17. Pharmacodynamics: Receptor Theory

Question 1

What is the equation for molarity?

Answer 1

Molarity = g/L / molecular weight

Question 2

What range are ligand concentrations at receptors usually in?

Answer 2

Micromolar to picomolar

Question 3

What are the 2 way drugs can act in?

Answer 3

Block the binding of an endogenous agonist - antagonist

Activate a receptor - agonist

Question 4

What is affinity?

Answer 4

How well a ligand binds to the receptor

i.e. higher affinity = stronger binding

Question 5

What is intrinsic efficacy?

Answer 5

Activation of a receptor caused as a response to agonist binding

Question 6

Why is there no response when an antagonist binds?

Answer 6

No intrinsic efficacy

Only has affinity

Question 7

Why can agonists stimulate a response?

Answer 7

Have affinity
Have intrinsic efficacy - can activate the receptors
Have efficacy - cause a measurable response

Question 8

What is clinical efficacy?

Answer 8

An indication of how well a treatment succeeds in achieving its aim
E.g. lowers blood pressure, cure headache

Question 9

How do you measure binding of ligands?

Answer 9

By binding of a radioactively labelled ligand (radioligand) to cells or membranes prepared from cells
Measure number of ligands bound

Question 10

What is Bmax?

Answer 10

Maximum binding capacity

Question 11

What is Kd?

Answer 11

Dissociation constant
Inverses proportional to affinity
Lower the Kd, higher the affinity
Concentration of ligand required to occupy 50% of the available receptors

Question 12

Why is high affinity good?

Answer 12

It allows binding at low concentrations of hormones, neurotransmitters, drugs etc.

Question 13

What is EC50?

Answer 13

Effective concentration giving 50% of the maximal response
Measure of agonist potency
Depends on both affinity and intrinsic efficacy

Question 14

What is the difference between concentration and dose?

Answer 14

Concentration: known concentration of drug at site of action e.g. in cells and tissues
Dose: concentration at site of action generally unkown e.g. dose to a patient in mg or mg/kg

Question 15

Spare receptors

Answer 15

In some cases <100% occupancy but still with 100% response, this means there are spare receptors

Question 16

Why do spare receptors exist?

Answer 16

Amplification in the signal transduction pathway
Response limited by a post-receptor event
They increase sensitivity/potency and allow responses at low concentrations of agonists

Question 17

What can affect receptor numbers?

Answer 17

Vary with cell type
Tend to increase with low activity - up-regulation
Tend to decrease with high activity - down-regulation

Question 18

How are partial agonists different to full agonists?

Answer 18

Partial have lower intrinsic activity as lower efficacy than full agonists
Partial agonists EC50 =~ Kd
Partial have no spare receptors and have insufficient intrinsic efficacy for maximal response

Question 19

What are the advantages of partial agonists?

Answer 19

Can allow a more controlled response

Work in absence of low levels of endogenous ligand

Question 20

What is the disadvantage of partial agonists?

Answer 20

Can act as antagonist if high levels of full agonist

Question 21

What is an example of a partial agonist?

Answer 21

Opioids - pain relief, recreational use (heroin)

Question 22

What happens to sustained-drug taking people?

Answer 22

They have tolerance
Reduced receptor numbers
Reduced post-receptor signalling

Question 23

Reversible competitive antagonism

Answer 23

Relies on a dynamic equilibrium between ligands and receptors
Greater concentration of antagonist means greater inhibition

Question 24

What is IC50?

Answer 24

Gives an indication of antagonist affinity but influenced by concentration of antagonist and strength of stimulus (agonist)

Question 25

What is the effect of reversible competitive antagonists on the graph?

Answer 25

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

Question 26

What is an example of competitive antagonism clinically?

Answer 26

Naoxone - high affinity, competitive antagonist at mu-opioid receptors

Question 27

What is irreversible competitive antagonism?

Answer 27

Occurs when antagonist dissociates slowly or not at all

With increased concentration of antagonist or increased time, more receptors are blocked by antagonist

Question 28

What affect do irreversible competitive antagonist have on the graph?

Answer 28

Cause a parallel shift to the right of agonist concentration-response curve
At higher concentrations suppress the maximal response as there are insufficient receptors for full response

Question 29

What is non-competitive antagonism?

Answer 29

Endogenous ligand binds to orthosteric site

Agonists and antagonists bind to allosteric sites - reuse orthosteric ligand affinity and/or efficacy