L3 Pharmacodynamics II

Question 1

What is the difference between a full and partial agonist?

Answer 1

Full agonist can generate the maximal observed effect (Emax)

Partial agonist can generate a fractional effect

Question 2

_________ means that a substance/drug binds to a receptor and influences its activity.

Usually depicted as a “concentration-response” curve

Answer 2

Agonism means that a substance/drug binds to a receptor and influences its activity.

Usually depicted as a “concentration-response” curve

Question 3

How is agonism usually depicted?

Answer 3

As a concentration-response curve

Question 4

_______ means that a substance/drug binds to a receptor and influences its response to an agonist

Answer 4

Antagonism means that a substance/drug binds to a receptor and influences its response to an agonist

Question 5

What are the two extreme methods of antagonism?

Answer 5

1. Competitive antagonist
2. non-competitive antagonist

Question 6

__________: a higher concentration of agonist is required to generate a given response, but efficacy is not changed

Answer 6

Competitive Antagonist: a higher concentration of agonist is required to generate a given response, but efficacy ​is not changed

Question 7

What effect does a competitive antagonist have on the agonist?

Answer 7

When competitive antagonist is present, a higher concentration of agonist is required to generate a given response.

Effects agonist concentration (potency) but NOT efficacy

Question 8

_______: Reduce agonist efficacy but has no effect on potency

Answer 8

Non-competitive antagonist: Reduce agonist efficacy but has no effect on potency

Question 9

What effect does a non-competitive antagonist have on the agonist?

Answer 9

Non-competitive antagonists reduce agonist efficacy but have NO effect on potency

Question 10

Define competitive antogonist

Answer 10

A compound that occupies the same binding site as the agonist but does not elicit a biological response

I = competitive antagonist

A = Agonist

Question 11

Why might it be difficult to measure how competitive antagonists interact with a receptor?

What can be used to overcome this?

Answer 11

Because antagonists do not generate a biological effect on their own.

Can measure competitive antagonism by generating a schild plot based on dose ratio (or concentration ratio)

Question 12

What is a schild plot?

Answer 12

Graph based on the dose ratio (or concentration ratio) that allows to measure how competitive antagonists interact with a receptor

dose ratio: ratio of agonist EC50 in the presence vs absence of atagonist

• done for multiple concentrations of antagonist

Question 13

How do you calculate dose ratio?

Answer 13

Dose ratio = [EC50 (in presence of antagonist)] / [EC50 (control)]

Question 14

The x-intercept of a Schild plot is sometimes called the _____ or _____ and reflects the ________

Answer 14

The x-intercept of a Schild plot is sometimes called the pA2 or pKi and reflects the potency of the antagonist

Question 15

Competitive antagonists shift the ________ of an agonist, but do not change the ________

Answer 15

Competitive antagonists shift the apparent potency of an agonist, but do not change the efficacy (maximal response)

Question 16

Provide an important example of a competitive antagonist (think opioid overdose)

Answer 16

Naloxone (‘Narcan’) is a competitive non-specific opioid receptor antagonist used as an antidote for opioid overdoses

Question 17

Why might more than one naloxone administration be required to rescue an opioid overdose victim?

Answer 17

A single dose might not be sufficient if the overdosing patient has a large concentration of opioids

ie you would need a higher concentration of Naxolone to compete with the opioid

Question 18

How can partial agonists act as antagonists?

Answer 18

By competing for binding with the full agonist - lead to decreased overall response

Question 19

What is irreversible competitive antagonism?

Answer 19

Where the antagonist binds irreversibly to the drug binding site (cannot be displaced by increasing [agonist]) and reduces the apparent efficacy of the agonist

aka “non-competitive antagonism”

Question 20

A pure Non-competitive Antagonist will have what effect?

Answer 20

Non-competitive antagonist will reduce agonist efficacy but NOT potency (ie will not shift EC50); no matter how much agonist is administered, a full effect cannot be observed.

Does not compete for drug binding site but instead binds to a different location on the receptor and alters agonist effect

Question 21

What is an allosteric potentiator?

Answer 21

Drugs that, when bound to allosteric site, enhance the receptor response to agonist binding

Can enhance efficacy or potency or both

Question 22

What causes non-competitive inhibition?

Answer 22

Antagonist binding at a distinct site from the agonist (called the allosteric site)

Question 23

What effects might occur from the binding of the antagonist to an allosteric site?

Answer 23

1. might prevent activation of the agonist bound receptor (pure non-competitive antagonism)
2. binding of the antagonist might alter the properties of the agonist binding site leading to a combination of effects on potency and efficacy

Question 24

Describe the equations shown in the image:

E:

Emax:

EC50:

B

Bmax

Kd

Answer 24

Describe the equations shown in the image:

E: Biological Effect

Emax: Efficacy Maximum Effect

EC50: [Drug] that gives you 50% of the maximal effect (Emax)

B: Binding

Bmax: maximal # of receptors that can be bound (usually 1)

Kd: Dissociation constant = chemical constant where you have 50% binding of receptors

Question 25

Why can there be a mismatch between binding and effect?

Provide an example using GPCR

Answer 25

Often there are more receptors present than are required for activation of a full biological effect

eg

activation of a single GPCR can lead to generation of many cAMP molecules and activation of many effector proteins. Because of this amplifying effect, there is not a direct relationship btwn agonist binding and biological effect

Question 26

What is receptor reserve?

Answer 26

The difference between binding and effect

• measure biological effect in the presence of increasing concentrations of an irreversible antagonist
  
  • prevents receptors from being activated (A, B, C)
  • full biological effect is observed
  • In C, D, E all the receptors are involved in generating the biological effect, so the Kd and EC50 are similar