Term
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Definition
| general classification for poisons designed to kill various pests (plant & animal) |
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Term
def
chlorinated hydrocarbon insecticides |
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Definition
| group of fat-soluble, low molecular wt., stable compounds with low water solubility |
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Term
| Why do chlorinated hydrocarbon insecticides s.a. DDT have poor biodegradability? |
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Definition
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Term
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Definition
| interfering with inactivation of sodium channel => alteration of sodium & potassium transport across axonal membranes => rapid repetitive firing in most neurons |
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Term
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Definition
| support physiological function |
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Term
| What is the primary short-term effect of DDT? |
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Definition
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Term
| What insecticides have largely replaced chlorinated hydrocarbon insecticides? |
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Definition
| organophosphorus insecticides |
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Term
| Why are organophosphorus insecticides uned even though they persist in the environment? |
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Definition
| extrememely low carcinogenic potential (though much higher acture toxicity in humans - need only sm. dose to be lethal in children) |
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Term
| What organophosphorus insecticide is the most frequent pesticide invilved in fatal poisoning? |
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Definition
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Term
| How are organophosphorus insecticides absorbed? |
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Definition
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Term
MOA
organophosphorus insecticides |
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Definition
| inhibition on AchE by phosphorylating the esteric site |
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Term
Sx
organophosphorus insecticide poisoning |
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Definition
Sx of persistent Ach hyperstimulation (muscarinic, nicotinic, CNS)
death
delayed neurotoxicity in some substances |
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Term
MOA
carbamates insecticides |
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Definition
| inhibit AchE by carbamoylation of esteratic site |
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Term
Sx
carbamate insecticide poisoning |
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Definition
| ~organophosphorus insecticide poisoning |
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Term
| Why are carbamate insecticides less toxic than organophosphorus insecticides? |
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Definition
| they easily dissociate fro enzyme => shorter duration of action |
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Term
| Why are carbamates thought to have little negative environmental impact? |
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Definition
| nonpersistent in the environment |
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Term
| Which pesticides persist in the environment? |
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Definition
| cholorinated hydrocarbons & organophosphorus insecticides |
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Term
| Which is the only pesticide to bioaccumulate? |
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Definition
| cholorinated hydrocarbons |
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Term
| What pesticides do not accumulate in animals? |
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Definition
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Term
| What are herbicides used for? |
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Definition
| control many broad-leaf woody plants |
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Term
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Definition
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Term
| Why don't herbicides accumulate in animals? |
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Definition
| readily excreted (though slowly metabolized) |
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Term
| What is the half life of herbacides? |
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Definition
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Term
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Definition
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Term
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Definition
high dose: ventricular fibrillation
loe dose: neuromuscular involvement |
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Term
| Why are the 2 bipyridyl herbacides? |
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Definition
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Term
| What are the 3 primary sites of damage due to paraquat toxicity? |
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Definition
lungs, liver, & kidneys
(lung fibroblast widespread proliferation) |
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Term
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Definition
| redox cycling in cells to generate lg. amount of ROS => change in regulation of cell function => necrosis |
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Term
| What is the main environmental pollutant caused by plastic, flame retardant, etc thru the 70s & still persists today? |
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Definition
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Term
| What are the characteristics of PCBs? |
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Definition
| very lipophilic, highly stable, poorly metabolized |
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Term
| Why does PCB bioaccumulate in the food chain? |
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Definition
| very resistant to environmental degradation |
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Term
| What is the major source of human exposure to PCB? |
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Definition
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Term
| What mechanisms may be imployed by chamical interactions? |
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Definition
1) alteration of absorption
2) protein binding effects
3) biotransformation alteration
4) excretion effects on any number of interacting toxicants
5) ADME |
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Term
| What can happen to the effects when 2+ chemicals ineract together? |
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Definition
1) additive (10+2=12) - assume to be the case
2) synergistic (10+2=20)
3) potentiation (10+0=20)
4) antagonistic (10+2=5) |
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Term
| What is an antagonist to coumarin poisoning? |
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Definition
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Term
def
physiological antagonism |
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Definition
| drugs that stimular antagonistic physiological mechanisms |
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Term
| Why is physiological antagonism not used clincally? |
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Definition
little clinical value & may decrease survival:
-difficult to titrate-duration of action may differ |
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Term
| When are DDI of importance? |
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Definition
| When margin of safety for a drug is small |
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Term
| What increases lielihood of DDI? |
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Definition
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Term
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Definition
1) physical interaction
2) plasma protein binding
3) competition for enzzymes/excretion
4) induction/inhibition of metabolizing enzymes |
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Term
| What legal & uncontrolled substances are often overlooked for potential DDI? |
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Definition
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Term
| What DDI are caused by EtOH? |
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Definition
induction of CYP450
competition for CYP450
CNS effects |
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Term
| What DDI are caused by caffeine? |
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Definition
Inducer/sunstrate for microsomal metabolizing enzymes
potential harm with common medication interactions |
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Term
| What DDIs are caused by tobacco? |
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Definition
induction of metabolizing enzymes
decrease effect of common drugs |
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Term
| Which CYP450 enzyme is a major culprit of DDI? |
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Definition
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Term
| What are the 3 major sources of problems in geriatric toxicology? |
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Definition
1) altered physiology
2) altered drug metabolism
3) polypharmacy |
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Term
| Where are age-related changes seen in drug disposition? |
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Definition
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Term
| What 4 considerations should be taken into account when perscribing for elderly patients? |
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Definition
1) dose adjustments
2) progress monitoring
3) individualize therapy
4) benefit:risk ratio |
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Term
def
activation (bioactivation) |
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Definition
| metabolic ranx of a xenobiotic in which the product is more toxic than the substrate |
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Term
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Definition
| various short-lived, highly reactive intermediates in the reduction of oxygen |
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Term
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Definition
| chemicals that can add alkyl groups to DNA => mispairing of bases or chromosome breaks |
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Term
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Definition
| binding of toxicants or their reactive metabolites to endogenous molecules to produce stable adducts |
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Term
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Definition
| metabolic rxn or sequence of rxns that reduces the potential for adverse effects of a xenobiotic |
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Term
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Definition
| molecules that have unpaired electrons |
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Term
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Definition
| tripeptide, γ-glutamyl-Lcysteinylglycine (involved in many detoxification rxns in cells since resistant to proteases) |
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Term
def
reactive intermediates |
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Definition
| chemical compunds, produced during the metabolism of xenobiotics that are more chemically reactive than the parent compund => greater adverse effect potential |
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Term
def
bioactivation vs. detoxification |
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Definition
| drug metabolism rxns can function as both detoxification & bioactivation mechanisms |
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Term
| What is GSH role in drug metabolism? |
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Definition
| involved in many detoxification rxns in cells since it's resistant to proteases |
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Term
| What are the 5 mechanisms of bioactivation? |
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Definition
1) bioactivation to stable, toxic metabolites
2) biotransformation to reactive, electrophilic metabolits
3) biotransformation to free radicals
4) formation of reduced oxygen metabolites
5) metabolic derangements |
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Term
30 yo man brought to ER in stuporous state with nausea, protracted vomiting & malaise. Over-treated himself with Tylenol (APAP) with up to 30 pills/day to relieve pain/discomfort with a whiplast neck injury a week ago.
PE shouw jaundice & asterixis. Patient was slightly confused & dehydrated. Retinal exam was normal
Labs showed markedly elevated serum transaminases, bilirubin, creatinine & BUN. Mild hypoglycemia & metabolic acidosis. Serum APAP levels were in toxic range.
Liver biopsy reveals over coagulative necrosis. Cells are shrunken & pyknotic with marked presence od nrutophils.
What TX should be administered? |
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Definition
N-acetylcysteine to replace GSH levels & supportive Tx.
Liver transplant may be considered in severe case |
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Term
| Why is the bioactivation of xenobiotics to stable, toxic metabolites limited? |
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Definition
| few chemicals are stable & toxic |
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Term
| What 2 toxins are stable? |
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Definition
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Term
| How common are xenobiotics metabolized to reactive, electrophile metabolites? |
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Definition
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Term
| What principle do reactive electrophiles use to interact with cellular nucleophiles? |
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Definition
| Pearson's principle of hard & soft acids & bases |
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Term
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Definition
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Term
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Definition
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Term
| According to Pearson's principle, what do hard electrophiles interact preferentially with? |
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Definition
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Term
| According to Pearson's principle, what do soft electrophiles interact preferentially with? |
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Definition
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Term
def
hard base (nucleophile) |
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Definition
donor atom/molecule that:
1) high electronegativity
2) low polarizability
3) difficult to oxidize
(i.e. amino groups) |
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Term
def
soft base (nucleophile) |
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Definition
a donor atom/molecule that:
1) low electronegativity
2) high polarizability
3) easy to oxidize
(i.e. thoil group of GSH & cycteine) |
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Term
def
hard acid (electrophile) |
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Definition
an acceptor atom/molecule:
1) high positive charge
2) sm. size
3) lacks unshared electrons in valence shell
(i.e. alkyl carbonium ion) |
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Term
def
soft acid (electrophile) |
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Definition
an acceptor atom/molecule that:
1) low positive charge
2) relatively lg. size
3) contains unshared electron pairs in valence shell
(i.e. michael acceptors) |
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Term
| What toxins have reactive, electrophilic metabolites? |
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Definition
| APAP, bromobenzene, benzo(a)pyrene, 2-acetylaminofluorine, nitrosamines, trichloroethylene) |
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Term
| Which of the reactive electrophile examples produce soft electrophiles? |
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Definition
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Term
| Which of the reactive electrophile examples produce soft/hard electrophiles (usually epoxides)? |
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Definition
bromobenzene, benzo(a)pyrene
GSH conjugation when nephrotoxic |
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Term
| Which of the reactive electrophile examples produce hard electrophiles? |
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Definition
| 2-acetylaminofluorine & nitrosamine |
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Term
| What metabolizes bromobenzene, benzo(a)pyrene, 2-acetylaminofluorene, & nitrosamine to their reactive electrophile conformation? |
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Definition
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Term
| What elements can carry a free radical? |
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Definition
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Term
| What are the 3 ways free radicals can be induced? |
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Definition
one electron oxidation
one electron reduction
homolytic s-bond cleavage |
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Term
Rxn
one electron oxidation |
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Definition
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Term
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Definition
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Term
Rxn
homolytic s-bond cleavage |
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Definition
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Term
| What are the 2 ways free radicals can be propagated? |
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Definition
Abstraction of H atoms (H·)
Addition |
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Term
Rxn
Abstraction of H atoms |
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Definition
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Term
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Definition
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Term
| What are the 3 ways free radicals can be terminated? |
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Definition
Dimerization back to neutral
Disproportionation
Rxn with anti-oxidant |
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Term
Rxn
Dimerization back to neutral |
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Definition
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Term
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Definition
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Term
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Definition
| R· + Antiox -> RH + Antiox· -> neutral |
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Term
| What metabolizes carbon tetrachloride to a free radical? |
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Definition
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Term
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Definition
| 1) HO2· (perhydroxyl radical)
2) H+ + O2-· (superoxide anion)
3) H2O2 (hydrogen peroxide)
4) HO· (hydroxy radical) |
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
| What intracellular nonenzymatic rxn forms ROS? |
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Definition
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Term
| How does Paraquat produce ROS? |
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Definition
Via redox cycling.
A free radical is formed & the extra electron is donated to oxygen to reform the parent compound |
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Term
| What is the quinone protective mechanism from ROS? |
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Definition
| DT-diaphorase (enzyme that skips the ROS step, and allows for 2 electron reduction) |
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Term
| How do nitro anions cause ROS? |
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Definition
| they form free radicals & are recycled back to the parent species via the formation of ROS |
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Term
def
metabolic derangements |
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Definition
| xenobiotic acts by being metabolized to an inhibitor of the metabolic pathway or may produce a depletion of a metabolic intermediate/coenzyme |
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Term
| What is depleted by galactosamine? |
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Definition
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Term
| What is depleted by ethionine? |
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Definition
| ATP (& many others)via antagonizing methionine to form S-adenosylethionine => liver damage |
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Term
| What is depleted by fructose? |
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Definition
| ATP via rapid metabolism to fructose 1-P => hepatotoxicity |
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Term
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Definition
toxicity of fluoracetate
the process by which a toxicant similar in structure to an endogenous substrate is incorporated into the same metabolic pathway as the endogenous substrate => transformation to a toxic/lethal product |
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Term
| What is fluoroacetate (which simulates acetate) converted into? |
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Definition
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Term
| What is inhibited by fluoracetate? |
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Definition
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Term
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Definition
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Term
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Definition
| 3 ring ether with 2 C & an O |
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Term
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Definition
| N-R where N has 6 valence electros therefore an electrophile |
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Term
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Definition
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