ICPP 9 Pharmacodynamics

Question 1

Types of targets for drugs

Answer 1

GPCRs
Ion channels
Kinases
Nuclear receptors
Enzymes, transporters, DNA

Question 2

What are olfactory receptors?

Answer 2

Related to smell and taste

Question 3

What are orphan receptors?

Answer 3

Potential drug targets

Question 4

What a body does to the drug is defined as what?

Answer 4

Pharmacokinetics

Question 5

What a drug does to the body is defined as what?

Answer 5

Pharmacodynamics

Question 6

What factor is critical in determining drug action and therefore in what concentration drugs need to be considered in?

Answer 6

The concentration of drug molecules around receptors
Molarity

Question 7

What is a ligand?
Examples

Answer 7

Something that binds to a receptor
e.g. drug, hormones, neurotransmitter

Question 8

Molarity equation

Answer 8

M = g/L divided by MWt (molecular weight)

Question 9

Ligand concentration at receptors usually in which range?

Answer 9

Micromolar > nanomolar > picomolar

Question 10

How do drugs exert their effects?

Answer 10

Binding to a target (mainly proteins)

Question 11

What are the prefixes for?
10^0
10^-3
10^-6
10^-9
10^-12

Answer 11

Molar M 10^0
Millimolar mM 10^-3
Micromolar uM 10^-6
Nanomolar nM 10^-9
Picomolar pM 10^-12

Question 12

Why do most drugs bind reversibly to receptors?

Answer 12

Binding is governed by association and dissociation

Question 13

What is avogadro’s number?

Answer 13

6x10^23

Question 14

For a ligand to bind to a receptor what must it have?

Answer 14

Affinity

Question 15

Define affinity

Answer 15

A measure of how tightly a ligand binds to its receptor

Question 16

What are the two effects of most drugs?

Answer 16

Agonist - activate receptor
Antagonist - block the binding of activating ligands/agonist

Question 17

Define efficacy

Answer 17

The ability of a ligand to evoke a response

Question 18

Relationship between affinity and binding

Answer 18

Higher affinity = stronger binding
Lower affinity = weaker binding

Question 19

What is receptor activation governed by?

Answer 19

Intrinsic efficacy

Question 20

Compare and contrast efficacy and affinity in agonists and antagonists

Answer 20

Agonists - have affinity, intrinsic efficacy and efficacy
Antagonists - only have affinity (no efficacy)

Question 21

Define intrinsic efficacy

Answer 21

How good a ligand is at causing a conformational change in its target to produce an active receptor

Question 22

Agonist efficacy vs intrinsic efficacy

Answer 22

Efficacy - ability of an agonist to elicit a response

Intrinsic efficacy - how good a ligand is at causing a conformational change in its target to produce an active receptor

Question 23

Why is affinity important for a ligand?

Answer 23

High affinity allows binding at low concentrations of ligands

Question 24

What is Bmax?

Answer 24

Max binding capacity

Question 25

What is Kd?

Answer 25

Dissociation constant Conc. of drug required to occupy 50% of available receptor

Question 26

What can you derive from a bound vs ligand conc. plot?

Answer 26

**Bmax** - mac binding capacity **Kd** - conc. of drug needed to occupy 50% of available receptors

Question 27

Relationship between Kd and affinity

Answer 27

Low Kd = higher affinity Reciprocal relationship

Question 28

Which drug has a higher affinity and why? Drug A: Kd = 10^-9 Drug B: Kd = 10^-3

Answer 28

Drug A lower Kd = higher affinity Lower conc is needed to occupy 50% of receptors

Question 29

What drug is used to treat morphine/heroin overdose? How does this drug act?

Answer 29

*naloxone* High affinity antagonist for u-opioid receptors Out competes opioids

Question 30

What is *naloxone* used for? How does it work?

Answer 30

Treat morphine/heroin overdose High affinity antagonist for u-opioid receptors Out competes opioids

Question 31

What is the common plot used for drug concentrations vs binding graphs? Common shape

Answer 31

Semi-logarithmic Drug on x-axis if logarithmic Sigmoidal shape

Question 32

How can we measure receptor response to agonist? What can be derived from the plot?

Answer 32

Concentration-response curve **Emax** - effect max **EC50** - effective concentration giving 50% of maximal response (drug potency)

Question 33

Difference between concentration and dose

Answer 33

**Concentration** - known amount of drug at site of action **Dose** - amount of drug at site of action is unknown due to excretion or metabolism

Question 34

What is potency?

Answer 34

**EC50** Effective conc. giving 50% of the maximal response

Question 35

What does potency depend on?

Answer 35

Affinity Intrinsic efficacy Cell/tissue specific components

Question 36

Relationship between EC50 and drug potency

Answer 36

Low EC50 = high drug potency Less conc. needed to give 50% of maximal response

Question 37

What do spare receptors indicate?

Answer 37

<100% occupancy = 100% response

Question 38

Why do we have spare receptors?

Answer 38

Increase sensitivity/potency Allows responses at low concentrations of agonist

Question 39

What is a partial agonist?

Answer 39

Ligand that evoke responses lower than Emax Lower intrinsic efficacy

Question 40

Outline the relevance of altered receptor number

Answer 40

Receptor numbers are not fixed: - tend to **increase with low activity** (up-regulation) - tend to **decrease with high activity** (down-regulation)

Question 41

In terms of EC50, compare and contrast partial and full antagonists

Answer 41

**Full** - EC50 < Kd **Partial** EC50 = Kd

Question 42

How can partial agonists provide antagonism?

Answer 42

Can inhibit the effect of another drug Stops drug from binding

Question 43

Describe the properties of a partial agonist

Answer 43

Lower intrinsic activity Lower efficacy Insufficient intrinsic efficacy for maximal response No spare receptors

Question 44

Clinical relevance of partial agonists

Answer 44

- Allow for more controlled response - Works in the absence of endogenous ligand - Acts as antagonist if high levels of full agonist

Question 45

What are the 3 types of receptor antagonism?

Answer 45

- reversible competitive antagonism - irreversible competitive antagonism - non-competitive antagonism

Question 46

Outline reversible competitive antagonism

Answer 46

- Same binding site as lignad - can be overcome as antagonist dissociates - conc-response curve moves right - Emax achieved

Question 47

How can a partial agonist become a full agonist?

Answer 47

Increasing receptor number to produce a full response

Question 48

What is IC50?

Answer 48

Conc. of antagonist that gives 50% inhibition

Question 49

Outline irreversible competitive antagonism

Answer 49

- bind to same site as ligand - antagonists dissociate very slowly or not at all - cant be overcome e - conc-response curve moves right and down

Question 50

Concentration response curve in reversible competitive antagonism

Answer 50

Moves right

Question 51

Concentration response curve in irreversible competitive antagonism

Answer 51

Moves right and down

Question 52

Outline non-competitive antagonism

Answer 52

Binds to allosteric site + causes change in shape of active site/receptor

Question 53

Apparent volume distribution equation

Answer 53

Vd = dose/plasma conc