Session 6: Pharmacodynamics

Question 1

What is molarity?

Answer 1

The concentration of moles of a substance

Question 2

Why is molarity important as oppose to just giving the concentration (mg/L) of a substance?

Answer 2

The molarity takes into account the molecular weight and can give completely different molarity of compounds of different Mr, even when given at the same concentration

Question 3

What is a ligand?

Answer 3

A molecule (or ion) that binds specifically to a receptor

Question 4

Most drugs work in one of two ways.

What are these two ways of drug action.

Answer 4

1) By blocking the binding of an endogenous agonist (Antagonist)
2) By activating a receptor (Agonist)

Question 5

In order to bind to a receptor, a ligand must have what for the receptor?

Answer 5

Affinity

Question 6

The higher the affinity of a ligand for the receptor, the ________ the binding

Answer 6

Stronger

Question 7

In order to activate a receptor, a ligand must have what towards the receptor?

Answer 7

Intrinsic efficacy

Question 8

Binding of ligand is governed by what?

Answer 8

Affinity

Question 9

Receptor activation is governed by what?

Answer 9

Intrinsic efficacy

Question 10

True or false: A response is generated if there is enough intrinsic efficacy to generate one

Answer 10

False, other things need to happen inside the cell apart from intrinsic efficacy in order to generate a response

Question 11

What is the name given to the ability of the ligand to activate the receptor AND activate cell and tissue dependent factors that are required to cause a response?

Answer 11

Efficacy

Question 12

Do agonists have intrinsic efficacy or efficacy?

Answer 12

BOTH!

Question 13

Do antagonists have intrinsic efficacy or efficacy?

Answer 13

Neither!

Question 14

Do antagonists have affinity?

Answer 14

Yes

Question 15

When an antagonist binds to a receptor, how does this prevent a response?

Answer 15

The antagonist binds to block the receptor, but there is no intrinsic efficacy, the receptor is not activated and the shape of the receptor is not changed, cannot activate the effector

Question 16

How do we measure drug-receptor interactions by binding?

Answer 16

Binding of a radioactively labelled ligand (radioligand) to cells or membranes prepared from cells

Question 17

When the proportion of bound receptors is plotted against the concentration of drug, what kind of curve can be seen?

Answer 17

Rectangular hyperbola

Question 18

What is the Kd?

Answer 18

The dissociation constant: the concentration of drug at which 50% of AVAILABLE receptors are occupied

Question 19

What is Bmax?

Answer 19

The maximum binding capacity receptors

Question 20

The Bmax gives us information about what?

Answer 20

The receptor number

Question 21

The Kd gives us information about what?

Answer 21

The affinity of the drug for the receptor

Question 22

The _______ the Kd value, the higher the affinity of the drug for its receptor

Answer 22

Lower

Question 23

Does the affinity affect how much ligand of it is needed to bind to the target to produce an affect?

Answer 23

Yes
High affinity= less ligand is needed to bind to the target to produce an affect
Low affinity= more ligand is needed to bind to the target to produce an affect

Question 24

Drug concentration is usually plotted how to allow for more accurate measurements?
What kind of curve does this produce

Answer 24

On a logarithmic scale

A sigmoidal shape curve

Question 25

Give two examples of what the "response" of an agonist could be

Answer 25

Change in a signalling pathway | Change in a cell or tissue behaviour (e.g. contraction)

Question 26

In a concentration-response curve, what is EC50? | What is it a measure of?

Answer 26

The effective concentration giving 50% of the maximal response It is a measure of agonist potency

Question 27

What is the difference between concentration and dose?

Answer 27

The concentration is the known concentration of a drug at the site of action whereas with the dose, the concentration at the site of action is unknown

Question 28

EC50 (Agonist potency) depends on what three things?

Answer 28

Affinity Intrinsic efficacy Cell/tissue components to generate a measurable response (including the number of receptors)

Question 29

True or false: The same potency could occur with different combinations of affinity and efficacy

Answer 29

True

Question 30

Give an example of a drug used to treat an illness that needs to infer specificity for its receptors over another

Answer 30

Asthma beta2-adrenoceptors are the target as we want to relax the airways beta1-adrenoceptors in the heart may be activated which causes problems in patients with angina as it would speed up the heart

Question 31

Salbutamol is said to have selective __________ for beta2 adrenoceptors This means what?

Answer 31

Efficacy If it interacts with beta1 adrenoceptors it won't activate them very well If it interacts with beta2 adrenoceptors it will activate them well

Question 32

Salmeterol has selective _________ for beta2 adrenoceptors | This mean what?

Answer 32

Affinity | It will activate each receptor equally, but is more likely to interact with beta2 adrenoceptor than beta1 adrenoceptor

Question 33

What are some of the problems with both salbutamol and salmeterol?

Answer 33

Salbutamol: speeds up the heart so can cause problems in patients with angina Salmeterol: is unsoluble so cannot be given IV

Question 34

Out of salbutamol and salmeterol which is long-acting and which is short-acting?

Answer 34

Salbutamol is short-acting | Salmeterol is long-acting

Question 35

How do cell/tissue dependent factors such as receptor number influence agonist potency.. What would you expect and what is actually the case?

Answer 35

We might expect the binding to correspond to the response i.e. 50% binding, 50% response (Response curve and binding curve in the same place) The response is often controlled or limited by other factors e.g. limited muscle contraction, limited gland secretion. (Response curve in a different place to the binding curve)

Question 36

In some cases <100% occupancy of receptors = 100% response, how can this be explained?

Answer 36

There are spare receptors that don't need to be occupied to elicit 100% response

Question 37

When are spare receptors often seen? | Give examples

Answer 37

When receptors are catalytically active | GPCRs or tyrosine kinase

Question 38

Why do spare receptors exist?

Answer 38

INCREASE SENSITIVITY: by increasing the number of receptors we increase the sensitivity and the ability of the cell to respond to a ligand Amplification in the signal transduction pathway Response limited by post-receptor event

Question 39

Give an example of an area of the body with abundant "spare" receptors

Answer 39

The airway smooth muscle M3 GPCRs activated by ACh: 10% occupancy causes maximal contraction (90% spare receptors)

Question 40

How can we define sensitivity in terms of response to ligand?

Answer 40

The concentration that is required of a ligand in order to generate a response

Question 41

Changing the number of receptors changes what? | It can also affect what?

Answer 41

Agonist potency | It can also affect the maximal response

Question 42

Receptor number tends to increase with what?

Answer 42

Low activity (Up-regulation)

Question 43

Receptor number tends to decrease with what?

Answer 43

High activity (Down-regulation)

Question 44

Down-regulation of receptors can contribute to what?

Answer 44

Tachyphylaxis (Drug tolerance)

Question 45

True or false: receptors are on-off switches

Answer 45

FALSE! You can have partial agonists that only elicit partial response

Question 46

Maximal response indicates _______ activity

Answer 46

Intrinsic

Question 47

Full agonist is often what kind of ligand?

Answer 47

Endogenous

Question 48

Partial agonists have ________ intrinsic activity than full agonists. As they have lower _______ than full agonists

Answer 48

Lower | Efficacy

Question 49

Partial agonists allow what kind of response?

Answer 49

Controlled

Question 50

Partial agonists work in the absence or low levels of what?

Answer 50

Ligand (endogenous)

Question 51

Partial agonists can act as what if there are high enough levels of full agonist?

Answer 51

Antagonists

Question 52

What is a partial agonist?

Answer 52

A ligand that binds to a receptor but only has partial efficacy at the receptor compared to the agonist

Question 53

What is intrinsic activity?

Answer 53

The ability of a drug-receptor complex to produce a maximal response

Question 54

What is an antagonist?

Answer 54

A ligand that blocks the effects of agonists and prevent receptor activation

Question 55

What is functional antagonism?

Answer 55

Where two agonists interact with different receptors to produce opposing effects

Question 56

What is reversible competitive antagonism?

Answer 56

A ligand that competes with the receptor of the agonist but does not cause a response and can be outcompeted with the addition of enough agonist

Question 57

What is irreversible competitive antagonism?

Answer 57

When the antagonist binds to the receptor of the agonist and dissociates from the receptor slowly, or not at all

Question 58

What is non-competitive antagonism?

Answer 58

Negative allosteric modulation: ligands bind to allosteric sites and reduce orthosteric ligand affinity and/or efficacy

Question 59

Increasing what can change a partial agonist into a full agonist?

Answer 59

The number of receptors

Question 60

Increasing what can change a partial agonist into a full agonist?

Answer 60

The number of receptors

Question 61

Partial agonists have lower _______ than full agonists

Answer 61

efficacy

Question 62

Full agonists with identical intrinsic activities may have different what?

Answer 62

efficacies

Question 63

Full agonists with identical intrinsic activities may have different what?

Answer 63

efficacies

Question 64

Efficacy in a clinical setting means what?

Answer 64

How good a drug is at producing a response

Question 65

What are the three types of antagonism?

Answer 65

1) Reversible competitive antagonism 2) Irreversible competitive antagonism 3) Non-competitive antagonism (generally allosteric or even post-receptor)

Question 66

Reversible antagonism relies on what? | Greater antagonist concentration means?

Answer 66

Dynamic equilibrium between ligands and receptors | Greater inhibition

Question 67

Reversible antagonist inhibition of agonist is ___________ with increased agonist concentration

Answer 67

Surmountable

Question 68

Reversible competitive antagonists cause a parallel shift to the _______ of the agonist concentration-response curve

Answer 68

Right

Question 69

Reversible competitive antagonists cause a parallel shift to the _______ of the agonist concentration-response curve

Answer 69

Right

Question 70

What is an example of a high affinity, competitive antagonist at mu-opioid receptors?

Answer 70

Naloxone

Question 71

Why might Naloxone be clinically useful?

Answer 71

In reversal of opioid-mediated respiratory depression | The high affinity of Naloxone means that it will compete with heroin (or other opioids) for receptors

Question 72

With increased what two things are more receptors blocked by antagonist?

Answer 72

Antagonist concentration | Time

Question 73

Non-reversible competitive antagonism is _________________. Meaning that it cannot overcome the affect of the antagonist by addition of agonist

Answer 73

Non-surmountable

Question 74

Irreversible competitive antagonists cause a parallel shift to the _____ of the agonist concentration-response curve and at higher concentrations ________ the maximal response

Answer 74

Right | Suppress

Question 75

What is pheochromocytoma?

Answer 75

Rare tumour of the adrenal gland tissue

Question 76

What is an example of a non-selective, irreversible competitive antagonist that is used to treat pheochromocytoma?

Answer 76

Phenoxybenzamine

Question 77

Where does phenoxybenzamine act? | How does it cause it's therapeutic affect here?

Answer 77

alpha 1 adrenoceptors blocks the receptors so that the excessive adrenaline produced will not act on them and can therefore not cause vasoconstriction and the hypertension that this then leads to

Question 78

Name a common irreversible competitive antagonist

Answer 78

Clopidogrel

Question 79

What is an orthosteric site?

Answer 79

The site on a receptor where the endogenous ligand will bind

Question 80

What is an allosteric site?

Answer 80

The site on a receptor where a ligand may bind that is not the active site

Question 81

What disease is negative allosteric modulation potentially a treatment for?

Answer 81

HIV (Maraviroc)