SESSION 6

Question 1

Define a ligand

Answer 1

A molecule that binds to another molecules

Question 2

Define affinity

Answer 2

The degree to which a substance tends to combine with another

To bind to a receptor a ligand must have affinity for the receptor

Higher affinity -> stronger binding

Question 3

Define partial agonist

Answer 3

Drugs that bind to/ and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist

All receptors occupied- insufficient efficacy fro maximal response
Low intrinsic efficacy

Question 4

Define intrinsic activity/ efficacy

Answer 4

The ability of a ligand to cause a response (receptor activation)
Efficacy is governed by intrinsic efficacy
The number of receptors, influence the response

Question 5

Define functional antagonist

Answer 5

An antagonist may act as a completely separate receptor, initiating effects that are functionally the opposite of the agonist

Question 6

Define reversible competitive antagonism

Answer 6

a receptor antagonist that binds to a receptor but does not activate the receptor.
The antagonist will compete with available agonist for receptor binding sites on the same receptor
- the inhibition is surmountable

Relies on dynamic equilibrium between ligands and receptors

Cause a parallel shift to the right of the agonist concentration- response curve

Question 7

Define irreversible competitive antagonism

Answer 7

A type of antagonist that binds permanently to a receptor, either by forming a covalent bond to the active site that does not dissociate or dissociates too slowly

Non surmountable
- with increased antagonist or increased time more receptors are blocked

Cause a parallel shift to the gist of the agonist concentration- response curve
And at high concentrations suppress the maximal response

Question 8

Define non- competitive antagonism

Answer 8

Non- competitive antagonism is when the antagonist binds to an allosteric site of the receptor

No competition for binding site- reduce orthosteric ligand affinity and/ or efficacy

Question 9

Define agonist

Answer 9

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

Question 10

Define antagonist

Answer 10

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

Question 11

What is drug action determined by?

Answer 11

The concentration of drug molecules around receptors

Question 12

What is the significance of molarity?

Answer 12

An international unit of measure- allowing easy comparison

LEARN MOLE CONCENTRATION TABLE

Question 13

What is drug- receptor interactions governed by?

Answer 13

Binding governed by association and dissociation

Question 14

What is the difference between agonists and antagonists in terms of efficacy?

Answer 14

Agonists:

• have intrinsic efficacy- activate the receptors
• have efficacy- cause a measurable response

Antagonists:

• only have affinity
• no efficacy as the receptor is not activated

Question 15

How do we measure drug -receptor interactions by binding?

Answer 15

• bind radioactively labelled ligands to cells

- these radio ligands enable us to track and measure the drug- receptor interactions

Question 16

Define Bmax

Answer 16

Bmax is the maximum binding capacity- all the receptors are saturated, adding more ligand will have no further effect

Question 17

Define Kd

Answer 17

Kd is the dissociation constant
Kd is the concentration of ligand required to occupy 50% of the available receptors
Indicated the strength of interaction

Kd- index of affinity
Lower value = higher affinity

Question 18

Is affinity important for ligand?

Answer 18

High affinity allows binding at low concentrations

As a result sensible seized tablet can be given

Question 19

Define Emax

Answer 19

Emax is the effective maximum response achievable from an applied or dosed agent

Question 20

Define EC50

Answer 20

Effective concentration giving 50% of the maximal response
This is a measure of agonist potency
It depends on both affinity and intrinsic efficacy

Question 21

Define potency

Answer 21

The generation of a measurable response to efficacy and affinity
Affinity + efficacy = potency
Same potency could occur with different combinations of affinity and efficacy

Question 22

What is required for a ligand o have potency (generate a measurable response)?

Answer 22

1) ligand binding to the receptor- affinity
2) receptor activation - intrinsic efficacy
3) things to happen to generate measurable response

2&3 are efficacy

Question 23

Define concentration

Answer 23

Known concentration of drug at site of action

E.g. In the cells or tissues

Question 24

Define dose

Answer 24

Concentration at site of action unknown

E.g. Dose to a patient in mg

Question 25

Using asthma as an example explain the clinical relevance of receptor selectivity

Answer 25

Asthma results in the airways contracting
It is treated by adrenaline- attaches to B2- adrenoreceptors (GPCR)- causing the airways to relax

Problem:
It is hard to create a drug that is specific to B2 - adrenoreceptors
As B1 receptors are very similar and result in increased contraction of the heart

Question 26

How do we achieve selectivity in treating asthma?

Answer 26

Salbutamol
Small difference in affinity but large difference in efficacy so doesn’t activate b1

Salmeterol:

• No selective efficacy
• Selectively based on affinity
• B2 affinity is a lot higher

Salbutamol cannot be given to people with heart problems as it isn’t;t selective enough
May result in angina- sipped up of the heart

Question 27

Define spare receptors

Answer 27

The situation in which maximum tissue response occurs when not al the receptors of the tissue are occupied by the drug

Question 28

What factors other than the number of receptors limit response?

Answer 28

• a muscle can only contract so much

- a gland can only secrete so much

Question 29

Why are spare receptors important?

Answer 29

Spare receptors increase sensitivity
- allow response at low concentrations of agonist

10% occupancy of muscarinic receptors –> 90% of receptors are spare

Question 30

What is the relevance of altered receptor number ?

Answer 30

Changing receptor number changes agonist potency
- and can affect the maximal response

Tend to increase with low activity (increase regulation)
Tend to decrease with high activity (down regulation - result in tolerance with reference to drugs)

Question 31

Define full agonist

Answer 31

Full agonists have affinity for/ and activate a receptor, producing full efficacy at that receptor

Often endogenous ligands

Question 32

What is the relevance of partial agonists?

Answer 32

• allow a more controlled response
• work in the absence of low levels of endogenous ligands
• act as antagonist if high levels of full agonist

Question 33

Give an example of a partial agonist

Answer 33

Buprenorphine- higher affinity but lower efficacy than morphine

Advantageous to morphine in some clinical settings:

• pain control
• less respiratory depression

If a heroin addict is placed on buprenorphine they may become ill as a result of withdrawal symptoms
Buprenorphine will inhibit the effect of heroin, ie. partial agonist

Question 34

Are partial agonists always partial agonists?

Answer 34

NO:

• increasing receptor number can change partial agonists to full agonists
• partial agonist still has low intrinsic efficacy at each receptor
• BUT sufficient receptors to generate a full response

Question 35

Define IC50

Answer 35

IC50- index of antagonist potency

Determined by strength of stimulus (ie. agonist)

Question 36

Give an example of an irreversible competitive antagonist that is used clinically

Answer 36

Phenoxybenzamine- non- selective irreversible a1- adrenoceptor blocker used in hypertension episodes

Pheochromocytoma - tumour of adrenal chromaffin cells
Resulting in excessive adrenaline
Phenoxybenzamine prevents vasoconstriction by a1- adrenoreceptors

Question 37

Give an example of a non- competitive antagonist that is used clinically

Answer 37

Maraviroc:

• negative allosteric modulator of chemokine receptor 5
• used in AIDs treatment
• usually used by HIV to enter the cells