mechanisms of toxicity Flashcards
give example of exaggerated pharmacology leading to toxicity (side effect isnt toxic but the desired effect is)
NSAIDs: cox inhibition, renal failure and GI bleeding
Ergot alkaloids: Alpha agonists, vasoconstriction leading to gangrene and limb loss
eserine: cholinesterase inhibitor, leads to breathing difficulties convulsions and nausea
Tetrodotoxin: Na channel blocker leading to paralysis and breathing difficulties (cadmium has same effx)
strychnine: glycine antagonist leading to convulsions and paralysis
opiates /(opioid agonist)/anaesthetics (glutamate antagonism)/barbituates (GABA agonism): respiratory depression
give examples of toxicity due to enzyme inhibition
enzyme inhibition:
eserine solanine sarin and nerve agents inhibit cholinesterase leading to respiratory paralysis
old insecticide fluoroacetate (converted to fluorocitrate) inhibits aconitase leading to convulsions cardiac failure and respiratory arrest
cyanide inhibits cytochrome oxidase leading to respiratory failure.
give examples of toxicity due to transporter inhibition
cholestatic agents (chlorpromazine and tetracycline) block bile ducts inhibiting bile secretions which lead them to leak into the blood.
(toxicity is to the algae) rifampicin blocks OATP-1 treating microcystin (goes into liver cells via OATP-1) poisoning from algae
what factors kinetic factors can lead to organ specific toxicity
-hepatic portal vein transfers contents from GI tract directly to liver. it is a prime target of toxicity as it is the first organ thats hit
-kidney filtration systems concentrate agents so non-tox concentrations in body can reach toxic concentrations here
-Lungs are interface with outside world and can easily absorb noxious airborne chemicals. high concentrations of oxygen here make the lung susceptible to oxidative stress.
-BBB excludes substances from brain but also leads to the CNS being deficient in antioxidant defences. some chemicals can therefore become toxic when they cross BBB
give examples of toxicity due to metabolic activation
ex: ranitidine decomposes to nitrosamine (carcinogen). was originally produced because cimetidine inhibited CYP450
ex: hydroxy-urea decomposed in solutions to generate hydrogen cyanide.
prostaglandin-H-synthase is a mediator of oxidative metabolism can also generate reactive oxygen species/reactive metabolites which can be cellularly toxic. it is generated more with inflammation.
ex: cyclophosphamide for cancer activated by CYP450 or COX produces toxins acrolein (unsaturated aldehyde) and phosphoramide mustard
indomethacin inhibits cox can help reduce the lung and bladder toxicity of this reaction.
describe how carbon tetrachloride is a liver toxin due to metabolic activation
loses a chlorine to form free radical trichloromethyl which
1.interacts with peroxide to form phosgene (toxic)
2.covalently binds
3. interacts with hydrogen to produce free radicals and chloroform (toxic). the free radicals formed here react with peroxide causing lipid peroxidation in the liver
leading to hepatic necrosis
vitamin E is a lipid soluble antioxidant. it inhibits lipid peroxidation via scavenging for radicals and delivering hydrogen atoms to the free radicals. protects against CCL4 liver toxicity
give examples of toxicity at remote sites
liver failure leads to ammonia accumulation which can cross the BBB and reach the brain causing toxicity and cerebral oedemas
cyclophosphamide metabolites aren’t toxic to the liver and are metabolized there but they are toxic to immune cells.
trichloroethylene glutathione conjugates in liver are converted to toxic cysteine conjugates in kidneys.
renal failure can lead to electrolyte imbalances leading to cardiac problems like QT elongation.
rhabdomyolysis releases myoglobin from muscles which can lead to acute renal failure.
describe how vitamin K poisoning is related to oxidative stress
oxygen derived metabolites contribute to most chemical toxicities (mitochondriated cells evolved to reduce oxygen toxicity when plants started releasing oxygen into atmosphere.)
vit K defficient babies were given menadione. radical menadione was formed via reductases. the radical form donates an electron to o2 to form a superoxide anion and produce menadione again. this forms a cycle producing oxygen radical superoxide. (redox cycling)
paraquat and mptp toxicity has similar mechanism
What are the key processes related to reactive oxygen species (ROS) in cells
- o2 gains electron to form superoxide radical
- superoxide dismutase (antioxidant enzyme) forms less reactive hydrogen peroxide with superoxide radicals
- H2O2 converted to H2O via glutathione peroxidase.
- if that route is overwhelmed H2O2 reacts with iron ions to form OH- free radical which leads to cell death.
- H2O2 also leads to thiol oxidation which helps cell signalling.
- neutrophils and macrophages have NADPH oxidase which forms superoxide which is used as part of antimicrobial defence mechanisms, killing invading pathogens
list cellular defences against oxidative stress
- glutathione (GSH) has an unusual thiol group (SH) which is resistant to auto oxidation. thiol groups can also react with superoxide to neutralize them
- glutathione peroxidase detoxifies hydrogen peroxide forming glutathione disulphide (GSSG) and H2O. also destroys lipid peroxidases
- glutathione reductase uses NADPH to reduce GSSG back to GSH
- glutathione-s-Transferases catalyse rxns betweehn GSH and reactive metabolites
-metallothioneins chelate heavy methals which can generate reactive oxygen species
-vitamin E destroys lipid peroxide radicals
-vit c maintains alpha tocopherol and scavanges for alkoxy radicals and peroxynitrite. however can act as pro oxidant when it reduces Fe3 tgo fe2
differentiate between the mechanisms of apoptosis and necrosis
necrosis:
1. unregulated
2. cell contents released and membrane gets damages
3. can start when stimuli such as mitochondrial dysfunction leads to loss of atp which causes a lack of energy dependent procedures.
4. increase in ROS
5. calcium influxes or is released intracellularly which activates proteases and other enzymes
6. inflammatory cells invade the area
biomarkers: lactate dehydrogenase and potassium
apoptosis:
1. regulated
2. requires protein synthesis (active)
3. mitochondrial memb. potential lost and cytochrome c is released from mitochondria which activates caspase. (caspase can be inhibited in certain cancer making them hard to treat)
4. nucleus condenses and cell contents shrink
5. phosphatidyl serine is exposed on cell surface which marks the cell (which breaks into fragments) to be phagocytosed without causing inflammation.
6. has two pathways which cause caspase activation.
–mitochondrial/intrinsic
triggered by loss of survival signs, dna damage and accumulation of misfolded proteins.
–death receptor/extrinsic
the receptors are activated by CD8 lymphocytes
this pathway is used to inactivate self reactive t cells.
Ferroptosis features characteristics from both apoptosis and necrosis.
it is dependent on iron and accumulation of oxidatively damaged proteins.
can be inhibited by iron chelators
responsible for cell death in cold organ stores.
relate the immune system to oxidative processes
neutrophils initiate an oxidative burst which produces oxygen radicals.
uses H2O2 to to synthesize hypochlorite via myeloperoxidase.
macrophases can either
M1: release oxygen radicals and reactive nitrogen species in response to inflammatory cytokines
M2: be anti inflammatory
scar tissue can be formed if inflammatory cells and fibroblasts cause collagen and connective tissue to replace normal tissues.
