaneous reports of adverse reactions to substances
Provides NZ specific information to support clinical decision making
Detects patterns of ADRs to determine potential clinical changes


What causes adverse drug reactions?

80% of adverse drug reactions are a result of pharmacological responses (20% are not)
Adverse drug reactions are due to the interaction of a drug or its metabolite with a biological target


What are the biological targets in ADRs?



How do ADRs lead to the end points of death?

The drug or its metabolite interacts with a macromolecule to alter its function
This can either:
1- cause it to become recognised as foreign, generating an immune response multiple organ failure and death
2-Loss of the organelle function leading to cell death, organ failure and death
3- DNA replication is altered leading to a lack of cell regeneration which can lead to organ failure and death or alternatively uncontrolled replication leading to cancer and death


How are ADRs classified?

Can be classified according to mechanism, relationship to target or dose and predictability


What are the mechanistic classes of adverse drug reactions?

Type A,B,C,D,E


What is a type A adverse drug reaction?

Augmented ADR which can be predicted from known pharmacology usually dose dependant and fixed by dose reduction


What is a type B adverse drug reaction?

Bizarre Not predicted from basic pharmacology with no simple dose-response relationship may be dependant on host


What is a type C adverse drug reaction?

Chemical where there are reactions whose biological characteristics can be predicted or clearly rationalized in terms of the chemical structure of the metabolite or drug


What is a type D adverse drug reaction?

Delayed, occur after many years of treatment after secondary tumours with chemotherapeutic agents


What is a type E adverse drug reaction?

End of treatment due to withdrawal of treatment, especially when drugs are removed suddenly eg seizures on stopping phenytoin


How common are the ADRs of NSAIDs?

Responsible for 25,000 deaths per year
Induce gastro-duodenal ulceration and bleeding in 15-30% of chronic users


What causes the gastrointestinal toxicity of NSAIDs?

Long thought to be due to chronic COX inhibition however now thought to create lesions by interacting with phosphotidyl choline and reduce the ability of the gastric mucosa to protect itself from the gastric acid
Inhibition of COX is still important because some prostaglandins are cytoprotective and so the initial lesion results in more severe damage


What is the importance of metabolism in ADRs?

Metabolism may lead to the formation of a chemically reactive species that binds to and inhibits the biological function of a macromolecule
Formation of toxic metabolites may be influenced by dose, inter-individual variability in enzyme expression or pharmacokinetic interactions


How does paracetamol cause ADRs?

Saturation of detoxification pathways resulting in it being dose dependent and predictable
The toxic metabolite formed is a quinoneimine that can react with sulfhydryl groups in critical cellular proteins
Loss of intracellular calcium regulation disrupts mitochondrial function leading to necrotic cell death