Toxicokinetics Flashcards
Toxicity is the (intrinsic or extrinsic?) quality of a chemical to __________
Intrinsic
produce an adverse effect
Toxicity is the Capacity to induce ______,_______, and ___________ effects
teratogenic, mutagenic and carcinogenic
Anything can be a poison
T/F
T
The _____ makes the poison
Dose
Absorption
The process by which toxicants ————————
cross body membranes and enter the bloodstream
Many environmental toxicants enter the food chain and are absorbed together with food.
T/F
T
_________ is the most common route of unintentional exposure to a toxicant (especially for children)
While
intentional overdoses most frequently occur via the ______
accidental ingestion
oral route.
Poisons in the GI tract usually produce systemic injury to an individual before they are absorbed
T/F
F
They usually do not
Absorption of toxicants can take place along the entire GI tract: from the mouth to the rectum.
T/F
T
Organic toxicant (acid or base) are usually absorbed by ________ in the part of the GI tract where it exists in its (ionized or non-ionized?) form
simple diffusion
non-ionized
The ______________ can be used to determine the fraction of a toxicant that is in the non- ionized form and estimate the rate of absorption from the stomach or intestine
Henderson–Hasselbalch equations
According to the HH equation, weak organic acids are mainly present in the non-ionized (lipid soluble) form in the ________ and ionised form in the ______
stomach
intestine
Factors that affect the HH equation include __________ and _________
surface area and blood flow rate.
Most toxicants are absorbed by __________ though
simple diffusion
After oral ingestion, about ___% of lead,__% of manganese, ___% of cadmium, and __% of chromium salts are absorbed.
10
4
1.5
1
Absorption: GIT
Particles and particulate matter can also be absorbed
T/F
T
Absorption: GIT
Particles and particulate matter can also be absorbed
In this case, ______ determines absorption and is _______ related to absorption
particle size
inversely
_______ arsenic significantly more toxic than its _______ form due to increased ________
powdered
coarse granular
surface area
Absorption: GIT
In general, absorption through the GIT is influenced by:
Characteristics of the toxicant
○ Must have sufficient _______ partition
○ Be relatively (ionizer or non-ionized?) in most parts (lipid- soluble)
○ If a particle, must be of relatively ___ size
aqueous - lipid
non-ionized
low
Absorption: GIT
Affected by Other xenobiotics/toxicants:
○Cd decreases the absorption of _______
Ca decreases ____ absorption
Mg decreases absorption of ______
Zn and Cu
Cd
Fluoride
Absorption: GIT
Affected by GI ________/______ within various segments of the GI tract
- could be as an effect of _____/______
Motility/residency time
Laxatives/Anti-diarrheas
Absorption: GIT
Affected by Age
- Well water with a (low or high?) nitrate content produces _______ more frequently in (infants or adults ?) than in (infants or adults?)
*(Lower or Higher?) pH of the neonatal GI tract is permissive for the growth of bacteria
*Bacteria in the GI tract convert ____ to _____, increasing the risk of methemoglobinemia
High; methemoglobinemia
Infants
Adults
Higher
nitrate to nitrite
Absorption: GIT
Snake venoms are much (more or less?) toxic by the oral route relative to intravenous exposure
Why?
Less
because they are broken down by digestive enzymes
Absorption : GIT
nitroaromatic compounds are reduced by intestinal microflora to potentially ______ and ________ amines.
toxic and carcinogenic aromatic
Absorption: Lungs
Absorption or deposition of airborne poisons in the lungs can result in
Death from poisoning— __________
Occupational disease— _________
carbon monoxide
silicosis
Absorption: Lungs
Gases (e.g., _______,_______ ,_______ )
Vapors of volatile or volatilizable liquids (e.g., _______ and __________)
Aerosols
carbon monoxide, nitrogen dioxide, and sulfur dioxide
benzene and carbon tetrachloride
Absorption: Lungs
Depends on Gas molecules partition between two media:
_______ and ______ during the absorptive phase
______ and ———- during the distributive phase
Air and blood
blood and other tissues
Absorption: Lungs
Factors such as _______ and ______ of molecules are less important
more important is the _________________
dissociation and lipid solubility
blood-to-gas partition coefficient.
Chloroform has a relatively (low or high?) blood to gas partition coefficient (approximately ___), whereas ethylene has a (low or high?) coefficient (____)
High
20
Low
0.14
Absorption: Lungs
The site of deposition of aerosols and particulates depends largely on the __________
size of the particles
Absorption: Lungs
The __________ the particle, the further into the respiratory tree the particle will deposit
As particle size ____eases, the number of particles in a unit of space increases along with the total surface area of the particles
smaller (finer)
decr
Absorption: Skin
Exposure is usually limited by its __________ nature.
relatively impermeable
Absorption: Skin
Fatal exposures to insecticides (and even gases e.g. sarin – nerve gas) have occurred in _______ after absorption through intact skin
agricultural workers
Absorption: Skin
Passage through the ________ is the rate-determining step.
stratum corneum
Absorption: Skin
All toxicants move across the stratum corneum by ________
passive diffusion
____philic compounds are absorbed more readily across the stratum corneum , ____ proportional to their lipid solubility and _____ related to molecular weight
Lipo
directly
inversely
Absorption: Skin
Hydrophilic compounds are more likely to penetrate the skin through appendages such as _______
hair follicles
The permeability of hydrophilic molecules doesn’t depend on diffusivity and thickness of the stratum corneum
T/F
F
also depends on it
Absorption: SKIN
Arrange in terms of decreasing absorption rate
Forehead skin, scrotal skin, palm skin
Scrotal skin > forehead skin > palm
Absorption: Skin
Several factors influence the absorption of toxicants through the skin:
*The ______ of the stratum corneum: caustic agents/Diseases
*The _____ state of the stratum corneum e.g. occlusive application
*_______: occupational exposure e.g. agricultural workers
*______ as carriers - dimethyl sulfoxide (DMSO)
*____________
integrity
hydration
Temperature
Solvents
Molecular size (again nanoparticles)
Nanoparticles are relevant in absorption in which of the following routes
Skin
GIT
lungs
All 3 bby!
In studying effects of toxicants, other routes of administration may also be used.
Intravenous – ____% absorption Intraperitoneal – _______
Subcutaneous – influenced by _____/____
Intramuscular - influenced by _____/_____
100
Hepatic first pass
blood flow/formulation
blood flow/formulation
Distribution is a (slow or rapid ?) process.
Rapid
The rate of distribution to organs or tissues is determined primarily by
________ and ________
blood flow
rate of diffusion
Distribution
Some toxicants selectively accumulate in certain parts of the body as a result of
_____ binding
high solubility in ____
Lungs e.g. ______ accumulates in the lungs
Bone e.g. ____
protein
fat; paraquat
Lead
The target organ for toxicity may be the site of accumulation
T/F
T
The target organ for toxicity may be the site of accumulation and this is always the case
T/F
F
this is not always the case
Distribution
Binding to plasma proteins is the major site of protein binding
Several different plasma proteins
Albumin
α1- ___ glycoprotein
Transferrin-a ______- transports ___
Ceruloplasmin, which carries _____
Acid
beta globulin; Fe
copper
Distribution
Because of their high _______, plasma proteins and the toxicants bound to them (can or cannot?) cross capillary walls.
molecular weight
Cannot
Consequently, the fraction of a toxicant bound to plasma proteins is not immediately available for distribution into the extravascular space but available for filtration by the kidneys
T/F
F
Not available for both
a toxicant in a storage depot (including fat deposits) is not in equilibrium with the free fraction of the toxicant in plasma
T/F
F
It is
Distribution
The binding of chemicals to plasma proteins is important for two reasons:
1) Toxicity is typically manifested by the amount that is (bound or unbound?) .
2) Risk of adverse effects resulting from ________________ – ______ displacement
unbound
interactions with other highly bound compounds
protein binding
Distribution
The potential for these compounds to produce carcinogenic, developmental, and endocrine effects is related to their ______________
accumulation/storage in body fat
toxicants with a (low or high?) lipid/water partition coefficient may be stored in body fat
concern is the possibility of increase in the concentration of toxicant in blood/target organ of toxicity may occur if ______________ occurs
High
rapid mobilization from fat
Distribution
Compounds such as _____,_____, and _____ may be incorporated and stored in the bone matrix.
fluoride, lead, and strontium
___%of the lead in the body is eventually found in the _______.
90
skeleton
Toxicants can be released from the bone by ________ at the ____ surface and _____ of bone crystal through _______ activity.
ionic exchange
crystal
dissolution
osteoclastic
Toxicants are also distributed into the brain
T/F
T
Only the free fraction of a toxicant equilibrates rapidly with the brain.
T/F
T
Distribution
Most toxic chemicals pass the placenta by _________
Exceptions → antimetabolites (_____ transport): structurally similar to ____________________
simple diffusion
Active transport
endogenous purines and pyrimidines
Under steady-state conditions, the concentrations of a toxic compound in the plasma of the mother and fetus are usually different
T/F
F
They are usually the same
Metabolism
Rationale for metabolism:
Eventual _______________.
Unacceptably _____________
accumulation to toxic levels
long duration of action.
Metabolism
It can make the xenobiotic less toxic ( _______ ), but in some cases it can make it more toxic (________).
E.g. the oxidation of ethanol (alcohol) to _______ ( _______ ), and the subsequent oxidation of that to _____ is an example of _________.
detoxication; activation
Acetaldehyde; activation
acetic acid; detoxication
Metabolism
So, the biotransformation of drugs can result in:
a loss of activity e.g., acetaminophen to _______________; morphine to _____________)
no change in activity e.g., the conversion of fluoxetine to its N-demethylated metabolite ___________
an increase in activity (e.g. codeine to _________; morphine to ________
acetaminophen glucuronide
morphine 3-glucuronide
norfluoxetine
morphine
morphine 6-glucuronide.
Inhibitors/Inducers can not inhibit or induce their own metabolism
T/F
F
They can
Inhibition/Induction are (reversible or irreversible?) , adaptive responses
reversible
Metabolism
Four discernable phenotypes:
List them
Poor metabolizers (PMs)
Intermediate metabolizers (IMs) Extensive metabolizers (EMs)
Ultra-rapid metabolizers (UM)
organophosphate toxicity is more in male or female???
Female
( male or female?) rats sleep longer than (male or female?) on hexobarbital
Female sleep longer than male
The _______ is perhaps the most important organ for the excretion of xenobiotics
kidney
Toxicants with (low or high?) lipid/water partition coefficient are reabsorbed from the tubules of the nephron more efficiently
High
Elimination
In this case, urinary excretion (i.e., not reabsorbed) of the (ionized or non-ionized?) moiety is favored
ionized
bases are excreted to a greater extent at (lower or higher?) pH whereas excretion of acids predominates at (lower or higher?) urinary pH
Lower
Higher
Elimination
A practical application of this knowledge is illustrated by the treatment of phenobarbital poisoning with ___________
In a similar manner, urinary ______ can be used to increase the excretion of a weak _____ like phencyclidine (PCP) in drug abusers.
sodium bicarbonate.
acidification
base
there is competition for renal secretion
T/F
With reason
T
It’s by active transport
Penicillin is actively secreted by the organic acid systems (OATs) of the kidney; competes with ______ and thus lengthen its half-life and duration of action
probenecid
many functions of the kidney are incompletely developed at birth
T/F
T
some xenobiotics are eliminated more (slowly or rapidly?) in newborns than in adults, and therefore may be (more or less?) toxic to newborns.
Slowly
More
the clearance of penicillin by premature infants is only about ____% of that observed in older children.
20
Elimination
The non-absorbed portion contributes to the _________ of most chemicals to some extent.
One other factor contributing to that is __________, which likely occurs by ______ out of enterocytes or via ______ of intestinal cells during the normal turnover of this epithelium.
fecal excretion
intestinal secretion
passive diffusion
exfoliation
First Pass Effect and direct excretion into the bile is also a source of elimination.
T/F
T
Protein bound compounds are not available for active biliary excretion
T/F
F
They are fully available
_______ and ________ conjugates have a high predilection for excretion into bile
Glutathione and glucuronide
_____ excretion of toxicants and/or their metabolites is most often the major source of fecal excretion
Biliary
The secretion of toxic compounds into milk is extremely important
T/F
With reasons
T
1)a toxic material may be passed with milk from the mother to the nursing offspring
2)compounds can be passed along the food chain via dairy products
Toxic agents are excreted into milk by _______
simple diffusion
Compounds that can accumulate in fat such as pesticides, PCBs, PBBs and furans have been found in human breast milk, and milk can be a major route of their excretion
T/F
T
Metals chemically similar to Ca, such as Pb, and chelating agents that form complexes with calcium also are also excreted into milk to considerable extents
T/F
T
Quantitatively, the excretion of toxic agents in sweat and saliva is of major importance.
T/F
F
Minor
Toxic compounds excreted into sweat may produce ________.
Substances excreted in saliva enter the ____, where they are usually ____ to become available for ______
dermatitis
mouth
swallowed
GI absorption.
