2 - Pharmacodynamics 1b: Antagonists

Question 1

What is an antagonist?

Answer 1

Something that inhibits of blocks the effects of an agonist.

Question 2

What are the three types of antagonists?

Answer 2

Chemical: actually combine with the agonist

Physiological: activate opposing physiological inputs

Pharmacological: block the effects of an agonist of a receptor

Question 3

What is the function of competitive pharmacological antagonists?

Answer 3

They act at the same binding site as the agonist (D).

Occupies the site and occludes the binding of endogenous agonist.

Question 4

Competitive antagonists have an intrinsic activity of __?

Answer 4

0.

Question 5

What is a measure of the degree of inhibition of an antagonist? How can an antagonist be overcome?

Answer 5

The more antagonist present, the higher the agonist EC50 (KACT).

Antagonist can be overcome but additional agonist.

Question 6

What equation can be used to calculate the shift in agonist EC50 that occurs in the presence of an antagonist? What else can this equation be used for?

Answer 6

EC50’ = EC50 (1+ ([antagonist]/KI))

EC50’ is always higher than EC50.

This can also be used to calculate KI, which is the KD of the antagonist.

Question 7

The amount of inhibition of a competitive pharmacological antagonist depends on what? What would produce a greater inhibition if all else was equal?

Answer 7

The concentrations of both agonist and antagonist.

An antagonist with higher affinity for the receptor (lower KI) would cause greater inhibition.

Question 8

What is the action of irreversible competitive antagonists? What effect does this have?

Answer 8

Once the receptors are bound by them, they can never be activated by an agonist again.

This reduces the receptor pool and ultimately decreases Emax. EC50 stays the same.

Question 9

How does the graph of a irreversible competitive antagonist change when the antagonist is added and there are no spare receptors present?

Answer 9

Emax is decreased and EC50 does not change

(to calculate ED50 you use the Emax that is determined in the presence of the antagonist).

Question 10

What are some implications of using a non-equilibrium (irreversible) antagonist as a therapeutic agent?

Answer 10

New receptor synthesis is the only way to overcome the effects of the antagonist.

The inhibition produced is not influenced very much by the amount of agonist present.

Question 11

What is the action of noncompetitive antagonists? What is it independent of?

Answer 11

Block the effects of agonist activation of a receptor, but at a site other than the binding site.

Independent of the agonist concentration and can be used to inhibit signaling of several receptors on the same effector.

Question 12

What effect do spare receptors have on non-competitive antagonists? What happens to Emax and EC50 of the agonist with increasing antagonist?

Answer 12

They have the same effect regardless of the presence of spare receptors.

Emax of the agonist is decreased, EC50 doesn’t change.

Question 13

What is a partial agonist/antagonist?

Answer 13

Ligands with affinity for the receptor and intrinsic acticities between 0 and 1.

Question 14

What happens when a partial agonist (PA) is present alone? What about when it’s present with an agonist?

Answer 14

When present alone: it produces an agonist-like effect.

When present with an agonist, it produces an antagonist-like effect.

Question 15

A fundamental tenet of therapeutics states that there is a relationship between the dose of a drug and it’s therapeutic effect. What is this called?

Answer 15

The dose-response relationship.

Question 16

Define potency. How is ED50 related to potency?

Answer 16

The relationship of the amount of drug administered and its effect.

ED50 is inversely related to potency. The more potent a drug is, the less you need for to achieve the effective dose.

Question 17

What two things determine a drugs potency?

Answer 17

It’s affinity for the site of action (ie the receptor)

It’s ability to reach the site of action.

Question 18

What is efficacy?

Answer 18

The maximal effect that is produced by a drug.

Question 19

What are determinants of efficacy?

Answer 19

1. For a receptor ligand, the intrinsic activity
2. The characteristics of the effector
3. Limitations on the amount of drug that can be administered (usually due to adverse effects)

Question 20

How does the graph of a irreversible competitive antagonist change when spare receptors are added?

Answer 20

Low concentrations of the antagonist shift the agonist concentration curve right and increase the EC50.

This makes sense because more agonist is needed to compensate for the antagonists effects.

Emax will decrease.

Question 21

Why is the Emax reduced in the presence of a non-competitive antagonist?

Answer 21

Because the non-competitive antagonist “eliminated” an effector.

Question 22

What type of antagonist both reduces the Emax for an agonist and increases the EC50 value?

Answer 22

A competitive (irreversible) antagonist.

Question 23

What is Ra/Ri?

Answer 23

The ratio of active to inactive receptors .

Question 24

What effect does each have on Ra/Ri: Agonist, antagonist, and inverse agonist.

Answer 24

Agonist: converts more receptors from inactive to active

Antagonist: doesn’t alter the ratio of active to inactive form because it binds to the receptor and those that were active stay active and those inactive stay inactive.

Inverse agonist: pushes more receptors into inactive form

Question 25

In an ideal world, what would a dose response curve mirror? Why don’t they look the same?

Answer 25

The concentration-effect curves one obtains in a laboratory setting.

They aren’t the same because things have to happen for the drug to get from the site of administration to where it has its effects.

Question 26

In an idealized dose-response relationship, what does the ED50 tell us? What about the maximal effect?

Answer 26

ED50 tells us the potency.

Maximum effect tells us the efficacy.

Question 27

When effect is only dependent upon the law of mass action, _______ of a drug dose are needed to cover the range from 0 to 100% maximal effect. Is this always true?

Answer 27

3 log units.

No; this isn’t always true, which tells us that something about this system violates the law of mass action.

Question 28

What can cause the shape of a curve to deviate from the ideal S-shaped curve in which 3 log units get you from 0 to 100% maximal effect?

Answer 28

The additive, synergistic, or opposing effects of the drug at multiples sites.

Threshold at which an effect can be measured (ie a ceiling that prohibits max effect from being reached).

Question 29

What does the shape of a dose-response relationship tell us?

Answer 29

The ease of the drugs use in patients.

-a very steep or u-shaped curve can be difficult to get dose “just right”

Question 30

Most drugs follow a log-normal distribution, what does this mean?

Answer 30

The response frequency (yes or no to a drug response) is plotted against the log dose.

The mean and median end up being the same point and you get a symmetrical distribution where 68% of people are within one standard dev of the the mean.

Question 31

More often than a log-normal graph, what is often used? What is the ED50 on this graph?

Answer 31

A cumulative frequency distribution, which looks at the cumulative response of individuals to the dose of a drug and at every dose below that.

ED50 is when 50% of the population of people respond to the dose.

Question 32

What are the four reasons that people respond differently to the same dose?

Answer 32

1. Pharmacokinetics
2. Variation in amount of endogenous agonist
3. Changes in the number or function of target (ie tolerance)
4. Differences in a component distal to the target

Question 33

What is an idiosyncratic drug response?

Answer 33

A surprising response to a drug typically discovered early on when the drug comes onto the market.

Question 34

What does it mean if someone is hypo or hyper-reactive to a drug?

Answer 34

They are at the tails of the dose response curve.

Question 35

What is hypersensitivity? How is this different from being hyper-reactive to a drug?

Answer 35

Hypersensitivity differs from hyper-reactive because it involves an allergic or inflammatory response.

Question 36

What is tolerance? What is tachyphylaxis?

Answer 36

Tolerance: slowly developing resistance to a drug (days to weeks)

Tachyphylaxis: rapidly developing resistance to a drug (ie nicotine)

Question 37

What are three characteristics of a “quantal” dose response curve?

Answer 37

1. Y axis is a quantal measure of effect (yes or no)
2. ED50, LD50, or TD50 values are obtained depending on response measured
3. Share of curve demonstrates variability in response in pop

Question 38

Define for a dose-response curve:
ED50
LD50
TD50

Answer 38

ED50 - effective dose in 50% of pop

LD50: lethal dose in 50% of individuals

TD50: toxic dose in which 50% of individuals have adverse effects

Question 39

What is the therapeutic index?

Answer 39

The ratio of the TD50/ED50

The bigger the difference, the less likely there’s going to be overlap between them and the safer the drug is to use.