Toxicity Flashcards
What is cytotoxicity vs genotoxicity
cytotoxicity- cellular destruction
Genotoxicity- Changes in genetic material that is passed along
What is an example of cytotoxicity and genotoxicity
Cytotoxicity- lipid peroxidation
Genotoxicity- Covalent binding
What is receptor mediated toxicicity and how long does it last
toxicity is caused by binding of the parent compound to receptor/enzyme/ion channel (very targeted)
-adverse rxn is usually disapates when drug administeration is discontinued or further expose terminated
What is naloxone and what receptor does it work on
Naloxone for emergency tx for opiod addiction tx
-antagonist at mu receptor site for opiote (has short half life so needs to be repeatdly admined)
How does acetaminophen work and what does it target
Works on cyclooxgenase enyme to inhibit protaglandin systhesis
Where does acetaminophen work better
Works better on cyclooxgenase in CNS compared to the peripherry
What will happen when too much acetaminophen is injested
Will go thru phase II using p450 and create reactive intermediate which can leads to covalent binding to sulfhydryl groups of hepatic pros
How can the reactive intermediate in acetaminophen phase II be delt with
Glutathione (GSH) will protect + convert it to a non reactive product
What is used to produce more GSH for aceaminophen overdoses
N-acytl-cystein
What is the mathew rumack nomogram used for
To determine if one has acetaminophen poisining or if there is a potential for it
What does a depletion of GSH in phase II cause
Cause an increase of intracellular calcium (damaging)
How can acetaminophen be used as a marker for liver damage
If half life of acetaminophen increases from 4 to 8 hours
-it indicates that biotransformation of acetaminophen is taking a hit aka liver damage
What is the typical route of biotransformation of isoniazid
will be transformed to acetylisoniazid then to either isonicotinic acid or diacetylyhrazine which are both non tox
Why does isoniazid go thru phase I rxn
Slow acetylators are more suseptible as there is a greater degree of intermediate Acetylhdrazine that will instead go thru phase I then to the non toxic substance
What is the phase I rxn of isoniazid
Intermediate (acetylhydrazine) will go through phase I rxn and generate free radicals that can lead to covelent binding (causing liver necrosis)
What happens in iproniazid biotransformation in slow acetalators
intermediate (isopropyl hydrazine) will go thru phase I pathway in slow acetylators and be biotransformed in to free rads that cause damage
What happens in normal ox dissociation curve
as PO2 goes down more o2 will be released
what occurs in the presence of CO for the oxygen dissociation curve
In presense of CO; it will bind to hemoglobin and shift curve to right and reduce carrying capacity
-Need more of a reduction of PO2 to release O2
At 50% COHb what percentage decrease do you need in PO2 to release 1 o2 at tissues
90% reduction in PO2
What is the mechanism of action for cyanide posioning
reversible binding to cytochrome oxidase in the mitochondria blocking electron transport
How is cynanide delt with in the body
Enzymes rhodanese and thiosulfate ion (50% of cyanide in 1 hour)
What can be formed to clean up cyanide and how is it made
Methemoglobin
-can be produced with sodium nitrite
What is the mechanism of toxicity for organophosphate pesticides
- toxicity is caused by inhibition of cholinesterase (responsible for hydrolysis of acetylcholine)
- blocks active site (pseudosubstrate)
What is the tx for organophosphate pesticides
Tx involves pralidozime and atrophine- bind out inhibitor
How do free rads cause cell injury
Free radicals can initiate chain rxns by taking an electron from a stable molecule which then becomes an unstable free radical itself
What is the defense mechanism against free radicals and what does it form
GSH
-will donate proton (H) to deal with substrate (free rad) then form GSGS
What are the 3 ways nucleophilic thiol group (GSH) helps deal with free rads
- Conjugation catalyzed by glutathione transferase
- Donation of a proton to reactive metabolites or free radicals
- Chemical rxn with rective metabolite to form a conjugate
How is GSH remade after it is made to GSGS
Must be transfered back through the use of NADPH and GSSG reductase
Where does the NADPH come from that is needed for the formation of GSH
NADPH comes from NADP using G6P dehydrogenase
What does a deficiency in the conc of GSH in the rbcs cause
Leads to hemolysis
What are the most significant reactive oxygen species (3)
Superoxide anion
Hydroxyl radical
hydrogen peroxide
What is redox cycling and example of it
Production of reactive oxygen species
ex- quinone is reduced to produce unstable semiquinone which is oxidized again (process keeps repeating)
What doe reactive oxygen species do in the body
Damage DNA
Oxidise fatty acids in lipids
Oxidation of amino acids in pro
Oxidation of enzyme cofactors
What systems deal with reactive oxygen species (3)
Superoxide dismutase
Glutathion peroxidase
catalase
What vits are natural scavengers of ROS
Vit C + E
What are the steps to deal with superoxide (2)
- Superoxide–> Hydrogen peroxide by Superoxide dimutase
2. Hydrogen peroxide–>water by Catalase/ Glutathione peroxidase
How are hydroxyl radicals delt with and what enzyme is utalized
Glutathione peroxidase is used with GSH
Which are the major pathways that a cell can go thru that has no point of return (cytotoxic events) (5)
- Lipid peroxidation (#1 for cell damage)
- Covalent binding to macromolecules
- Changes in Thiol status
- Enzyme inhibition
- Ischemia
How does lipid peroxidation develop and what is responsible for it
A hydroxyl radical removes a hydrogen atom from the unstaurated fatty acid of the membrane phospholipid and produces a free radical
-Lipid radical reacts w molecular oxygen and produces a lipid peroxide radical (and continues again and again)
