W19&21 Agonists and Antagonists

Question 1

What is an agonist?

Answer 1

A substance which initiates a physiological response when combined with a receptor.

Question 2

How is Propanalol an antagonist?

Answer 2

• Is a beta blocker
• Binds to beta 1 receptor so adrenaline cannot bind

Question 3

Drug affinity:

Answer 3

Receptor (inactive) = Free, inactive
Receptor (active) = Bound, inactive
Receptor (active) = Bound, active

Question 4

What do agonists need to have? (2)

Answer 4

Affinity and Efficacy to produce a physiological response

Question 5

What do antagonists have?

Answer 5

ONLY affinity (not efficacy)
Can only bind to receptor but will not conformationally change it from inactive to active
Does not produce a response, will block the ability of an agonist’s response

• Efficacy= capacity to bind to a receptor to produce an effect.

Question 6

What is the Law of mass action?

Answer 6

Association= Disassociation
D + R = DR

Question 7

What is the definition of
Affinity?
Efficacy?

Answer 7

Affinity- The ability of drug binding to receptor
Efficacy- The ability of a drug to activate the receptor

Question 8

What is kD?

Answer 8

(Dissociation constant)

The concentration required to occupy 50% of receptor
= Measure of drug affinity

Question 9

What is EC50/Potency?

Answer 9

EC50 - Effective Concentration of agonist for 50 % of a response

It is an empirical measure of agonist potency

Question 10

A lower kD value means..

Answer 10

A higher affinity as the drug is associated to the receptor
- inversely proportional

Question 11

Plotting drug concentration and receptor occupancy:

Answer 11

Better to plot a log concentration/dose vs Receptor occupancy/affinity
- as a sigmoid curve is produced and is easier to read

Question 12

What is meant by ‘Efficacy’ of drug?
Where do you find the Efficacy of a drug?

Answer 12

Once drug bound to receptor complex, how well it can covert drug from inactive to active

By looking at RMax (at top of curve)

Question 13

What is meant by Full Agonist/ Receptor reserves?

Answer 13

Produces 100 % response with 50% occupation (Full Agonist); Receptor reserves

e.g. only 2/4 receptors bound but leads to an 100% receptors

Question 14

What is a Partial agonist?

Answer 14

Produces less than 100 % max response with maximal receptor occupation

e.g. all receptors filled but only a 40% response

Acts as an antagonist in the presence of a full agonist.
e.g Tolazoline effect on Phenylephrine

Question 15

What does potency mean?

Answer 15

Response

Question 16

Examples of full agonists (for info)

Answer 16

Morphine, Heroin, Oxycodone

Question 17

Examples of partial agonists (for info)

Answer 17

Codeine, Acebutolol

Question 18

What is an antagonist?

Answer 18

A substance which interferes with or inhibits the physiological action of another.

Question 19

What is antagonism?

Answer 19

Drug/ligand that reduces/blocks the agonist response

Question 20

Types of antagonism?

Answer 20

1. Receptor antagonism
2. Pharmacokinetic
3. Reversible/Irreversible competitive
4. Chemical

Question 21

Define:
Orthosteric (Competitive binding)
Allosteric (Non-competitive)

Answer 21

• Same binding site of the endogenous hormone
• Different binding site of the endogenous hormone

Question 22

Non-competitive antagonism?

Answer 22

• Non-competitive antagonist blocks agonist response by binding different binding site from the agonist
• Non-competitive antagonists doesn’t need to have identical chemical signatures (look at the structure of glutamic acid and memantine)

Question 23

What are Reversible antagonists?

Answer 23

Can bind and then dissociate from the receptor

Dissociation of a reversible competitive antagonist from the receptor enables either agonist or antagonist molecules to re-occupy the binding site

Question 24

Reversible competitive antagonists

Answer 24

Most common
- Competition between antagonist and agonist about which will bind to the receptor. If agonist conc increases it will replace the agonist. e.g. Naloxone

By adding more agonists, the agonist maximal response can still be achieved, if the antagonist drug/ligand is reversible and competitive,
(surmountable antagonism)

Increasing agonist concentration could reverse and regain agonist maximal response (surmountable antagonism)

Question 25

What is Irreversible Competitive antagonism?

Answer 25

Inc conc of agonist has no effect on antagonist. This is because antagonist binds irreversibly to receptor.
- Still competitive as both molecules compete for the same receptor

Question 26

What is Allosteric non-competitive antagonism?

Answer 26

Binds to an allosteric site near receptor, modifying its shape so agonist can no longer bind.
- Reduces affinity of agonist
e.g. Ticargrelor (anti-platelet)

Question 27

What is chemical antagonism

Answer 27

Only chemical interactions, no drug targets (receptors) involved.

examples:
Heavy metal chelators/ chelating agents- binds to heavy metal and reduces their toxicity
Neutralising antibody/Antibody therapy= Avastin (bevacizumab) or Infliximab

Question 28

What is pharmacokinetic antagonism?
(ADME)

Answer 28

An antagonist that effectively reduces the concentration of the active drug at its site of action.

e.g. Phenytoin inc hepatic metabolism of warfarin which decreases the conc of warfarin

PK antagonism is also found in:
1. Decreased absorption / altered distribution
-Anti-diarrhoeal drugs inhibit gut absorption of other drugs from the GI tract
-Vasoconstriction by adrenaline restricts the distribution of local anaesthetics

2. Increased metabolism
   -phenobarbital increases liver enzyme activity and
   stimulates the metabolism of many drugs, including warfarin
   -Increases renal excretion

These lead to decrease in concentration at site of action

Question 29

What are the 4 phases of Pharmacokinetics?

Answer 29

Absorption
Distribution
Metabolism
Excretion

Question 30

Why is adrenaline injected along with local anaesthetic during tooth extraction

Answer 30

Adrenaline is a vasoconstrictor and so it will ensure there is no spreading of the local anaesthetic except in that specific area

Question 31

Why is adrenaline injected along with local anaesthetic during tooth extraction

Answer 31

Adrenaline is a vasoconstrictor and so it will ensure there is no spreading of the local anaesthetic except in that specific area

Question 32

What is physiological antagonism?

Answer 32

Antagonist binds to completely different receptor. Physiological response resulting from this will antagonise the effect of the agonist.

Different physiological mechanism
-Blood pressure regulation by DIURETICS
- Diuretics increase the urine output and by which it reduces the sympathetic control of blood pressure (by adrenaline)

Question 33

Match the most appropriate enzyme with its major function:

1.Synthesis of cAMP
2.Synthesis of vasodilator NO
3.Breakdown of phospholipids
4.Prostaglandin synthesis
5.cAMP/cGMP breakdown
6.Synthesis of cGMP
7.Acetylcholine breakdown

Answer 33

1. Adenylyl cyclase
2. Endothelial nitric acid synthase
3. Phospholipase C
4. Endothelial nitric acid synthase
5. Cyclooxygenase
6. Phosphodiesterase
7. Guanylyl cyclase
8. Acetylcholine estrase

Question 34

What is surmountable antagonism?