Antagonism and Dose response relationships and Principles of Therapeutics Flashcards Preview

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Flashcards in Antagonism and Dose response relationships and Principles of Therapeutics Deck (56)
1

inhibit or block the effects of an agonist

Antagonists

2

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

Chemical

3

Physiological agonists:

1. Activates an opposing physiological input
2. Could be an agonist

4

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

physiological antagonists

5

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

Pharmacological

6

Binds to exactly the same site as the agonist

Competitive pharmacological antagonist

7

EC50’ is

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

8

K-sub-I is

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

9

EC50’ =

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

10

Binds to exactly the same site as the agonist

Competitive pharmacological antagonist

11

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

the affinity of the antagonist for the receptor and its concentration

12

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

its concentration and the concentration of agonist that is present

13

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

produce the greatest inhibition

14

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

Irreversible, competitive antagonist

15

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

Irreversible, competitive antagonist

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 ________.

does not change
reduced

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 ....

-the only way to overcome the effects of the antagonist
-the concentration of agonist present

18

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

Noncompetitive pharmacological antagonist

19

blocks the signal transduction step

Noncompetitive pharmacological antagonist

20

D + R DR --X--> Effect

Noncompetitive pharmacological antagonist

21

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

Same

22

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

reduced
does not
is not

23

Noncompetitive pharmacological antagonist:
Antagonist effect is dependent or independent of agonist concentration at the receptor

independent

24

Noncompetitive pharmacological antagonist:
Can be used to inhibit the effects of multiple agonists that use

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

25

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

1 and 0

26

When a partial agonist is present alone, one sees an

agonist effect

27

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

antagonist-like effect

28

receptors are in equilibrium between

actively signaling (Ra) and inactive (Ri) forms

29

An agonist shifts the equilibrium of Ra and Ri relationship towards

more receptors in the Ra form

30

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

A true antagonist

31

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

“inverse agonists”

32

Inverse agonists ___________tonic activity of the receptor

decrease

33

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

The dose response relationship

34

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

The dose response relationship

35

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

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

36

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

Potency

37

ED50 value is inversely/directly related to potency

Inversely

38

Potency determines the position of the curve on the

x-axis

39

Determinants of potency

(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

40

_________is the maximal effect that is produced by a drug

Efficacy

41

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

y-axis

42

Determinants of efficacy include:

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

43

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

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

44


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

Biological variability among patients

45

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

log-normal distribution
cumulative frequency

46

Reasons for variations in responses among individuals

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

47

unexpected based upon the mechanism of action of the drug

idiosyncratic drug responses

48

at the tails of the frequency distribution

hyporeactive or hyperreactive

49

allergic or inflammatory response to the drug

hypersensitivity

50

slowly developing resistance to the drug

tolerance

51

rapidly developing resistance to the drug

tachyphylaxis

52

Cumulative frequency relationships between drug dose and population response are called

quantal dose response curves

53

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

Y

54

the ratio of TD50/ED50

Therapeutic index

55

Shape of the curve reflects

the variability in response in the
population

56

These three things are all obtained depending upon the response measured

ED50, TD50, LD50