Tox- Toxicokinetics 2

kelseyfmeyer's version from 2016-10-02 23:23

Kinetics continued

Question Answer
in essence what is this chart sayingo B- has a small therapeutic dose window and more ability to be toxic easier w/ a small dose change. A has a larger therapeutic window and09 will not really be toxic even w/ a large dose change
you determine ED50 from individual or quantal dose response relationships?quantal
what is ED50? LD50? LC50?ED50= effective dose in 50% of the individuals. LD50= lethal dose in 50% of the individuals. LC50= lethal concentration in 50% of the individuals (KEEP IN MIND: effective dose can be tox dose, depends on target or end point we define- is an inc in BP what we want, or is this a toxic side effect?)
diff between lethal dose and lethal concentration?dose is what you give to the animal, concentration is what you measure in the body (such as conc in the plasma)
DOSE RESPONSE RELATIONSHIP GRAPH: EXPLAIN IT. A and B are diff drugs. Red line is toxic concentration. Green line is minimum effective concentration. So you can see that Drug A is effective throughout dose range and never reaches toxic effects and has a gradual increase in response. A is more safe. Drug B has an abrupt increase and response and becomes toxic @ 7mg/kg. If using this drug- need to be more precise with dosing bc smaller therapeutic window than A.
Evaluating the Dose-response Relationship as comparison of relationships (explain graph) ED= effective dose of anesthesia. TD= toxic dose of anesthesia on liver. LD= lethal dose of anesthesia on respiratory system= respiratory arrest. Therapeutic index= TI= TD50/ED50. Margin of safety and exposure= TD1/ED99 (toxic dose in 1% of patients /effective dose in 99% of patients). Red line is ED 50% and green line is NOAEL= NO observed Adverse Effect level-bc starts before toxic dose but only includes 50% of patients. If want 100% of patients to have ED-orange line-then almost all patients would have toxic doses and some would have lethal doses (pink line). This means that this compound is relatively toxic. What if the ED, TD, LD lines were parallel? Then this wd indicate extension of ED effects but TD/LD effects not related to pharmacology and occurring in the diff organ systems.
what are the 3 Assumptions in deriving the dose-response relationship?(1) The response is due to the chemical administered (toxicodynamics) (2) The magnitude of the response is in fact related to the dose: (a) There is a molecular target site for the compound (b) Production and degree of the response are related to the concentration of the compound at the target site (c) The concentration at the target site is related to the dose (3) There is a quantifiable method of measuring and precise means of expressing toxicity
what is PBPK (Physiologically based pharmacokinetic modeling) modelling? What is it used for?Mathematical modelling technique to predict ADME (absorption, distribution, metabolism excretion). Q= bloodflow, [X]= concentration of the substance
what is the equation for Therapeutic index (TI)?TD50/ED50 (gives you a measure of how safe is this drug. how precise must you be. )
what is the equation for Margin of safety and exposure?TD1/ED99 ( toxic in 1% of the pts, and effective in 99% of the patients. )
why are the slopes in this graph not parallel to each other, but slope differently instead?It is the pharmaco kinetics/dynamics which determine the slope of curve. If toxic effects were from exactly the same interaction (receptor) in a tissue that is as accessible as the lungs, it would be a parallel curve. In this graph, ED LD AND TD have diff receptors and interaction so diff logarithmic slopes. (ED is effective anesthesia dose, TD is liver injury, and LD is because of resp arrest)
why might the toxic dose be a faster rate (sharper slope) than the ED?because TD in the liver because it runs out of enzymes to metabolize it. Also ED and TD might be measured different ways (ED is how well under anesthesia they are, TD is how bad you're messing up the liver)
what is LT50?LT50= the time required for half the animals to die.
what is MOE (margin of exposure index)Exposure related to TD10 or NOAEL. The MOE approach uses a reference point, often taken from an animal study and corresponding to a dose that causes a low but measurable response in animals. This reference point is then compared with various dietary intake estimates in humans, taking into account differences in consumption patterns (The MOE is a ratio of two factors which assesses for a given population the dose at which a small but measurable adverse effect is first observed and the level of exposure to the substance considered.)
Dose-response relationship--> explain this graph the Dose-response relationship to look at potentcy versus efficacy. we are looking at response of the group over the dose. You can see that Chemical A is more potent than chemical B (lower dose is where you start to see effect). Chemical C is more potent than chemical D (also starts at a lower dose). However, Maximal efficacy of chemical D is greater than of chemical C, because if you keep increasing the dose, the response stays the same around 30% but as you inc the dose of D, you will continue to see inc response.
flowchart which shows how to go about TOXICOLOGICAL EVALUATION OF NEW CHEMICALS.
LD50 measures what kinda tox?ONLY ACUTE tox--Toxicity testing should include sub-acute, chronic, carcinogenic, and reproductive toxicity among others

Recap from last lecture (intro)

Question Answer
admin of organophosphates leads to?mm spasms, urination, pupillary construction (inhibits ach-esterase-- means more ach in synapse, ach is active at parasympathetic receptors, and the nicotinic receptors of the neuromuscular junction.)
_________ determines toxicitydose
know the diff between type A and type B drug rxnsA= predictable based on drugs action. B= unpredictable, idiosyncratic
at least 2 examples of immediate vs delayed toxicity (3 examples delayed!!!!) DELAYED= *Asbestos toxicosis, Diethylstilbestrol toxicosis** (delayed/skips generations), Organophosphate induced delayed polyneuropathy (delayed)
describe how drugs can become immunogenic.Drug (hapten) binds to endogenous protein, how it's big enough for immune system to recognize it.
know the small vs large animal toxicitiesremember major sm ani is antiparasites, food ani is food contaminants
know the differences between the hypersensitivity reactionsI- allergies. II- cytotoxic. III- complex formation. IV- delayed type
know what an idiosyncratic reaction isdepends on the individual's genetics as to how they will react to the drug (like how chloramphenicol can only give some ppl aplastic anemia)
understand importance of exposuretype and duration of exposure
differentiate the diff adverse drug reactionstype a= augmented= expected. Type b=bizarre= often idiosyncratic

RECAP of kinetics

Question Answer
know Basic kinetic information from term 2ADME: absorption - distribution - metabolism - excretion. <--this is in essence pharmacokinetics. Bioavailability depends on pKa of the drug, pH at the site of absorption, transporters, etc.... Understand routes of admin, etc
Exposure is dependent on which parameters?k
What is the difference between individual and quantal dose-response relationships?individual- look at curve of their response. Quantal: is this individual in the group a responder or a non-responder.
Describe the therapeutic indexThis is the TD50/ED50-- gives you a measure of how safe is this drug. how precise must you be. (how much difference in dosing between killing them and being effective?)
Describe the margin of safetyTD1/ED99-- looking at the dose between where it is toxic in 1% of the pts, and effective in 99% of the patients.