Sesh 6- Pharmacodynamics

Question 1

What 3 general factors affect potency?

Answer 1

1. Affinity-strength of binding
2. Intrinsic efficacy- ability wto activate the receptor
3. Cell/tissue-dependant factors

2+3= efficacy

Question 2

Do G proteins bind GDP or GTP in their inactive state?

Answer 2

GDP

Question 3

Do most drugs bind reversibly or irreversibly to receptors?

Answer 3

Reversibly

Question 4

The affinity of a ligand for a receptor describes the ________ of binding.

Answer 4

Strength

Question 5

What is the intrinsic efficacy of a ligand?

Answer 5

The ability of a ligand to activate the receptor.

*Applies to agonists only

Question 6

What is meant by a ligand’s efficacy?

Answer 6

The ability of a ligand to produce a measurable biological response. This is governed by the intrinsic efficacy plus cell/tissue-dependant factors.

Question 7

Do antagonists have intrinsic efficacy?

Answer 7

No, only affinity, as they bind to block the receptor.

Question 8

How are drug-receptor interactions by binding measured?

Answer 8

By using a radioligand, you can calculate Bmax and Kd.

Question 9

What does Bmax give information about?

Answer 9

The maximum binding capacity i.e. Number of receptors

Question 10

Kd is an index of________ of a _________ for a __________.

Answer 10

1. Affinity
2. Ligand
3. Receptor

Question 11

Define Kd.

Answer 11

Kd is the dissociation constant. It is the concentration of ligand required to occupy 50% of the available receptors.

Question 12

A drug binding curve plotted on a logarithmic scale produces a ________ shape plot.

Answer 12

Sigmoidal.

Question 13

Define EC50.

Answer 13

The ligand concentration required to produce 50% of the maximal response (Emax).

Question 14

The EC50 value of an agonist gives a measure of its _____________.

Answer 14

Potency.

Question 15

What is functional antagonism?

Answer 15

Opposing a response in a way that is independent of the mechanism causing that response.

Question 16

Give an example of a cell or tissue-specific factor that can influence drug potency.

Answer 16

The number of receptors in that cell or tissue.

Question 17

Spare receptors increase the _______ of cells to a ligand, and increases the agonist ________.

Answer 17

1. Sensitivity
2. Potency

*ligand doesn’t need to occupy all receptors for max response.

Question 18

Increasing the activation of a receptor pharmacologically, e.g. By dosing successively, will ___________ the receptor number.

Answer 18

Decrease/down regulate. This can lead to tolerance or tachyphylaxis.

Question 19

Buprenorphine is a _____________ at the mu opioid receptor.

Answer 19

Partial agonist.

Question 20

Why are partial agonists sometimes referred to as mixed agonist/antagonists?

Answer 20

Because if they have higher affinity for a receptor than another ligand, but lower efficacy, they can antagonise that ligand, and limit the response produced.

Question 21

Partial agonism is dependent on the _______and _________.

Answer 21

1. Compound

2. System-e.g. Receptor number can change a partial agonist into a full agonist

Question 22

What is the IC50?

Answer 22

The concentration of antagonist needed to inhibit 50% of the max response. It is an index of antagonist potency.

Question 23

Why is competitive inhibition surmountable?

Answer 23

If you increase the agonist concentration, it can compete with the antagonist for binding sites and eventually elicit the maximal response.

Question 24

What type of antagonism is non-surmountable?

Answer 24

Irreversible competitive antagonism.

Question 25

How do irreversible competitive antagonists work?

Answer 25

They block the receptor binding site and dissociate slowly or not at all e.g. covalently bind.

Question 26

That receptor site that the endogenous ligand binds is termed the __________ site.

Answer 26

Orthosteric.

Question 27

What is intrinsic activity?

Answer 27

A measure of the level of response produced.

Question 28

What do RGS proteins do?

Answer 28

They regulate the rate that the G-alpha intrinsic GTPase hydrolyses GTP to GDP, thereby affecting the length of the response.

Question 29

How does cAMP activate pKA?

Answer 29

It binds the cAMP binding sites on the regulatory subunits of pKA, causing a conformational change. This shape change releases the catalytic subunits of pKA, which are then free to phosphorylate target proteins.

Question 30

For signal amplification to occur, downstream target molecules need to be very _________.

Answer 30

Specific. Prevents amplification of many unwanted processes within the cell.

Question 31

What effect does adrenaline have on cardiac muscle at the cellular level?

Answer 31

• Binds to beta 1 adrenoceptors (Gs coupled)
• shape change recruits Gs G protein
• GDP displaced for GTP on Gs-alpha
• Gs alpha dissociates from beta-gamma to stimulate adenylyl cyclase
• ad cyc converts ATP to cAMP
• cAMP activates pKA
• pKA phosphorylates voltage-gated calcium channels, so they are more likely to open upon depolarisation
• therefore get increased calcium influx, and inotropic effect.

Question 32

Outline the steps of the cascade that occurs when morphine binds a mu opioid receptor.

Answer 32

• changes receptor shape
• Gi recruited
• Gi-alpha binds GTP, displacing GDP
• beta gamma subunit dissociates and directly binds to the voltage gated calcium channels to inhibit them
• get less pre-synaptic calcium influx
• reduced pre-synaptic neurotransmitter release