Session 10 - Pharmacodynamics: 2

Question 1

What are the 2 factors that effect the selectivity of a drug?

Answer 1

• Selectivity via affinity: I.e. the drug binds much more preferentially to a specific receptor over another
• Selectivity via efficacy i.e. 2 drugs may have the same affinity but if there efficacies differ then this increases/decreases their selectivity (by generating a greater/smaller response)

Question 2

Using salbutamol and salmeterol as examples demonstrate how specificity can be achieved via affinity and/or efficacy

Answer 2

Both salbutamol and salmeterol show B2-adrenorecptor selectivity. Salbutamol achieves this largely on the bases of differences in its efficacy (the difference in affinity is small), while salmeterol achieves this on the basis of differences in its affinity. This has no difference on the outcome of the drug.

Question 3

What effect can “spare” receptors have on the response?

Answer 3

• Having spare receptors means that, for example, having 10% occupancy of muscarinic receptors generates 100% maximal contraction (90% are spare)
• This exists because of:
  - Amplification in signal transduction pathways yet the response is limited by a post-receptor event.
• As such this means that having a higher number of receptors (“spare” receptors) there is increased sensitivity/potency.

Question 4

Receptor numbers on cells are not fixed why may this change and what effects can it have?

Answer 4

Receptor numbers:

• Tend to increase with low activity (up-regulation)
• Tend to decrease with high activity (down-regulation), down regulation can lead to drug tolerance and withdrawal symptoms (when drugs removed normal function is less resulting in need for more)

Question 5

What is the difference between a full and partial agonist?

Answer 5

• Not all agonists elicit maximal responses in the same assay
• A partial agonist is an agonist that can’t elicit the maximal response of a full agonist. This can mean that if there are no “spare” receptors a full response is never achieved (it has a lower intrinsic efficacy)

Question 6

What effect does receptor number have on the type of agonism, partial/full?

Answer 6

A partial agonist may be redefined as a full agonist simply if receptor concentration is increased

Question 7

Buprenorphine is a partial mu-opioid agonist and is used for heroin overdoses. How does this work?

Answer 7

Buprenorphine has a higher affinity than heroin so binds to most/all of the receptors displacing heroin. As such acting as an antagonist (blocker) for heroin.

Question 8

What are the different types of antagonism?

Answer 8

1) reversible competitive antagonism (surmountable)
2) Irreversible competitive antagonism (unsurmountable)
3) Non-competitive antagonism

Question 9

What is IC50?

Answer 9

IC50 = the concentration of antagonist giving 50% inhibition.
It gives an indication of antagonist affinity and strength of stimulus (i.e. [agonist])

Question 10

What effects do the different types of antagonists have on concentration-response curves?

Answer 10

Reversible competitive - increasing [antagonist] results in a shift to the right. Maximum response is achieved (surmounted)
Irreversible - cause a parallel shift to the right as “spare receptors” are filled. Then once the “spare” receptors are occupied the magnitude of maximum response decreases.

Question 11

What are the effects of allosteric binding to receptors?

Answer 11

• Allosteric binding generally enhances or reduces (antagonism) effects of agonists (they generally don’t prevent binding just effect it slightly)
• Non-competitive - reducing orthosteric ligand affinity/efficacy