Pharmacodynamics: Receptor Theory

Question 1

Define ligand.

Answer 1

Something that binds to a receptor. A drug, hormone or neurotransmitter for example.

Question 2

What is molarity?

Answer 2

The molar concentration. Often expressed as M= (g/L)/MWt which can be rewritten as M=n/V or M=n/L

Question 3

Why is molarity important when administering a drug?

Answer 3

Because the concentration doesn’t equal molar concentration. This means that if you have the same concentration of acetylcholine and insulin in mg/L you might have different concentrations in molar concentration. An increased amount of molecules around a receptor increases the receptor response.

Question 4

What does a higher molecular weight indicate for the molarity?

Answer 4

That the molarity will be lower.

Question 5

What is intrinsic efficacy?

Answer 5

The ability to activate a receptor. Not the ability to generate a measurable response!

Question 6

What is efficacy?

Answer 6

The ability a drug has to elicit a measurable biological response.
This means that agonists have intrinsic efficacy (can activate a receptor) and efficacy (can cause a measurable response).

Question 7

Do antagonists have intrinsic efficacy?

Answer 7

No. They only have affinity as they block the effects of an agonist.

Question 8

What is pharmacological efficacy or clinical efficacy?

Answer 8

A measure of how well a drug is in achieving its aim. Like lowering blood pressure.

Question 9

How does efficacy and clinical efficacy differ? Give an example.

Answer 9

Efficacy is how well a drug can cause vasodilation for example. Clinical efficacy is how well a drug lowers blood pressure.

Question 10

How is binding measured?

Answer 10

Usually done by binding of radioactively labelled ligands called radioligands to cells or membranes prepared from cells. What is usually measured is the bound radioligands, not the free.

Question 11

What is Bmax?

Answer 11

The max binding capacity when all receptors are bound.

Question 12

What is Kd?

Answer 12

The dissociation constant. This is the concentration of ligands when 50% of the receptors are occupied.

Question 13

What is a low Kd value an indication of?

Answer 13

High affinity

Question 14

What is a high Kd value an indication of?

Answer 14

Low affinity

Kd is the reciprocal of affinity.

Question 15

The plot bound vs. ligand concentration graph is logarithmic. If Kd is a value of -9, what does this mean?

Answer 15

That 50% of the receptor are occupied at a concentration of 10^-9 molar or 1 nM.

Question 16

What type of shape is the concentration-response curve and plot bound vs. ligand concentration graph as they are shown as logarithmic?

Answer 16

Sigmoidal

Question 17

What is Emax?

Answer 17

Not the maximum occupancy this time as with affinity but this relates to efficacy. It stands for Effect maximum and means that it is the maximal response of the tissue e.g.

Question 18

What is EC50?

Answer 18

The concentration of a drug which gives 50% of the maximal response. It is a measure of something called potency.

Question 19

Define potency.

Answer 19

The amount of a drug needed to produce an effect of given intensity. This is measured by EC50.

Question 20

What does potency depend on?

Answer 20

Both affinity and intrinsic efficacy.

Question 21

What is the difference between concentration and dose?

Answer 21

Concentration gives a known concentration of drug at the site of action
Dose does not give a known concentration of the drug at site of action.

Question 22

How does Kd relate to selectivity?

Answer 22

A low Kd and therefore high affinity usually indicates that a drug is more selective to one receptor than another.

Question 23

If salmeterol has a high Kd for b1-adrenoceptors and a low Kd for b2-adrenoceptors (3455 fold) what does that tell you in terms of selectivity?

Answer 23

That salbutamol is selective to b2-adrenoceptors based on affinity.

Question 24

Salmeterol is more selective than salbutamol. How can this be a problem for salbutamol?

Answer 24

That it might bind to b1-adrenoceptors in the heart and cause positive inotropy and tachycardia.

Question 25

What are spare receptors?

Answer 25

Receptors that are not in use when a maximum response is elicited. This means that a 100% occupancy is not needed in order to get a maximum response.

Question 26

How do spare receptors influence potency?

Answer 26

The response curve and the binding curve separate. Kd stays at the same place but EC50 will be different and shift to the left. This means that Kd might give an Emax even though it is only half of the occupied receptors. In this case 50% occupancy gives 100% response.

Question 27

Why do spare receptors exist? How is it that as small a number as 10% of ligand binding can cause a 100% response?

Answer 27

Due to amplification in the signal transduction pathway.
They also increase the sensitivity and allows a smaller concentration of a drug to elicit a 100% response. For example with 10000 receptors and full response requiring 100% occupancy Kd can be 1nM for example which means 1nM generates 50% response. With spare receptors ending up in 20000 receptors and only 50% occupancy required for a full response Kd is still then 1nM and generates a full response.

Question 28

What happens if the number of receptors decrease?

Answer 28

Emax shifts to the right meaning more of a ligand is needed to elicit a full response. The number of receptors can decrease so much that a 100% occupancy won’t be enough to generate a full response even.

Question 29

What is up-regulation?

Answer 29

When receptors are exposed to low activity up-regulation happens which means that the number of receptors increase.

Question 30

What is down-regulation?

Answer 30

When receptors are continuously exposed to high activity the number of receptors decrease.

Question 31

How does down-regulation happen?

Answer 31

When exposed to drugs for a prolonged time. This can cause tolerance or withdrawal symptoms.

Question 32

What is a full agonist?

Answer 32

An agonist which elicit maximal response.

Question 33

What is a partial agonist?

Answer 33

An agonist which does not elicit a maximal response. Even though all receptors are occupied a maximal response will not be reached. This is because there is an insufficient intrinsic efficacy for maximal response.

Question 34

What is intrinsic activity?

Answer 34

Emax

Question 35

Why are partial agonists used?

Answer 35

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

Question 36

Give examples of partial agonists.

Answer 36

Buprenorphine for example to treat heroin and morphine dependency. Buprenorphine has a higher affinity and a lower intrinsic activity. This makes buprenorphine advantageous in some clinical settings as it can be used to create adequate pain control and the patient is less prone to respiratory depression.

Question 37

How does buprenorphine work on heroin?

Answer 37

It will inhibit the effect of heroin so the partial agonist works as an antagonist in that sense but still elicit a response.

Question 38

Briefly explain withdrawal or abstinence syndrome.

Answer 38

Continued drug-taking leads to tolerance which causes down-regulation which means a reduced number of receptors. When the drug is withdrawn the endogenous ligands will now be less effective which causes withdrawal symptoms.

Question 39

What type of antagonists are there?

Answer 39

Reversible competitive antagonists
Irreversible competitive antagonists
Non-competitive antagonists (generally allosteric)

Question 40

How does concentration of the antagonist relate to maximum response.

Answer 40

A higher concentration of an antagonist gives a lower Emax.

Question 41

What is IC50?

Answer 41

The concentration of an antagonist which gives 50% inhibition.

Question 42

What is IC50 an index of?

Answer 42

Antagonist potency.

Question 43

How can inhibition by competitive antagonism be treated?

Answer 43

By increasing the concentration of the agonist.

Question 44

How do reversible competitive antagonists alter the concentration-response curve of the agonist?

Answer 44

An increasing concentration of the antagonist shifts the curve to the right meaning EC50 shifts to the right. This means that a higher concentration of the agonist is needed to elicit a 50% response.

Question 45

Naloxone is a high affinity, competitive antagonist at u-opioid receptors. How can this drug be important clinically?

Answer 45

The high affinity means that heroin and morphine can’t bind as easy to the receptors. This is favourable in case of a drug overdose to relieve respiratory depression.

Question 46

How do irreversible competitive antagonists alter the concentration-response curve of the agonist?

Answer 46

Irreversible competitive antagonists bind with a much higher affinity so it’s very hard to make them dissociate. This shift the EC50 to the right. At higher concentrations of the antagonist there will be insufficient receptors for a full response as there are no spare receptors left.

Question 47

Give an example of when a irreversible competitive antagonist is used clinically.

Answer 47

Phenoxybenzamine. which binds non-selectively to a1-adrenoceptors in the smooth muscle of blood vessels to treat hypertension. This is used when a patient has pheochromocytoma which is a tumour of the adrenal chromaffin cells. This means that excessive adrenaline is produced and causes hypertension by vasoconstriction. The Phenoxybenzamine is used here to block the vasoconstriction.