Pharmacodynamics II - The concept of antagonism

Question 1

What are the types of antagonists?

Answer 1

Chemical antagonist

Competitive receptor antagonist

Irreversible receptor antagonist

Negative allosteric modulator

Inverse agonist

Signalling pathway inhibitor

Functional antagonist

Question 2

What are chemical antagonists?

Answer 2

Chemicals that bind directly to the soluble agonists (eg antibodies)

Question 3

What does infliximab do?

Answer 3

It is a monoclonal antibody that binds to and inhibits pro-inflammatory mediator TNF-alpha which is a treatment used for rheumatoid arthritis.

Question 4

What do competitive receptor antagonists do?

Answer 4

Compete with agonists for the same binding site on receptor

Question 5

Competitive receptor antagonists have affinity for the receptor but no _____

Answer 5

Efficacy

Question 6

What determines the effectiveness of the antagonist at inhibiting the agonist?

Answer 6

The relative concentration of both agonist and antagonist and the affinity of the antagonist to the receptor.

Question 7

What are irreversible receptor antagonists?

Answer 7

Antagonists that form an irreversible bond with agonist binding site preventing agonist from binding to receptor.

Question 8

What is an example of an irreversible receptor antagonist?

Answer 8

Phenoxybenzamine is converted to aziridinium ion which forms a covalent bond with agonist binding site at the alpha-adrenoceptor

Question 9

What happens to reaction when an irreversible receptor antagonist is added?

Answer 9

The number of effective receptors decreases so the amount of agonist to carry out any effect is increased and the overall effect is diminished.

Question 10

Why is phenoxybenzamine rarely used?

Answer 10

It has many other target receptors (it lacks selectivity for alpha adrenoceptors)

Question 11

Which drug is used commonly that is a slowly reversible antagonist?

Answer 11

Tiotropium

Question 12

What conditions is tiotropium used for?

Answer 12

COPD/Asthma

Question 13

Why is tiotropium chosen over other drugs?

Answer 13

It has a long duration of action which means it can be used daily and will improve patient adherence

Question 14

What are allosteric antagonists?

Answer 14

Antagonists that bind to distinct site from binding site which induces conformational change in the receptor and thus reduces the affinity and efficacy of the agonist.

Question 15

What is another name of allosteric antagonists?

Answer 15

Negative allosteric modulators (NAMs)

Question 16

Are allosteric modulator effects reversible?

Answer 16

Yes

Question 17

Can NAM antagonism be overcome with higher concentration of agonists?

Answer 17

Yes

Question 18

What is the ceiling effect in NAM?

Answer 18

Binding sites for allosteric modulators are limited and so there is a ceiling effect for their action.

Question 19

What is the biggest advantage of using NAM?

Answer 19

The ceiling effect is associated with fewer side-effects and less likely to cause excessive blockade compared to other antagonists.

Question 20

What is maraviroc?

Answer 20

A drug designed to reduce HIV-1 rate of reproduction.

Maraviroc is a NAM that bids to CCR5 receptor decreasing viral entry into target host cells.

Question 21

What are inverse agonists?

Answer 21

Agonists that bind to receptors that are active in their unbound state

Question 22

When are inhibitors of intracellular signalling used most effectively?

Answer 22

When cells express unique signalling molecules that aren’t used by many other cells.

Question 23

What does imatinib do?

Answer 23

It inhibits expression of BCR-Abl by leukemic cells which is a singnalling molecule that is essential for their survival.

Question 24

What are functional antagonists?

Answer 24

Agonists that act on receptors that produce the opposite effects within the cell than what the problematic receptor is causing.

Question 25

Example of functional antagonists?

Answer 25

Epipens containing adrenaline to oppose the effect of histamine

Question 26

What kind of effect do functional antagonists cause?

Answer 26

Dose-dependent but limited antagonism due to ability for both receptor agonists to be saturated