Tox- Toxicokinetics 1

pbhati17's version from 2018-01-10 18:48


Question Answer
Characteristics of exposure--> what are some things the characteristics of the exposure depend upon? (5)(1) Chemical and physical properties of the agent (2) The exposure situation (he said absorption is exposure too) (3) How the agent is metabolised by the system (including ecosystem) (4) Concentration of the agent at target sites (5) Overall susceptibility of the biological system or subject
Route and site of exposure affects characteristics of exposure--> what are some different routes which can be taken, and how can absorption be affected?routes like ingestion (oral) - inhalation - percutaneous - parenteral. And then absorption depends on ADME.
what is ADME? what on earth is it about?ADME has to do with the kinetics (movement) of the drug in the body. A= Absorption: after initial exposure- absorption determines bioavailability. D= Distribution- reversible transfer of drug to compartments: depends on blood flow, molecule size, polarity, protein binding. M= Metabolism ie CP450- metabolites can be active or non-active. E= Excretion- urine, feces, bile, lungs
absorption determines _________bioavailability
Distribution of a drug depends on...depends on blood flow, molecule size, polarity, protein binding (remember distribution is reversible of drug to body compartments)
remember that if the drug is metabolized, it can or inactive afterwards
what are examples of "ecosystem" metabolism?UV exposure, temperature, soil may or may not break substance down
what are the approximate time frames for Acute, Subacute, Subchronic, and chronic?Acute (24 hrs) - subacute (< 1 months) - sub chronic (1-3 months) - chronic (> 3 months)
absorption determines what kinda toxicity?ACUTE toxicity
What part of a graph is the part that represents bioavailability?AUC (area under the curve)
what are some factors which determine the absorption of a drug/substance (3 major things)Depends on: (1) route and dose(exposure). (2) properties of the drug--->pKa, lipophilicity, molecule size. (3) Properties of the patient---> spp, sex, diseased, ABC transporters.
Explain this shit So you have the level of conc in the blood, over the amount of time. You also have the dotted like TC, which is the toxic concentration (if you exceed the TC, you will see signs of toxicity) (remember if the conc in blood is low that doesnt mean it's not high somewhere else like the liver. But conc in blood does drive conc in tissues!) Drug A reached max conc rapidly and has the biggest AUC meaning it has the most bioavailability. Drug B has half the bioavailability of drug a (because has half as much AUC). Drug C is completely bioavailable (has as much AUC as A) but has half the rate of A so doesnt go up as steeply.
AUC= what?bioavailability!
explain the phase of toxicokinetics each part of the graph has here, and what do you need to remember about this? slope is-- up is mainly absorption (goverened by absorption). top- absorption and distribution. starting downward is some distribution and some elim. low slope= elim [Remember though, that all of this is technically happening all at once, on the graph just shows what the predominant phase is]
how does A compare to B?A and B have same rate(reach peak at same time), but A has greater AUC and bioavailability and time over toxic conc. ii) B has only half bioavailability of A and no time spent over toxic conc
how does C compare to A?C takes a longer time to reach its peak and a longer time to be eliminated-thus slower rate and half the rate of A. But does reach toxic concentration, closer bioavailability to A
What is the difference between an unbound to plasma protein and bound to plasma protein drug?UNBOUND= CHEMICALLY ACTIVE. BOUND= INACTIVE
which plasma protein binds acidic drugs, which binds basic drugs?ACIDIC: Albumin binds acidic drugs. BASIC: Alpha 1 acid glycoprotein binds basic drugs
what are the major things that distribution depends on?(1) Plasma protein binding (2) VD (volume of distribution) of the drug (higher VD= more likely to get into compartments) (3) pKa of drug (4) molecule size of drug (5) polarity of drug (6) blood flow and membrane permeability (7) Depends on depot storage and redistribution to tissues/compartments
how does inflammation affect distribution?inflammation--> inc permeability of BVs and inc blood flow--> higher volume of distribution
What is going on with accumulation of toxins? (2 examples included)Toxins that are not readily excreted are usually stored in bone (lead) and fat (DDT= pesticide and its metabolite)
If something is accumulated... what can happen after this?REDISTRIBUTION can occur (conc in blood might be below tox conc for a while, but redistribution might bring it back out to tissues and leads to conc that does cause tx )
how can biotransformation affect toxicokinetics?Biotransformation might lead to bioactivation (can take non-toxic drug and bioactivate it making metabolite toxic or both drug and metabolite can be toxic.)


Question Answer
Remember this graph? (not in his tox notes, from pharm tho) What parts of the body are A, B, C, and D? A is IV route (blood) B is in well perfused tissues. C is in lean tissues (takes longer to get there than well perfused tissues, which is how you know its lean not perfused), D is fat
__philic compounds will penetrate the skinlipophilic
exposure and kinetics--> Cutaneous exposure/absorption--> A local skin reaction might cause irritation. What are some examples of different local skin areas youd need to considerSite of contact (sole of the foot), Furry skin (grooming cat), Mucous membranes (eye - mouth), Percutaneous absorption (lipophilic- exposure time)
Exposure and kinetics--> Oral absorption. What are the local reactions? what other factors do you need to consider?local reactions: irritation in mouth, oesophagus and stomach. Consider Interaction with feed materials (non-specific binding), Consider the Special function of the forestomach of ruminants (will this affect the substance?), Site of absorption: species differences (cow= rumen, dog= small intestine, etc) PIC= all the diff things that can happen with oral route
exposure and kinetics--> INHALATION--> what are the diff kinds of things you can inhale? what/where might local reactions be?can inhale Gasses, vapours, small (dust) particles - nano particles. Local reactions: irritation of mucous membranes and upper airways
INHALATION route--> what are two ways that there could be PRE-SYSTEMIC (before it gets into the blood) ways that an inhaled substance might be eliminated?Pre-systemic clearance from ciliated epithelium (push bigger things up and out) and CP450 in alveolar cells (metabolize them)
what components of the "gut barrier" can lead to PRE-SYSTEMIC elim of oral route substances?gut barrier= gut cells can do biotransformation, there are ABC transporters in the cells to keep things in a particular direction (such as transporting back out into the feces)
(pic) explaining the different routes an orally ingested substance might take
What is first pass effect?(wiki says:) The first-pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.[1][2] It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall. After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This `first pass` through the liver thus greatly reduces the bioavailability of the drug
Dose-response relationship--> what is this?dose determines extent of toxic effects
What concept is this graph relating to? dose-response relationship. What happens if we inc the dose? what happens if it is a continuous exposure?
explain what is going on hereThis is a dose-response relationship graph. Compares a single dose with repeated dose, and then looking at the range of concentration of a toxic response.
Dose response relationship--> The dose determines the extent of the...extent of the toxic effects
Individual dose-response relationship--> what is this?response in individual organism to varying doses of a chemical
Quantal dose-response relationship--> what is this?distribution of individual responses to different doses in a population of individual organisms
individual versus quantal dose-response relationshipINDIVIDUAL is when you are looking at individuals and their diff responses to diff doses (subject X had a 35% inhibition). QUANTAL is when you are looking at the distribution of MANY different individual's responses to diff doses (Subject A did respond at this dose, Subject B did not respond. At the next dose, Subject A and B did respond) (so quantal is responder versus nonresponder, and individual is graphing out what their response was like)


Question Answer
If you are going to look at the dose response relationship, you need to know what your endpoint is. (what does he mean by this in terms of toxicology?)basically, what kinda toxicicity are you looking at? Is your endpoint a rise in blood pressure, or is it carcinogenesis? and how easy is it to measure the endpoint?
Individual dose-response relationship--> what are the two main things we are looking at with this (remember individual dose response is when you look at one individual and their response to diff doses of a substance)(he said in individual dose response relationships, looking in group of animals, like 6, and see what is going to happen...) (1) Effects of the drugs and its metabolites on different organs (2) Multiple sites of action and multiple mechanisms of action. TRANSLATION: drug may not reach conc @ site desired for effect but may reach conc at other sites and cause toxicity
explain what is going on in this graph. (individual dose- response relationship)So we are looking at a substance's effect on cholinesterase and carboxylesterase. So for a drug like organophosphates which inhibit cholinesterase irreversibly. They have an effect on cholinesterase, and as you can see, with inc of the dose there is a gradual inc of the inhibition of the cholinesterase. At the same time, they have an effect on carboxylesterase. This is important bc it is an enzyme in our body so will see CSs associated with it. But what is the toxicity? Does it start at 25% inhibition or at 50% inhibition? So based on that dose-response relationship and knowledge we have about toxicities, we can determine effects of drugs and metabolites on diff organs. Mult sites of action can also be very important- what happens if these two enzymes were switched around? Then see carboxylesterase effects before we see cholinesterase effects.
which is more relative to toxicology in general- individual or quantal dose response relationships?quantal (this is how we get our LD 50 and shit-- bc its plotting number of responders and nonresponders to diff doses)
Quantal dose-response relationship--> how do we use this in toxicology?(distribution of indv responses to varying doses in a population) At any given dose an indv is either a responder or a non-responder. can determine ED50, LD50, etc
--- Which of these is an individual dose-response relationship and which is a quantal?
(1) is individual- looking at dose versus the effect (in this case enzyme inhibition) on that individual. (2) is quantal- it is looking at frequency of response of a population to diff doses
In this top graph, why does the amount of responders go up then down?Because some individuals need a higher dose to respond. So initially at a low dose there arent that many responders, then as you inc the dose MORE respond, then as the dose get higher there are less individuals who you START to see a toxic effect at, at that dose. So with this you can see the dose where there is the most response (in the middle of graph). this is diff from the cumulative responses-- in the end, all subjects responded