Section 1: Part 2

Question 1

Variability and transport objectives

Be able to list three factors whose variations contribute to the typical 9-fold range in blood-levels (pharmacokinetics) seen in many drugs.

Answer 1

F, CL, Vd

(bioavailability, concentration, and volume of distribution)

Question 2

Variability and transport objectives

Be able to explain using a population dose-response curve and a dose-toxicity curve how variation may contribute to adverse effects.

Answer 2

Variation, even in species, can create different effects. What works for one, may not work for the other. For instance, a len vs an obese animal.

Question 3

Variability and transport objectives

Be able to describe how changes in receptor number or prior changes in the activity of signal transduction pathways can lead to pharmacodynamic variability.

Question 4

Variability and transport objectives

Be able to contrast the types of molecules that move across membranes without transporters with those that may be carried across membranes by transporters. Which type is saturable?

Answer 4

without transporters: hydrophobic or uncharged molecules, could also be very small (nitric oxide or water). could depend on diffusion where surface area and concetration is important. this process is NOT saturable, cannot plateau out.

with transporters: any size and charge, very efficient and rapid (almost 100% of penicillin in blood is removed by single pass through the kidney), this IS saturable (other drugs may compete for transport)

Question 5

Variability and transport objectives

Be able to list important drugs transported by the p glycoprotein and explain how variations in p glycoprotein expression contribute to toxicities.

Answer 5

pglycoprotein is extremely non-specific, a lot fo drugs can be transported with it, like ivermectin. If other drug was given, can compete for trasnport with drug like ivermectin. So you end up inhibiting pglycoprotein.

drugs can can be transported (ivermectin, quinidine, verapamil, digoxin, spironolactone, etc)

Question 6

Variability and transport objectives

Describe where in the kidney transporters are important for drug secretion. What types of molecules are secreted at this site? What types of molecules will diffuse back out of the urine?

Answer 6

SLC & ABC usually on opposite sides of cell (get a flux across an epithelium) Enables efficient drug elimination into urine, bile.
Acidic drugs (organic anions) Penicillin, ampicillin, cephalosporins, thiazine diuretics, furosemide, probenicid, salicylate, etc. Basic drugs (organic cations) Histamine, amiloride, cometidine, procainamide, neostigmine, trimethoprim, atropine, etc

Question 7

What adds variability?

Answer 7

pharmacokinetics (uptake, elimination, distribution); blood concentration can range from .3 to 3 times the concentration.

pharmacodynamics: Variations in effect at a fixed concentration
(Mechanisms of signal transduction,
Changes in receptor number)

Question 8

things to remember in general

What is scours?

Answer 8

plain and simple, diarrha in young animals.

Answer 9

TI does not have to be low but if wide variability…

Question 10

What are the categories of adverse reactions?

Answer 10

Lack of efficacy
Side effects
Allergic reaction
Toxic drug reaction
Ideosyncratic reaction (not as important) - something that does not fit in with other reactions… Peculiar or individual

Question 11

Distinguish between the different types of adverse drug reactions.

Lack of efficacy

Question 12

Distinguish between the different types of adverse drug reactions.

Side effects

Question 13

Distinguish between the different types of adverse drug reactions.

Allergic response

Question 14

Distinguish between the different types of adverse drug reactions.

Toxic drug reaction

Question 15

Distinguish between the different types of adverse drug reactions.

Ideosyncratic reaction

Answer 15

“something that does not fit the other categories”

Question 16

What is cytochrome p450?

Answer 16

google: membrane-bound hemoproteins that play a pivotal role in the detoxification of xenobiotics, cellular metabolism and homeostasis. Induction or inhibition of CYP enzymes is a major mechanism that underlies drug-drug interactions.

Question 17

Lecture 8 Objectives

Be able to describe receptor mediated and non-receptor mediated toxicities.

Answer 17

receptor mediated:
Drug binds to important receptors/enzymes: Disrupt normal activity → damage/death
Overstimulation of “normal” receptors: Example: excitotoxicity
Low-affinity binding to “abnormal” receptors: High dose causes binding to receptors with low affinity for drug

non-receptor mediated:
Not very selective, usually not very potent (Toxic metabolites (Alkylating agents etc)), Bind to many proteins, DNA (Example: acetaminophen, ethylene glycol)

Question 18

Lecture 8 objectives

Be able to describe excitotoxicity and acetaminophen toxicities.

Answer 18

Excitotoxicity refers to an excessive activation of neuronal amino acid receptors. The specific type of excitotoxicity triggered by the amino acid glutamate is the key mechanism implicated in the mediation of neuronal death in many disorders.

AT: Does not depend on receptor-mediated inhibition of cyclooxygenase (COX)

Question 19

Lecture 8 objectives

Be able to contrast pharmacology and toxicology.

Madl’s differences

Answer 19

Pharmacology:
Compound not damaging
Study of “Potions”, L.: Potio, to drink
Compound given intentionally
Receptor mediated effects (usually)
Effects end when compound is gone, (No permanent damage?)

Question 20

Describe two examples of receptor mediated toxicity

Answer 20

Domoic acid toxicity in wildlife & people: overstimulated Glu receptors and damages/kills neurons of hippocampus etc., increases seizures (positive feedback)

Insulin toxicity in cats: insulin has a very low therapeutic index, if you accidentally inject more than once, that cat may have seizures.

Question 21

Describe an example of non-receptor mediated toxicity

Answer 21

acetaminophen toxicity:
common toxicity in veterinary medicine, especially damaging in cats.

depends on alkylation of macromolecules (DOES NOT depend on receptor-mediated inhibition of cyclooxygenase (COX)) - acetaminophen binds to and inhibits cyclooxygenase like NSAIDs do.

Question 22

What is the main damage of acetaminophen?

Answer 22

not stomach damage,
mainly liver and renal damae.

NSAIDs in general, get gastric distress (0-2 days) and get hepatic and renal damage (2-4 days)

Question 23

What will the graph look like if the antagonist is by itself? if it is affecting a competitive curve?

Answer 23

it would be flat. it would shift the curve to the right.