Lecture 21

Question 1

What is the importance of understanding toxic mechanisms?

Answer 1

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

Question 2

What is the mechanistic toxicology process?

Answer 2

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

Question 3

How common are adverse drug reactions?

Answer 3

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)

Question 4

What is CARM?

Answer 4

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

Question 5

What causes adverse drug reactions?

Answer 5

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

Question 6

What are the biological targets in ADRs?

Answer 6

Proteins
Lipids
DNA

Question 7

How do ADRs lead to the end points of death?

Answer 7

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

Question 8

How are ADRs classified?

Answer 8

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

Question 9

What are the mechanistic classes of adverse drug reactions?

Answer 9

Type A,B,C,D,E

Question 10

What is a type A adverse drug reaction?

Answer 10

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

Question 11

What is a type B adverse drug reaction?

Answer 11

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

Question 12

What is a type C adverse drug reaction?

Answer 12

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

Question 13

What is a type D adverse drug reaction?

Answer 13

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

Question 14

What is a type E adverse drug reaction?

Answer 14

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

Question 15

How common are the ADRs of NSAIDs?

Answer 15

Responsible for 25,000 deaths per year

Induce gastro-duodenal ulceration and bleeding in 15-30% of chronic users

Question 16

What causes the gastrointestinal toxicity of NSAIDs?

Answer 16

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

Question 17

What is the importance of metabolism in ADRs?

Answer 17

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

Question 18

How does paracetamol cause ADRs?

Answer 18

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