Pharmacodynamics: Receptor Theory

Question 1

Explain what a ligand is and give examples.

Answer 1

A ligand is a substance that interacts/binds with a receptor. Usually this is to GPCRs in the case of pharmacodynamics but it can be other targets as well.
Examples of ligands are such as drugs, hormones and neurotransmitters.

Question 2

What is molarity? Give the formula

Answer 2

Molarity is the concentration of a substance in a solution.
M (Molarity) = (g/L) / MWt where MWt is the molar mass.
This means that g/MWt is n (mole) and that gives M = n/L or M = n/V which is the same as c = n/V
The unit we use is M or molar.

Question 3

Why is it necessary to consider drug concentrations in molarity and not just in mg/L?

Answer 3

Because of the mole. Acetylcholine has a much smaller molar mass than insulin. That means that if we have the same mass of acetylcholine and insulin let’s say 100 mg the concentration of that will be 100mg/L in terms of mass.
However the amount of molecules in the solution with acetylcholine is much larger than that of insulin. Normal concentration does not take mole into account and therefore we need molarity.
Less MWt means a higher molarity if we have the same mass.

Question 4

What does a higher molarity mean?

Answer 4

That there is a higher concentration of molecules of a certain substance in a solution. This means in terms of pharmacodynamics that there is a larger concentration of a ligand. More ligands by a receptor means more binding and usually more of a response.

Question 5

What is an agonist?

Answer 5

An agonist is a ligand that activates a receptor.

Question 6

What is an antagonist?

Answer 6

An antagonist is a ligand which blocks the receptor from binding to an endogenous ligand. This is an inhibitory effect of the receptor and stops a response from happening.

Question 7

What is an endogenous agonist?

Answer 7

A ligand which is found in the body normally which activates a receptor.

Question 8

What is affinity?

Answer 8

The tendency of a ligand to bind to a receptor. Higher affinity means stronger binding. If you have two agonist, the agonist with higher affinity will bind to a receptor more if the agonists are in same molarities.

Question 9

What is intrinsic efficacy?

Answer 9

The ability of an agonist to activate a receptor.

Question 10

What is efficacy?

Answer 10

The ability of an agonist to cause a measurable response.

Question 11

What is clinical efficacy?

Answer 11

The ability of an agonist to cause a desired action in the body relating to the measurable response. “A measure of how well a treatment succeeds in achieving its aim.” For example efficacy can be vasodilation and the clinical efficacy is then a lowered blood pressure.

Question 12

How do agonists and antagonists differ in terms of affinity and intrinsic efficacy?

Answer 12

Both agonists and antagonists have affinity, however antagonists do not have intrinsic efficacy, i.e. they do not activate a receptor.

Question 13

How is binding of a ligand to a receptor measured?

Answer 13

Usually by binding of a radioactively labelled ligand (Radioligand) to cells or membranes prepared from cells.
Usually what is measured is the amount that is bound to receptors, not the free amount.

Question 14

Describe what kind of plot bound vs. ligand concentration graph looks like.

Answer 14

The proportion of bound receptors on the y-axis ranging from 0-1. On the x-axis there is the concentration of the ligand or the drug ([drug]). The plot is logarithmic so the x-axis is labelled as [Drug] log10 M. The curve is sigmoidal.

Question 15

What is Bmax?

Answer 15

The plateau of the s-shaped curve where an increased concentration of a drug will not bind more receptors. Saturation has occurred.

Question 16

What is Kd?

Answer 16

The concentration of which 50% of the receptors are bound to a drug.

Question 17

If you read off of a plot bound vs. ligand concentration graph and arrive at -9 on the x-axis, what does this mean?

Answer 17

Since it is logarithmic -9 means 10^-9 M or 1 nM.

Question 18

What is a concentration-response curve? Describe it.

Answer 18

How much of a concentration of a drug is needed to illicit a response.
It is a sigmoidal shaped curve that is logarithmic.
On the y-axis a percentage of the response is labelled ranging from 0 - 100%.
On the x-axis the concentration of the drug is labelled as logarithmic.

Question 19

What is Emax?

Answer 19

The plateau of the s-shaped curve where an increased concentration of a drug will not elicit more of a response. Emax can be at 100% or lower.

Question 20

What is EC50?

Answer 20

A measure of potency.

Similar to Kd in principle. The concentration of a drug which gives 50% of the maximal response.

Question 21

What is potency?

Answer 21

A measure of drug activity in terms of the concentration needed in order to produce a response of given intensity.
A highly potent drug needs a smaller concentration to give the same response as a less potent drug.
I.e. how effective a drug is at generating a response.

Question 22

What does potency depends on?

Answer 22

On both affinity and intrinsic efficacy.

Question 23

What is the difference between dose and concentration regarding a drug?

Answer 23

In concentration the concentration is known of a drug at site of action (molarity).
In dose the concentration of a drug at the site of action is unknown. Dose is therefore mg.

Question 24

Why are selective/specific agonists/antagonists important?

Answer 24

Because if you use an agonist to cause relaxation of airways for example in the case of salbumatol binding to beta2 adrenoceptors you don’t want the drug to also bind to beta1 adrenoceptors in the heart and cause tachycardia.

Question 25

How do we achieve selectivity/specificity of a drug?

Answer 25

By having a large contrast regarding Kd i.e. affinity. Making a drug that has a high affinity for one type of receptor and a low affinity for another.

Question 26

What are spare receptors?

Answer 26

Receptors that are not needed to be bound and activated in order to produce a full response of a tissue. For example only 50% of the the receptors might only be needed in order to produce a 100% response.

Question 27

How do spare receptors the response vs concentration curve and the binding vs concentration curve?

Answer 27

If 100% binding means a maximum response the curves would be in the same spot. However spare receptors causes the response curve to shift to the left. This means that less binding of receptors are needed cause a maximum response and therefore a lower concentration of a drug as well.

Question 28

How is it possible for a binding of 50% of the receptor cause a 100% response?

Answer 28

Due to amplification in the signal transduction pathway.

Question 29

What is an example where spare receptors can be found?

Answer 29

In airway of smooth muscle at the M3 GPCR receptor.

Here only a 10% occupancy of the muscarinic receptors of Acetylcholine is needed in or to gain full maximal contraction.

Question 30

Why do we have spare receptors?

Answer 30

It increases sensitivity to a ligand or drug. It allows a response at a lower concentration of agonists.

Question 31

How does the amount of receptors relate to agonist potency?

Answer 31

An increased amount of receptors means a higher potency and therefore a lower EC50.
For example 100000 receptors can give a full response at 10% occupancy.
20000 receptors can give a full response at 50% occupancy.
If there are only 5000 receptors a full response cannot occur even at 100% occupancy.

Question 32

What is the difference between efficacy and potency?

Answer 32

Efficacy relates to the maximum effect a drug can have (Emax). So a difference in Emax means a difference in efficacy.
Potency relates to both intrinsic efficacy and affinity. A shift in EC50 means a difference in potency.

Question 33

What is up-regulation?

Answer 33

When there is a low activity of a receptor, the amount of receptors tends to increase. This is usually caused by a low concentration of ligands.

Question 34

What is down-regulation?

Answer 34

When there is a high activity of a receptor, the amount of receptors tends to decrease. This is usually caused by a high concentration of ligands or drugs.

Question 35

How is down-regulation especially relevant in pharmacodynamics and a clinical setting?

Answer 35

A lower amount of receptor contributes to tolerance when a drug is constantly taken. For example heroin decrease the amount of opioid receptors, when heroin stops being taken the amount of endogenous ligands are not enough to cause a desirable response of the receptors and so you get withdrawal symptoms. This will eventually up-regulate but can be dangerous meanwhile.

Question 36

What is a full agonist?

Answer 36

An agonist which elicit a maximum response.

Question 37

What is a partial agonist?

Answer 37

A partial agonist has a lower intrinsic activity as lower efficacy than a full agonist. This means that Emax is lower than a full agonist and therefore can’t elicit a maximum response.

Question 38

What other targets than proteins can a drug bind to?

Answer 38

In some cases some antimicrobial and anti tumour drugs bind to DNA.

Question 39

Why can partial agonists be relevant as drugs?

Answer 39

They allow a more controlled response.
They work in the absence or low levels of endogenous ligands
They can act as antagonists if there are high levels of full agonists.

Question 40

Give an example of a partial agonist that is used in gradual withdrawal.

Answer 40

Buprenorphine is a partial agonist that is used in order to limit the response of a drug such as heroin. Buprenorphine has a higher affinity to opioid receptors and therefore works as a competitive antagonist to heroin. Buprenorphine only has partial efficacy so only elicit a partial response so it produces adequate pain control and less respiratory depression. Buprenorphine is therefore used in order to combat withdrawal from heroin.

Question 41

What is an antagonist?

Answer 41

A ligand which blocks the effect of an agonist. I.e. prevents receptor activation by agonists.

Question 42

What are the three main antagonist types?

Answer 42

Reversible competitive antagonists (most common)
Irreversible competitive antagonists
Non-competitive antagonists (generally allosteric so they don’t bind to the active site)

Question 43

What do reversible competitive antagonists depend on?

Answer 43

The dynamic equilibrium between ligands and receptors. More antagonists than agonists at a similar affinity means the antagonists are more prone to bind and block the active site for the agonists.
Greater [antagonist] means greater inhibition.

Question 44

Describe an response vs. antagonist concentration graph.

Answer 44

Y axis consists of response ranging from 0 - 100%.
X axis consists of the concentration of an antagonist with logarithms.
It is a sigmoidal shaped curve where Y decrease as X increases.

Question 45

What is IC50?

Answer 45

Measure of antagonist potency. The concentration of an antagonist where there is 50% inhibition. i.e. 50% response.

Question 46

What is Kb?

Answer 46

50% occupancy - reciprocal of affinity.

Question 47

What are surmountable antagonists?

Answer 47

Antagonists that can unbind to their receptors.

Question 48

How do we elicit a response in the presence of antagonists?

Answer 48

Add more agonists.

Question 49

In a response vs AGONIST concentration graph, how does a reversible competitive antagonist influence the curve?

Answer 49

With an increasing concentration of an antagonist the curve shifts to the right, i.e. EC50 increases and therefore potency decreases for the agonist.

Question 50

What is naloxone?

Answer 50

A high affinity competitive antagonist of u-opioid receptors. This means that if you have heroin in your body you can take naloxone to inhibit the response of the heroin (agonist) with naloxone (antagonist). “Reversal of opioid mediated respiratory depression”

Question 51

What is a non-surmountable antagonist?

Answer 51

An irreversible competitive antagonist where unbinding or dissociation occurs very slowly or not at all.

Question 52

In a response vs AGONIST concentration graph, how does an irreversible competitive antagonist influence the curve?

Answer 52

To a start in the same way as a reversible competitive antagonist by shifting the curve to the right. Emax is still being untouched because of spare receptors, but as the spare receptors come to an end the efficacy will eventually decrease (Emax).

Question 53

What is the consequence of an irreversible competitive antagonist starting to bind spare receptors?

Answer 53

Emax will decrease and therefore even though we increase the concentration of the agonist we won’t be able to elicit a full response of the receptor.

Question 54

Give an example of an irreversible competitive antagonist.

Answer 54

Phenoxybenzamine binds to alpha1-adrenoceptors in order to block the response of vasoconstriction. This can be used in pheochromocytoma where adrenal chromatin cells are cancerous and produce and excess of adrenaline which is supposed to bind to the alpha1-adrenoceptors and cause vasoconstriction.

Question 55

What is a non-competitive antagonist?

Answer 55

A ligand that binds to another place of the receptor than the active site. Conformational change happens and so the agonist cannot bind to the active site (reduces affinity and/or efficacy).

Question 56

How come partial agonists are not always partial agonists?

Answer 56

With an increasing number of receptors in a tissue a partial agonist can become a full agonist. E.g. if only 10% of occupancy is needed to elicit a full response a partial agonist can in this case become a full agonist.