Pharmacodynamics II

Question 1

Antagonists Types (3)

Answer 1

Chemical: Combines with the agonist and thereby disallows interaction with its site of action

Physiological: Activates an opposing physiological input

• Could be an agonist

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

Question 2

Types of Competitive pharmacological antagonist (2)

Answer 2

1) Competitive equilibrium antagonist
2) Irreversible, competitive antagonist

Question 3

Competitive equilibrium antagonist (Characteristics)

Answer 3

1. Reversible and can be surmounted by agonist
2. EC50’ is the EC50 for the agonist in the presence of a given concentration of antagonist (K_I is the K_D of the antagonist for the receptor)
3. EC50’ = EC50 (1+ ([antagonist]/K_I))
4. 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

Question 4

Competitive Equilibrium Antagonist: In the box below, D is the agonist and A is the antagonist - What are the implications for the therapeutic use of this type of antagonist?

Answer 4

1) The ability of the antagonist to be effective is dependent upon both its concentration and the concentration of agonist that is present
2) All else being equal, the antagonist with the highest affinity for the receptor will produce the greatest inhibition

Question 5

Irreversible, competitive antagonist (non-surmountable): Characteristics

Answer 5

1. Binds to the agonist binding site in a covalent or very slowly reversing manner
2. Once the receptors are bound by this type of antagonist, they cannot be activated by agonist. This reduces the receptor pool.
3. In the presence of a non-surmountable antagonist, the EC50 value does not change but the E_max is reduced

Question 6

Therapeutic implications of using a non-equilibrium antagonist

Answer 6

1. New receptor synthesis is the only way to overcome the effects of the antagonist
2. The degree of inhibition produced is not influenced very much by the concentration of agonist present

Question 7

What type of antagonist is this?

Answer 7

Irreversible, competitive antagonist (also called non-equilibrium or non-surmountable)

Question 8

Noncompetitive pharmacological antagonists (characteristics)

Answer 8

1) Blocks the activation of the receptor by an agonist at a site other than the agonist binding site
2) D + R ⇔ DR ≠ Effect
3) The agonist concentration curves look the same as the effect of an irreversible, competitive antagonist
- Emax is reduced
- EC50 does not change
- Not influenced by spare receptors

Question 9

Therapeutic implications of noncompetitive antagonists (2)

Answer 9

1) Antagonist effect is essentially independent of agonist concentration at the receptor
2) Can be used to inhibit the effects of multiple agonists that use the same signal transduction cascade

Question 10

Partial agonist/partial antagonist (PA)

Answer 10

Ligands that have affinity for the receptor and an intrinsic activity between 1 and 0

When a partial agonist is present alone, one sees an agonist effect

When a partial agonist is present in combination with a full agonist, one sees an antagonist-like effect

Question 11

What do these arrows represent?

Answer 11

1) Full agonist
2) Partial agonist

Question 12

R_i ⇔ R_a

What does this equilibrium equation represent?

How does it relate to agonists and antagonists?

Answer 12

Useful to think about receptors as in equilibrium between actively signaling (R_a) and inactive (R_i) forms

An agonist shifts the equilibrium of this relationship towards more receptors in the R_a form

A true antagonist has no effect, and therefore does not affect this equilibrium at all

There is a class of ligand that can shift the equilibrium toward the R_i form - called “inverse agonists”

Question 13

The Dose-Response relationship

Answer 13

1) A fundamental of therapeutics is that a relationship exists between the dose of a drug administered and its therapeutic effect
2) Idealized dose response curves mirror the concentration-effect curves one obtains in the laboratory
3) However, many factors can intervene between the site of drug administiration and its ultimate site of action

Question 14

Potency

Answer 14

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

Question 15

How are potency and ED50 (effective dose for 50% of the population) related

Answer 15

ED50 value is inversely related to potency

Potency determines the position of the curve on the x-axis

Question 16

Efficacy

Answer 16

Efficacy is the maximal effect that is produced by a drug

Question 17

Determinants of efficacy include:

Answer 17

Intrinsic activity

Characteristics of the effector

Limitations on the amount of drug that can be administered (often due to adverse effects)

Question 18

Deviations in the shape of this curve can occur because of:

Answer 18

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

Question 19

Biological variability among patients

Answer 19

Rarely is a physician able to determine a dose-response curve in an individual patient

Therefore, need an idea of the dose response relationship in an entire population of patients

Most drug effects follow a log-normal distribution

Question 20

What is a cumulative frequency distribution?

Answer 20

The total of a frequency and all frequencies below it in a frequency distribution

Question 21

Reasons for variations in responses among individuals

Answer 21

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 22

Biological variability: Idiosyncratic drug response

Answer 22

Unexpected based upon the mechanism of action of the drug

Question 23

Biological variability: Hyporeactive or hyperreactive

Answer 23

At the tails of the frequency distribution

Question 24

Biological variability: hypersensitivity

Answer 24

Allergic or inflammatory response to the drug

Question 25

Biological variability: tolerance

Answer 25

Slowly developing resistance to the drug

Question 26

Biological variability: Tachyphylaxis

Answer 26

Rapidly developing resistance to the drug

Question 27

Therapeutic Index

Answer 27

The ratio of TD50/ED50

TD50 = Dose at which toxicity occurs in 50% of patients

ED50 = effective dose for 50% of patients