Drug Receptor Interactions

Question 1

What are receptors ?

Answer 1

Receptors are specialised, localised proteins whose role it is to recognise stimulants and translate this event into an activation of the cell.

Question 2

Describe the interaction between drug and receptor

Answer 2

Interaction is loose & freely reversible and does not involve strong chemical bonds.

Question 3

Agonist

Answer 3

Recognise the active site of the receptor as its chemical structure has a similarity to the binding site

Once it binds to the receptor, the agonist can cause a response.

Question 4

Antagonist

Answer 4

Recognises the active site of the receptor.

Once it is bound to the receptor it does not cause a response.

Question 5

Difference between agonists and antagonists

Answer 5

Agonists bind and cause a response, whereas antagonists just bind, and do not have a response.

Question 6

State the 4 receptors (regulatory protein families - commonly drug targets)

Answer 6

Enzymes

Carrier molecules (transporters)

Ion channels

Neurotransmitter, hormone or local hormone receptors

Question 7

How can drug receptor relationship be compared to ?

Answer 7

Lock and Key relationship

• Drug unlocks the response
• specificity of the lock is relative
• Lock may be jammed

Question 8

Describe the rules of drug receptor theory

Answer 8

Agonists and Antagonists :

Both bind same receptor and so must have chemical similarities.

One activates the receptor, the other does not : must also have chemical differences.

Question 9

Law of Mass Action

Answer 9

The rate of a chemical reaction is proportional to the product of the concentration of the reactants.

Question 10

Equation for Law of Mass action (applied to pharmacology)

Answer 10

[D] + [R] <=> [DR]

Question 11

[D]

Answer 11

Concentration of drug

Question 12

[R]

Answer 12

Concentration of receptors

Question 13

[DR]

Answer 13

Concentration of occupied receptors

Question 14

K1

Answer 14

Rate constant for associations

Question 15

K2

Answer 15

Rate constant for dissociations

Question 16

What happens as you add drug to the law of mass action ?

Answer 16

There will be a rate of associations (K1 x [D] x [R])

Also a rate of dissociations (K2 x [DR])

Question 17

Affinity of binding

Answer 17

How tightly a compound is bound, how difficult it is to dissociate.

Question 18

Non-Specific binding

Answer 18

As more drugs are added and the tissue is saturated, most of the drug will bind to the active site, but some drug will also bind to the receptor or to the tissue in a random fashion.

Won’t bind to the active site, will bind randomly.

Question 19

How can you measure non-specific binding ?

Answer 19

Bound drug to receptor.

Flush the system with unbound drug.

Unbound drug will displace the bound drug at the active site (as it recognises the active site).

Freely reversible

As the labelled drug comes off, and as you add more and more of unbound drug the probability of the unbound drug to bind to the active site becomes greater and displaces the labelled drug.

Only displaces the labelled drug at the active site.

Non-specific sites are not displaced, as they are random binding.

Probability of the unbound drug binding at the same site is very low.

Question 20

How to calculate specific binding ?

Answer 20

Calculate how much labelled drug is still left when saturated with a unlabelled drug.

Subtract non-specific binding from the total binding, this gives us the specific binding

Question 21

What is equilibrium dissociation constant ?

Answer 21

Equilibrium when the rate of associations = the rate of dissociations

Question 22

Kd

Answer 22

Equilibrium dissociation constant

Question 23

What does Kd represent ?

Answer 23

The concentration of drug required to occupy 50% of receptors at equilibrium.

Question 24

Describe the Kd relationship with drugs

Answer 24

Kd :

Different for every drug.

A measure of the affinity of any one drug for a receptor.

Question 25

High Affinity drug

Answer 25

You don’t need a lot of the drug to occupy the receptors.

Will be in a low concentration (nm)

Question 26

Low affinity drug

Answer 26

You need a lot of it to occupy the receptors.

Will be in a high concentration (mm)

Question 27

What is meant by the pD2 for an agonist ?

Answer 27

It is conventional to express the equilibrium dissociation constant (Kd) as -log10 of the Kd.

Question 28

pD2

Answer 28

-log10 of [D] that occupies 50% of the receptors at equilibrium

Question 29

pD2 equation

Answer 29

pD2 = -log10(Kd)

Question 30

Efficacy

Answer 30

Ability to elicit a response

Question 31

Describe efficacy

Answer 31

The maximum response of a tissue can be obtained by occupying less than 100% of the receptors.

(HIGH EFFICACY DRUG)

Question 32

How is max response achieved ?

Answer 32

When a particular stimulus is generated by receptor occupation.

Question 33

Receptor theory

Answer 33

Biological responses to drugs are graded.

Response is proportional to the fraction of receptors occupied

Question 34

What type of relationship exists between drug concentration and the magnitude of response obtained ?

Answer 34

Systematic response

Question 35

Occupancy theory

Equation

Answer 35

Response = [DR] / [RT]

[DR] = number of occupied receptors
[RT] = total number of receptors

Question 36

State the efficacy relationship

Equation

Answer 36

. beta
[D] + [R] <=> [DR] <=> [DR]*
alpha

Question 37

Alpha

Answer 37

Rate constant of receptor inactivation

Question 38

Beta

Answer 38

Rate constant of receptor activation

Question 39

Stimulus equation

Answer 39

Stimulus = [DR] / [RT]

Question 40

Response

Answer 40

Response = f [DR] / [RT]

Question 41

Spare receptor theory

Answer 41

If <100% of receptors are required to evoke a maximum response then these extra receptors are referred to as spare receptors.

Question 42

Describe the relationship between very efficacious drugs and receptors

Answer 42

Very efficacious drugs will require to occupy fewer receptors to give a response than less efficacious ones.

Question 43

Describe powerful drugs

Answer 43

Powerful drugs will produce a large stimulus upon receptor occupation, which summates until a max response is reached.