Mechanisms of Toxicity Flashcards
What are the 4 major causes of toxicity?
ADME mediated
1. Disruption of ADME leads to poor metabolization and higher chemical concentrations in the body
2. The metabolization of non-toxic chemical leads to generation of a toxic chemical = Bioactivation
Pharmacodynamic mediated
3. The chemical disrupts the physiology of the cell via non-specific pathways (e.g. oxidative stress, apoptosis, necrosis etc)
4. The chemical interact specifically with biological targets, leading to specific target-mediated toxicity.
- What is ADME mediated toxicity?
When drugs/chemicals disrupt ADME processes - can disrupt one or more
What are the major pharmacokinetic effects of ADME mediated toxicity?
Inhibition of metabolism
Induction of metabolism
Altered drug absorption
Displacement from plasma protein binding sites
ADME mediated toxicity - effect on metabolism
CYP450s can be induced or inhibited by chemicals.
- reduced metabolization of a drug can lead to build up (higher than usual concentrations) increasing the risk of toxicological effects
- increased metabolization can result in lower than expected drug levels and reduced therapeutic effects
Example of ADME mediated toxicity - Statins + CYP3A4 inhibitors
Statins reduce LDL cholesterol in the blood. Help prevent heart disease and stroke.
High dose statin therapy can lead to rhabdomyolysis (results in death of muscle fibres - release toxins into the blood). Can lead to renal failure
Some statins are highly metabolised by CYP3A4. Inhibitors of CYP3A4 (eg. fibrates or calcium channel blockers) can increase the concentration of these statins.
When administered together, these drugs can:
- reduce the metabolism of statins
- increase the levels of statins in the blood
- increase risk of rhabdomyolysis
The use of non-CYP3A4-metabolised statins is preferred for patients taking other drugs that inhibit the CYP3A4 pathway
Example of ADME mediated toxicity - Omeprazol + Clopidogrel
Clopidogrel - antiplatelet medication - used to reduce risk of heart disease and stroke in those at high risk
It is a prodrug.
Omeprazole - protein pump inhibitor - used to treat gastroesophageal reflux disease, peptic ulcer disease and to prevent upper gastrointestinal bleeding.
Omeprazole is a CYP2C19 inhibitor - decreases the antiplatelet activity of clopidogrel by inhibiting the biotransformation of clopidogrel to its active metabolite.
Example of ADME mediated toxicity - St John’s Wort
St John’s Wort is a traditional medicine/herbal supplement - used to treat depressive and anxious states, nervousness, restlessness and sleep disorders
Issue - has a lot of drug interactions.
Drug interactions:
Significantly induces intestinal and hepatic CYP3A4
Moderately activates CYP2C19 and CYP2E1
Example: ethinyl-estradiol (hormonal contraception) -
St johns wart causes an induction of ethinyl estradiol metabolism via increased CYP3A activity. As the drug is being induced and metabolised very quickly - limited active effects of that drug - reduces efficacy of the oral contraceptive.
ADME mediated toxicity - disruption of distribution
Two drugs may compete for the same binding sites - especially albumin binding sites
According to their affinity to the binding site, one drug may displace the other causing an increase in the free concentration of the displaced drug.
Results in increase of drug concentration at target site - may increase risk of developing adverse effects
Example of ADME mediated toxicity - disruption of distribution
Administration of aspirin to a patient treated chronically with warfarin results in displacement of the latter from its binding site.
The increase in plasma concentration of free warfarin causes serious hemorrhagic reactions
- Bioactivation
The metabolization of non-toxic chemical leads to generation of a toxic chemical
so parent compound gets metabolised and produces a a compound that’s not the same as the parent compound (reactive metabolite)
What metabolic systems are involved in bioactivation reactions?
CYPP450 and peroxidase enzyme - produce either electrophilic or radical metabolites
Types of reactive metabolites
Electrophiles
Free radicals
Types of reactive metabolites - Electrophiles
Reactive metabolites are usually electrophiles (positive centre)
- typically either positively charged or have a partial positive charge
If not detoxified properly, electrophiles can reaction with nucleophiles (molecules containing negative centres), through covalent bond formation - form a new structure which may be toxic.
Electrophiles also react with proteins causing changes in protein structure - not recognised by the body - can look ‘foreign’ to the immune system leasing to an immune response
Can also react with nucleic acids on the DNA thereby causing changes to DNA structure or gene expression. Changes in DNA can lead to mutagenicity, teratogenicity or carcinogenicity.
Types of reactive metabolites - Free radicals
Free radicals - compounds that have unpaired electrons
Electrons need to be paired to form a chemical bond - a free radical cannot covalently bond with nucleophiles, instead they:
- covalently bond with another free radical
- take a hydrogen atom from a neutral molecule
- take an electron to form an anion and generate a radical cation
Biological effects of reactive metabolites
If not detoxified, build up of reactive metabolites - leads to modification of biological macromolecules - build up of these molecules - leads to changes in DNA structure, proteins - leading to cell death via necrosis or apoptosis, carcinogenicity, hypersensitivity.
