7/11/16 Flashcards
Toxic action of a substance
a consequence of the physical/chemical interaction of the active form of that substance with a molecular target within the living organism
Magnitude of toxic effect
a function of the concentration of altered molecular targets, which in turn is related to the concentration of the active form of the toxicant at the site where the molecular targets are located
Toxicokinetics
what the body does to the agent Absorption Distribution Metabolism Excretion Storage
Toxicodynamics
what the agent does to the body - the active form of the agent at the sensitive target
TK/TD are affected by
- other drugs/xenobiotics
- genetic polymorphisms
- infection/GI flora
- age, weight, diet
Absorption and distribution
enteral (oral, sublingual, rectal)
parenteral (IV, IM, SC)
other routes (inhalation, topical, transderaml)
What is the common feature of all routes of administration (except IV)?
Absorption - epithelial cells line our body cavities and surfaces (epithelial cells lines our body cavities and surfaces)
Physicochemical factors that affect kinetics of absorption
pH, blood flow, gastric emptying, bowel transit, surface area (lung 140m2, GI 300m2, skin 1.5-2m2)
Diffusion
low MW, lipophilic compounds, requires concentration gradient
Carrier-mediated transport
ligand binds receptor on cell surface
ex: cholesterol/lipoprotein bind to LDL
Facilitated transport
mediated by membrane transport proteins
energy provided by concentration gradient
- glucose transporter
Active transport
major form of drug transport
- mediated by membrane transport proteins
- transports AGAINST a concentration gradient
- temeperature-dependent and saturable
Why is the blood-brain barrier less permeable to toxicants?
Capillary endothelial cells (tightly joined, contains ATP transporter - efflux pump)
Capillaries in CNS are surrounded by glial cells
Low protein content of interstitial fluid in brain limits movement of water-insoluble molecules by paracellular transport
Purpose of biotransformation (metabolism)
convert xenobiotics to water soluble forms so that they can be excreted in feces and urine
Why does biotransformation make resulting compound more toxic?
Most xenobiotics are liophilic and body readily excretes water soluble compounds so the body transform via Phase 1 or 2 reaction to make them more soluble.
Primary enzyme in phase 1 reactions
cytochrome p-450 (mixed function oxidase)
Phase 2 reaction enzymes
glucuronyltransferase
sulfotransferase
glutathione-S-transferase
acetyltransferase
Excretion pathways
respiratory (mucociliary exchange, gas exchange) GI (biliary excretion, entero-hepatic circulation) urinary excretion (glomerular filtration, trans-tubular secretion)
Other routes of excretion
milk, sweat, hair, nails, saliva
biological half-life
time required for chemical in the body to decrease to 1/2 its current value
toxicological endpoints
cell death, cellular/organ dysfunction, teratology, genetic changes, cancer
LD50
lethal dose to 50% of test population, lower ld50 - more toxic
Exposure
any condition which provides an opportunity for an external environmental agent to enter the body
Agent
any chemical, biological, or physical material capable of eliciting a biological response (diff than vector or carrier - air, water, soil, food)
Dose
amount of agent actually deposited within the body, distinction between exposure and dose is blurred
exposure assessment
exposure = intensity x frequency x duration
Vectors for exposure in context of environmental health
water, air, food, soil
toxicokinetics in the toxicological paradigm
exposure, internal dose, biologic effective dose
toxicodynamics in the toxicological paradigm
early biologic effects, altered structure & function, clinical disease
Patterns of exposure
continuous (cigarette) intermittent (uranium mining) cyclic random concentrated
Hierarchy of “exposure” data
Quantitative personal dosimeter measurements
quantitative ambient measurements in the vicinity
quantitative surrogates of exposure (estimates of drinking water or food consumption x conc.)
residence or employment in proximity to the source of exposure
residence or employment in the general geographic area of the source of exposure
Uncertainties in toxicology
high to low dose extrapolation
interspecies comparisons
Define dose-responser relationship
the relationship between the quantity of response and the dose of the drug or toxicant
- response is due to agent
- degree of response is due to compound concentration
- have a quantifiable response parament
Potency
Range of doses over which a drug produces increasing responses
Efficacy
maximal response; plateau of the dose-response curve
“Random” model
Risk of response is a function of dose, assumes no threshold, no dose is safe, any dose increases the risk (ex cancer)
“Deterministic” Model
Severity of response is a function of dose, assumes a threshold, a “safe” dose exist(ex radiation, chloracne)
Interactive responses
Additive (2+4=6)
Synergistic (2+5=20)
Potentiation (0+4=10)
Antagonism (2+6=3; 4+1=0)
Interactions of chemicals - additive
operating through same molecular mechanism - specific receptor or very specific interaction (ex 2 diff organophosphates interacting with cholinesterase receptor)
Interactions of chemicals -synergistic
Carbon tetrachloride w/ ethyl alcohol - people living above dry cleaning exposed and drink alcohol - synergy response -> liver toxicity
lung cancer & asbestos
Interactions of chemicals - potentiation
only one chemical has toxic effect at site of action
ex: isopropyl alcohol (rubbing alcohol, antifreeze, solvent not toxic to liver CNS depression w/ gastritis, pain, N+V) -> potentiates CCl4
* In the absence of pretreatment, little response
Interactions of chemicals - antagonism
1) functional mechanism, 2 chemicals counterbalance each other
- chemical producing convulsions plus anticonvulsant drug (diazepam)
2) dispositional mechanism, alters concentrations or residence time of toxin (ipecac, charcoal)
3) metabolic mechanism - modulation of CP450
4) receptor block mechanism (competitive inhibitors - naloxone, tamoxifen, atropine)
