Drug induced pathology

Question 1

What are the major pathological effects induced by drugs ?

Answer 1

1. Cell death/ tissue injury
2. altered phenotype function : a drug can change regulatory networks in on cell that has an effect on all the other cells
3. immunological hypersentivity
4. Genotoxicity and carcinogenesis
5. Teratogenesis

Cells have protective/regulatory responses such as DNA repair mechanisms and apoptosis/necrosis therefore the toxic response depends on extent of damage, temporal and dose relationships.

Question 2

Scheme of drug toxicity

Answer 2

Question 3

Molecular Mechanisms of drug toxicity

Answer 3

1. Drug or metabolite can cause on - or off -target adverse effects
2. Reactive metabolites may bind covalently bind/interact with DNA, small molecules such as glutathione (GSH) or cellular or plasma proteins leading to loss of function or trigger immune responses that can damage cells and tissues
3. Formation of unrepaired or mis-repaired DNA adducts is generally mutagenic (genotoxic) and can lead to cancer
4. Metabolism of a drug may generate a reactive intermediate that can reduce molecular oxygen directly to generate reactive oxygen species (ROS) e.g. hydrogen peroxide, superoxide dismutase (SOD), hydroxyl radicals

An increase in ROS can overwhelm the cellular defenses (enzymes such as SOD and catalase), this accompanied by a depletion of GSH can lead to oxidative stress resulting in damage to proteins, DNA and lipids.

Impairment of oxidative defenses can lead to inflammation and cell death (apoptosis/necrosis).

Question 4

Molecular mechanism of drug toxicity scheme

Answer 4

Question 5

Is there feedback mechanisms in the molecular mechanisms of drug toxicity ?

Answer 5

Question 6

Observable toxic responses in clinical trials

Answer 6

1. Local effects
2. Systemic effects
3. Reversible and irreversible ffects
4. immediate and delayed effects
5. morphological functional and biochemical effects
6. allergic and idiosyncratic reactions
7. dose and temporal aspects of toxicity

Question 7

the 3 r’s

Answer 7

replace

reduce

refine

Question 8

Aim of preclinical toxicity tests

Answer 8

1. characterisation of toxic effects
2. establish what dose / plasma levels toxicity occurs, what are the safety margins ?
3. Determine a chemical’s primary and cumulative toxicology
4. determine the no observed adverse effect level (NOAEL)
5. identify the target organs that should be monitored in clinical trials
6. examine reversibility of toxic effects
7. Examine effects that cannot be tested ethically in clinical studies