Exam 1 Flashcards
study of the adverse effects of chemical, physical or biological agents on people, animals, and the environment
toxicology
who said, “the dose makes the poison”
Percelsus
Hazard x Exposure=
Risk
a substance that is foreign to the body or to an ecological system, usually a synthetic chemical
xenobiotic
any toxic substance usually used to denote substances made by humans
toxicant
toxic substances that are produced naturally by a living organisms such as plants, animals, fungi, or bacteria
toxins
Dose that gives 1/2 the maximal response
ED50 (effective dose)
Dose required to get 50% of the population to report a specific toxic effect
TD50 (toxic dose)
dose required to kill 50% of a population
LD50 (lethal dose)
Ratio of the dose required to produce a toxic effect to the dose need to elicit the desired therapeutic response
TI (therapeutic index)
TD1/ED99=
MOS: Margin of safety
<24 hrs of exposure (often only a single dose)
acute
repeated exposure for 1 month or less
subacute
repeated exposure for 1 to 3 months
subchronic
repeated exposure for >3 months
chronic
the amount or concentration of drug responsible for a given level of response
potency
the level of response a drug can elicit
efficacy
what does ADME stand for?
Absorption, distribution, metabolism and elimination
Which in ADME: the transfer of a xenobiotic from the site of exposure into the systemic circulation
Absorption
Which in ADME: Xenobiotic reaching their site or sites of action
Distribution
Which in ADME: Xenobiotics are biotransformed thus increasing or decreasing toxicity
Metabolism
Which in ADME: Removal of xenobiotics from blood and their return to the extern environment
elimination
when repair is exceeded by dysfunction or when repair malfunctions toxicity can occur
toxicity
Transfer from site of exposure to systemic circulation; when lipid solubility increases this also increases
absorption
during first pass elimination, what is it they pass to gain enterance?
GI cells, liver and lungs
During first pass elimination, cells metabolize toxicants (incr./decre) their concentration at sites where toxicity can occur
Decrease
What are the major excretory organs?
liver and kidney
Diffusion back into the systemic circulation at sites of excretion as opposed to removal
reabsorption
Give electron status and philicity of lewis acids and bases
Lewis acid: accepts electrons, electrophiles
Lewis base: donates electrons, nucleophiles
A molecule or molecular fragment that contains one or more unpaired electrons in its outer orbital.
free radical
What happens in a Fenton Reaction?
Ferric turns to ferris
Free radical is always looking for unpaired electron and will take from other entity, causing damage
LEO the lion says GER
Losing Electrons is Oxidation
Gaining electrons is reduction
Imbalance of cellular oxidants and antioxidants in favor of oxidants
oxidative stress
Reversibility of noncovalent and covalent bonding
Noncovalent: reversible
Covalent: irreversible
Destroys cell membrane and/or subcellular organelles
Direct toxicities
Alter structure and function of proteins or DNA
Indirect Toxicities
Two types of cell deaths
Necrosis: sudden death
Apoptosis: self-removal
self-digestion of cell’s own components through lysosome-mediated mechanism
autophagy
Which part of the cell determines the form of cell death?
mitochondria
Three types of repair from toxicity
molecular, cellular, and tissue
Inflammation major events
Recruit inflammatory cells (macrophages and leukocytes) to undergo respiratory burst.
Phagocytosis of cell components for degradation by macrophages
What does Vd tell you about affinity?
Small Vd: toxicants have high affinity for plasma proteins
Large Vd: toxicants have high affinity for tissue proteins
In a Steady State Concentration (Css) model, the drug concentrations fluctuate within the upper and lower boundaries as a result of rate in being ______ rate out
equal to
How to solve for k
ln(y1)-ln(y2)/x2-x1
how to solve for T1/2
0.693/k
how to solve for Vd (volume distribution)
Vs=Dose/k*AUC
How to solve for CL (clearance)
Cl=0.636(Vd)/T1/2
How to solve for absolute F
F= (AUC/Dose)test/(AUC/Dose)IV
Non-saturated fatty acids provide ___, ____ and target for ______
Provide shape, fluidity and target for free radicals
Passive diffusion is not ___, not ______ to substance, and not requiring ____
not saturable, not selective to substance, and not requiring energy
Higher lipophilicity (TDD) means (higher/lower) Log P
higher
Active transport moves xenobiotics (against/not against) concentration gradients and (does/does not) require energy
against, does
Facilitated diffusion moves xenobiotics (against/not against) concentration gradients and (does/does not) require energy
not against, does not
Active and facilitated transport are (saturable/non-saturable) while active transport is (saturable/non-saturable)
saturable, non-saturable
Cmax depends on the ____ and _____ of absorption
rate and intensity
Tmax is inversely related to the ___ of absorption
rate
AUC is directly proportional to the ____ of absorption
intensity
Which ionization species is more easy to pass across the cell membrane?
non-ionized
For pulmonary absorption, particle ____ determines toxicity
size
Distribution occurs (slower/quicker) than elimination
quicker
What are the parameters to describe a distribution process?
Volume of distribution (Vd) and ratio of tissue to blood concentration (T/B)
Equation for Volume
Volume= amount/concentration
What is the relationship between volume and concentration
Inverse
What are the small, medium and large volumes of distributions?
Vd<0.5: small
0.52: large
What ratio provides information on tissue binding of a drug or toxicant?
Tissue/blood (T/B)
On a plasma/time curve for decrease renal blood flow, What is the relationship between Cmax and CLs? Tmax and AUC? T1/2 and F
Cmax/CLs: inverse
Tmax/AUC: inverse
T1/2/F= Bioavailability stays the same
On a plasma/time curve for increased hepatic enzyme activity, What is the relationship between Cmax and CLs? Tmax and AUC? T1/2 and F
Cmax/CLs: inverse
Tmax/AUC: direct
T1/2/F= direct
On a plasma/time curve for increased displacement, What is the relationship between Cmax and CLs? Tmax and AUC? T1/2 and F
Cmax/CLs: inverse
Tmax/AUC: t/max stays constant
T1/2/F= t1/2 stays constant
Which processes affect ADME?
Absorption: Cmax, Tmax, F, Ka
Distribution: (Vd, Css)
Metabolism: (Km,CLs)
Elimination: (K, t1/2, CLs)
A series of enzyme-catalyzed processes that alter the physiochemical properties of foreign chemicals from those that favor absorption across biological membranes to those favoring elimination in urine or bile
xenobiotic metabolism
Which principle #: xenobiotic metabolism is the process of converting insoluble compounds which are readily absorbed into soluble chemicals which can readily be excreted
P1
Which principle #: Biotransformation is catalyzed by various enzyme systems that can be divided into 4 categories based on the reaction they catalyze
P2
Which principle #: In general, individual xenobiotic-biotransformation enzymes are located on a single organelle
P3
Which principle #: In general, xenobiotic biotransformation is accomplished by a limited number of enzymes with broad substrate specificities
P4
Which principle #: several xenobiotic-biotransforming enzymes are inducible, meaning their expression can be increased
P5
Which principle #: There can be species and gender differences in xenobiotic metabolism that must be taken into account during research studies
P6
Which principle #: Genetic variation in xenobiotic-biotransformation enzyme results in inter-individual variations in toxic responses
P7
Which principle #: Environmental factors can also induce variation in drug metabolism
P8
Which principle #: Mass spectrometry is widely used to characterize the structure of metabolites
P9
Three phase I reactions
Hydrolysis, Oxidation, Reduction
Phase II reaction
Conjugation
Phase II reactions add endogenous _____ to the functional groups
moieties
Grapefruit uses ____ of (this enzyme) to (incres/decres) the effects of a variety of drugs by increasing their _______
inhibition of CYP3A4, increases, bioavailability
The primary functional unit of the kidney
nephron
What does the glomera filtrate?
Size and charge filter
(more/less) positive charge means more likely to gain access to the kidney
more
Which segment of the proximal tubule metabolizes glutathione (GSH)
S3
Why is the kidney susceptible to toxicants?
A lot of blood flow in comparison to size, sensitive to system vasoconstriction (BP)
What inorganic element binds to the S3 segment of the proximal tubul?
Inorganic mercury
Cadmium nephrotoxicity chart
Cd binds to GSH or MT.
If MT, goes to urine or kidney.
In kidney leads to cytotoxicity
If GSH, turns to bile and no nephrotoxicity occurs.
TCM chart to liver and kidney
To liver: processes with cP450
To kidney: combines with GSH then processed in proximal tubule. Beta-Lyase then converts to reactive thiol which causes nephrotoxicity
What happens to A2M in rats? Where is A2M present?
Cancer warning on gasoline, but A2M only affects male rats
Kidney uptake in S2 segment of proximal tubule where lysosome inefficiently breaks down A2M. This causes lysosomal overload leading to necrosis. Cell proliferation leads to neoplastic (carcinogenesis) in kidney
Ethylene glycol toxicity and intervention
Ethylene glycol turns to glycolaldehyde, turning to glyco-acids, turns to oxalate connecting to calcium. Calcium oxalate crystals accumulate in kidney leading to cell death and kidney failure.
Intervention: ethanol and fomepizole. Avoids crystallization process
or dialysis
The basic anatomic unit of the liver
lobule
What are the 5 functions of the liver?
nutrient homeostasis, synthesis, secretion, excretion and defense organ
Identify the livers zone: closest to portal vein and arterioles (peri-portal region). Youngest cells, highest glucose storage, high oxygen, high nutrients
zone 1
Identify the livers zone: most active regenerative activity
Zone 2 (mid-zone)
Identify the livers zone: centrilobular; high in p450 enzymes, relatively hypoxic
Zone 3
Excessive accumulation of fat or lipid materials; damage initially reversible
steatosis
Extensive damage in hepatocytes reversible in the early stages; becomes irreversible to coagulative
necrosis
slow or ceased bile flow; requires BSP test
cholestasis
disruption in hepatic architecture due to necrosis and deposition of collagen fibers
cirrhosis
formation of carcinoma
neoplasia
Determine the condition given the AST:ALT Ratio
AST:ALT > 1
2:1
AST:ALT=1
AST:ALT<1
AST:ALT > 1 (cirrhosis)
2:1 (alcoholic liver disease)
AST:ALT=1 (ischemia)
AST:ALT<1 (hepatocellular damage)
A _____ liver is pre-neoplastic
cirrhotic
What type of reaction phase in the liver is APAP
Phase II reaction
What is the treatment method for APAP?
activated charcoal
What is the ethanol metabolism?
Ethanol is treated with ADH, Catalase, or CYP2E1 to form acetaldehyde which is treated with ALDH to form acetic acid
Which compound promotes fatty acid steatosis in the liver?
acetic acid
CYP2EI is an ____ cP450 enzyme
inducible
Which liver zone does allyl alcohol target?
Liver zone 1
What metabolizes allyl alcohol? Which zone does this toxicity occur?
ADH metabolizes to acrolein, with toxicity occurring in zone 1 due to oxygen dependency
What is the mechanism of cell death for CCl4?
CCl4 causes lipid peroxidation. This increases plasma membrane permeability and Calcium, causing cell death
What is the penetration level of alpha, beta, gamma and x-rays for concrete, lead, plastic and paper?
Alpha- stopped by paper
Beta- stopped by plastic
Gamma and x-ray- stopped by lead
How is radiation measured?
By Bq (Baquro) and Ci (Curie)
What is the name for two and three centromeres chromosomes?
2: dicentrics
3: tricentric
Which phase of the cell cycle is low radio-sensitive? high?
S phase- low
M phase- high
Stage of ARS that lasts from a few minutes to days characterized by nausea, vomiting, diarrhea, lethargy, etc.
Prodromal Stage
Individual appears healthy, duration varies with dose
latent stage
What is the survival rate in increasing to decreasing order:
GI syndrome, Hematopoietic Syndrome and Cerebrovascular syndrome
Hematopoietic>GI>Cerebrovascular
