Pharmacodynamics

Question 1

What is a ligand?

Answer 1

Molecule that binds specifically to a receptor.

Question 2

What is the law of mass action?

Answer 2

Rate of a chemical reaction is proportional to the concentrations of the substances.

Question 3

What must ligands have to bind to a receptor?

Answer 3

Affinity (= strength of binding to receptor)

Question 4

What is the difference between agonist and antagonist ligands?

Answer 4

• Agonists: activate receptors.
• Antagonists: block the binding of an endogenous agonist.
• Both have affinity for receptors.

Question 5

What properties do agonists have but not antagonists?

Answer 5

• Intrinsic efficacy

- Efficacy

Question 6

What is intrinsic efficacy of a ligand?

Answer 6

• Its relative ability to activate a receptor.

- Determined by the conformational change of the receptor upon ligand binding.

Question 7

What is efficacy of a ligand?

Answer 7

• Its ability to cause a response.

- Determined by intrinsic efficacy + cell/tissue-dependent factors.

Question 8

What is potency of a ligand?

Answer 8

Affinity + efficacy

Question 9

Why is affinity and intrinsic efficacy of any ligand-receptor combination fixed, whereas potency is variable?

Answer 9

Because of the cell/tissue-dependent factors that affect efficacy.

Question 10

What is the effect of drug concentration on affinity?

Answer 10

Increasing the amount of drug increases the amount of binding until saturation (Bmax) is reached.

Question 11

What is Bmax? What does it give us information on?

Answer 11

• Bmax = maximum binding capacity.

- Gives info about R number.

Question 12

What is the dissociation constant Kd?

Answer 12

• Kd = concentration of ligand required to occupy 50% of available receptors.
• Is an index of affinity.

Question 13

Does a ligand have high affinity for a R if it has a high or a low Kd.

Answer 13

A low Kd - less drug required to saturate 50% of receptors.

Question 14

What is the effect of drug concentration on functional response (potency)?

Answer 14

Increasing drug concentration leads to an increase in response % until Emax is reached.

Question 15

What is Emax?

Answer 15

• Emax = maximum possible response (e.g. Muscle is as contracted as can be).
• Indicator of intrinsic activity.

Question 16

What is EC50?

Answer 16

• EC50 = effective drug concentration giving 50% of maximal response.
• Is a measure of agonist potency.

Question 17

Name an important cell/tissue-dependent factor affecting ligand potency.

Answer 17

Number of receptors.

Question 18

Why does 100% receptor binding not always generate 100% response?

Answer 18

The response is controlled/limited by other factors, e.g. A muscle can only contract so much, a gland can only secrete so much.

Question 19

What are spare receptors? When are these commonly seen?

Answer 19

• The left over receptors when <100% binding = 100% response.
• Often seen when receptors are catalytically active (e.g. Tyrosine kinases or GPCRs).

Question 20

Why do spare receptors exist?

Answer 20

1. Amplification of the signal transduction pathway.

2. Response limited by a post-receptor event.

Question 21

Give an example of signal amplification.

Answer 21

• A few adrenaline molecules binding to cell surface beta-adrenoreceptors can cause a relatively massive cellular response.
• Because activation of adenylyl cyclase generates many molecules of cyclic AMP - activate many PKA - etc.

Question 22

Give an example of spare receptors in the body.

Answer 22

10% occupancy of mAChRs generates maximal contraction of smooth muscle in airways.

Question 23

Why have spare receptors?

Answer 23

Spare receptors increase sensitivity - allow responses at lower concentrations of agonist.

• If no spare receptors, full response requires 100% occupancy - must have > Kd conc. of drug.
• If spare receptors (e.g. Double amount of receptors), full response requires only 50% occupancy - much have Kd conc. of drug.

Question 24

What is the effect of changing receptor number?

Answer 24

Changes agonist potency and can affect maximal response.

Question 25

Give examples of when receptor numbers can change.

Answer 25

Physiological, pathological or drug-induced changes:

• tend to increase with low activity (up-regulation)
• tend to decrease with high activity (down-regulation)

Question 26

What is the effect of receptor number down-regulation on drug treatment?

Answer 26

Can contribute to tolerance/tachyphylaxis: more drug is required to stimulate same effect.