Pharmacodynamics -> lecture 3

Question 1

What is pharmacodynamics?

Answer 1

How the body deals with drugs

Question 2

What are the two main modes of drug action?

Answer 2

Receptor activators => agonists.
Receptor blockers => antagonists.

Question 3

What are receptors?

Answer 3

Proteins in membrane that bind neurotransmitters + cause cell response.

Question 4

What are the different types of receptors?

Answer 4

• Ligand gated ion channels.
• GPCRs.
• Kinase-linked.
• Gene transcription.

Question 5

What are agonists?

Answer 5

Receptor activators

Question 6

What are the steps by which agonists activate receptors?

Answer 6

1. Agonist binds to receptor.
2. Agonist bound to receptor forms AR complex.
3. Receptor is conformationally changed.
4. Causes a response e.g. muscle contractions.

Question 7

What will make agonists bind to receptors better?

Answer 7

• Higher affinity = easier binding.

Question 8

What would cause an agonist to switch on a receptor better?

Answer 8

• Higher efficacy = better activator.

Question 9

What would cause an agonist to produce a higher response?

Answer 9

• Higher potency = larger response.

Question 10

What does a log (conc)-response curve of an agonist show?

Answer 10

• Shows maximum response via sigmoidal curve (top of peak).
• Can calculate the EC50.

Question 11

What is the EC50?

Answer 11

• The conc of agonist that produces 50% of maximum response.

Question 12

What is the maximum response?

Answer 12

• The response when all receptors are occupied (also called saturated response).

Question 13

Affinity vs Efficacy vs Response how is the max response and EC50 affected?

Answer 13

• High efficacy = close to high max response.
• Low efficacy = lower response.
• Same affinity = same EC50 => but efficacy can change max response.

Question 14

What is Kd?

Answer 14

The conc of drug that is required to occupy 50% of receptors.

Question 15

How does Kd link with affinity?

Answer 15

Lower the Kd = Higher affinity.

(lower conc needed to occupy 50% so higher affinity).

Question 16

How to measure affinity?

Answer 16

• Use a ligand binding assay:
  –> cannot measure response as is affinity + efficacy.

Question 17

What are the steps for a ligand binding assay?

Answer 17

Radio label drug (H, C, I) to make it hot, outcompete hot drug w cold ligand.

Question 18

What are the issues with Kd?

Answer 18

• Doesn’t take into account non-specific binding.

Question 19

How to take into account the non-specific binding?

Answer 19

• Make [radio drug] high enough so can’t be outcompeted.
• Measure non-specific binding + subtract from total to get specific.

Question 20

Can receptors be desensitised?

Answer 20

Yes

Question 21

How can receptors be desensitised?

Answer 21

• If agonist + receptor bound for too long.

Question 22

What is the difference between desensitisation and tachyphylaxis?

Answer 22

Tachyphylaxis = whole tissue stops responding due to desensitisation.

Question 23

What does it mean if a max response isn’t produced?

Answer 23

• Partial agonists present.

Question 24

What are partial agonists?

Answer 24

• Reduced effects of the agonists => doesn’t fully block basal activity.

Question 25

When are partial agonists useful?

Answer 25

• Useful when want lower adverse effects.

Question 26

What are inverse agonists?

Answer 26

• Produces a response that is opposite to an agonist.
• Switches off receptor activity after binding.

Question 27

What are competitive antagonists?

Answer 27

• Compounds that bind to a receptor without any activity.
• These block the receptors from being able to accept an agonist or inverse agonist.

Question 28

What is the efficacy of a competitive antagonist?

Answer 28

0% efficacy.

Question 29

What do competitive antagonists do to EC50?

Answer 29

• Increase the EC50, (more agonist is needed to produce same response).

Question 30

How to measure the potency of a competitive antagonist?

Answer 30

• How good are they at blocking agonist effects.
• pA2 => bigger = better antagonist.

Question 31

How to calculate pA2 of antagonist?

Answer 31

pA2 = negative log of [antagonist] reduces effect of [agonist] to half its original conc.

Question 32

What are non-competitive antagonists?

Answer 32

• Antagonists that cannot ever reach max response.
• Cannot be outcompeted by [agonist]
• Bond covalently to receptors (why they can’t be outcompeted).

Question 33

What are spare receptors?

Answer 33

• To get full response => not always 100% saturation of receptors.
• Sometimes only need 80% so 20% = spare.

Question 34

How to measure how many spare receptors?

Answer 34

• Measure via the addition of irreversible antagonists.

Question 35

Will Kd always = EC50 if there are spare receptors?

Answer 35

No, if there are spare receptors = don’t need to occupy 50% for full response.

Question 36

What are the theoretical reasons for there being spare receptors?

Answer 36

• Increases system sensitivity.
• Additional receptors mop up excess agonist to stop over the top response.

Question 37

What are use-dependent drugs?

Answer 37

Activity-dependent drugs i.e. compounds whose effectiveness increases w activity or use.

Question 38

What do use-dependent drugs target commonly?

Answer 38

• Bind to ion channels or receptors.

Question 39

What happens as the receptor is used more to the drug if it is activity-dependent?

Answer 39

• The more the receptor is used = more drug is active and binds.