Antagonism and Dose response relationships and Principles of Therapeutics

Question 1

inhibit or block the effects of an agonist

Answer 1

Antagonists

Question 2

Type of antagonist that combines with the agonist and thereby disallows interaction with its site of action

Answer 2

Chemical

Question 3

Physiological agonists:

Answer 3

1. Activates an opposing physiological input

2. Could be an agonist

Question 4

eg. Acetylcholine and norepinephrine are _________ of each other with respect to regulation of heart rate.

Answer 4

physiological antagonists

Question 5

Blocks the effects of the agonist at its site of action (i.e. receptor)

Answer 5

Pharmacological

Question 6

Binds to exactly the same site as the agonist

Answer 6

Competitive pharmacological antagonist

Question 7

EC50’ is

Answer 7

the EC50 for the agonist in the presence of a given concentration of antagonist;

Question 8

K-sub-I is

Answer 8

the K-sub-D of the antagonist for the receptor

Question 9

EC50’ =

Answer 9

EC50 (1+ ([antagonist]/ K1))

Question 10

Binds to exactly the same site as the agonist

Answer 10

Competitive pharmacological antagonist

Question 11

The ability of the agonist to produce a response in the presence of a competitive, equilibrium
antagonist is dependent upon

Answer 11

the affinity of the antagonist for the receptor and its concentration

Question 12

R + D RD–> Effect
+
A –> AR No Effect
The ability of the antagonist to be effective is dependent upon both

Answer 12

its concentration and the concentration of agonist that is present

Question 13

R + D RD–> Effect
+
A –> AR No Effect
All else being equal, the antagonist with highest affinity for the receptor will

Answer 13

produce the greatest inhibition

Question 14

Binds to the agonist binding site in a covalent or very slowly reversing manner

Answer 14

Irreversible, competitive antagonist

Question 15

Once the receptors are bound by this type of antagonist, they cannot be activated by agonist. This reduces the receptor pool

Answer 15

Irreversible, competitive antagonist

Question 16

Irreversible, competitive antagonist :
When we look at the effect of the agonist in the presence of a non-equilibrium antagonist, the EC50 value _________ but the Emax is ________.

Answer 16

does not change

reduced

Question 17

Therapeutic implications of using a non-equilibrium antagonist

(i) New receptor synthesis is ….
(ii) The degree of inhibition produced is not influenced very much by ….

Answer 17

• the only way to overcome the effects of the antagonist

- the concentration of agonist present

Question 18

a) Blocks the activation of the receptor by an agonist at a site other than the agonist binding site;

Answer 18

Noncompetitive pharmacological antagonist

Question 19

blocks the signal transduction step

Answer 19

Noncompetitive pharmacological antagonist

Question 20

D + R DR –X–> Effect

Answer 20

Noncompetitive pharmacological antagonist

Question 21

Noncompetitive pharmacological antagonist:

The agonist concentration curves look steeper/same as the effect of an irreversible, competitive antagonist

Answer 21

Same

Question 22

Noncompetitive pharmacological antagonist:
Emax is _________ for non-competitive inhibitor
EC50 does/does not change
Is/is not influenced by presence of spare receptors

Answer 22

reduced
does not
is not

Question 23

Noncompetitive pharmacological antagonist:

Antagonist effect is dependent or independent of agonist concentration at the receptor

Answer 23

independent

Question 24

Noncompetitive pharmacological antagonist:

Can be used to inhibit the effects of multiple agonists that use

Answer 24

the same signal transduction cascade (eg. inhibition of voltage operated calcium channels)

Question 25

Partial agonist/partial antagonist (PA) | 1. Ligands that have affinity for the receptor and an intrinsic activity between

Answer 25

1 and 0

Question 26

When a partial agonist is present alone, one sees an

Answer 26

agonist effect

Question 27

when a partial agonist is present in combination with a full agonist, one sees an

Answer 27

antagonist-like effect

Question 28

receptors are in equilibrium between

Answer 28

actively signaling (Ra) and inactive (Ri) forms

Question 29

An agonist shifts the equilibrium of Ra and Ri relationship towards

Answer 29

more receptors in the Ra form

Question 30

__________ has no effect, and therefore does not affect this equilibrium at all

Answer 30

A true antagonist

Question 31

There is a class of ligand that has been identified that can shift the equilibrium toward the Ri form – called

Answer 31

“inverse agonists”

Question 32

Inverse agonists ___________tonic activity of the receptor

Answer 32

decrease

Question 33

A fundamental of therapeutics is that a relationship exists between the dose of a drug administered and its therapeutic effect

Answer 33

The dose response relationship

Question 34

Idealized dose response curves mirror the concentration-effect curves one obtains in the laboratory

Answer 34

The dose response relationship

Question 35

Factors that can intervene between the site of drug administration and its ultimate site of action; include:

Answer 35

(1) Absorption (2) Distribution (3) Metabolism and excretion

Question 36

______ is the relationship between the amount of drug administered and its effect

Answer 36

Potency

Question 37

ED50 value is inversely/directly related to potency

Answer 37

Inversely

Question 38

Potency determines the position of the curve on the

Answer 38

x-axis

Question 39

Determinants of potency

Answer 39

(1) affinity for the site of action (2) ability to reach the site of action (3) Both are important as is shown in the beta blocker example

Question 40

_________is the maximal effect that is produced by a drug

Answer 40

Efficacy

Question 41

On the graph, Efficacy is the maximum point on the _______ that is reached

Answer 41

y-axis

Question 42

Determinants of efficacy include:

Answer 42

- Intrinsic activity - characteristics of the effector - limitations on the amount of drug that can be administered (often due to adverse effects)

Question 43

Deviations from this shape (sigmoid)can occur because of:

Answer 43

(1) Additive effects of the drug (2) Threshold effects (3) Antagonist effects

Question 44

Due to _____________ rarely is a physician able to determine a dose-response curve in an individual patient

Answer 44

Biological variability among patients

Question 45

Most drug effects follow a _________ | More often depicted as a ____________distribution

Answer 45

log-normal distribution | cumulative frequency

Question 46

Reasons for variations in responses among individuals

Answer 46

Pharmacokinetic differences Variations in the amount of endogenous agonist present Changes in the number or functioning of the drug target Differences in a component distal to the drug target

Question 47

unexpected based upon the mechanism of action of the drug

Answer 47

idiosyncratic drug responses

Question 48

at the tails of the frequency distribution

Answer 48

hyporeactive or hyperreactive

Question 49

allergic or inflammatory response to the drug

Answer 49

hypersensitivity

Question 50

slowly developing resistance to the drug

Answer 50

tolerance

Question 51

rapidly developing resistance to the drug

Answer 51

tachyphylaxis

Question 52

Cumulative frequency relationships between drug dose and population response are called

Answer 52

quantal dose response curves

Question 53

Y or X-axis is a quantal measure of the response or effect | (1) i.e. it is an all or none measure

Answer 53

Y

Question 54

the ratio of TD50/ED50

Answer 54

Therapeutic index

Question 55

Shape of the curve reflects

Answer 55

the variability in response in the | population

Question 56

These three things are all obtained depending upon the response measured

Answer 56

ED50, TD50, LD50