Session 6: Pharmacodynamics Flashcards Preview

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Flashcards in Session 6: Pharmacodynamics Deck (81)
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1
Q

What is molarity?

A

The concentration of moles of a substance

2
Q

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

A

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

3
Q

What is a ligand?

A

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

4
Q

Most drugs work in one of two ways.

What are these two ways of drug action.

A

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

5
Q

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

A

Affinity

6
Q

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

A

Stronger

7
Q

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

A

Intrinsic efficacy

8
Q

Binding of ligand is governed by what?

A

Affinity

9
Q

Receptor activation is governed by what?

A

Intrinsic efficacy

10
Q

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

A

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

11
Q

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?

A

Efficacy

12
Q

Do agonists have intrinsic efficacy or efficacy?

A

BOTH!

13
Q

Do antagonists have intrinsic efficacy or efficacy?

A

Neither!

14
Q

Do antagonists have affinity?

A

Yes

15
Q

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

A

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

16
Q

How do we measure drug-receptor interactions by binding?

A

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

17
Q

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

A

Rectangular hyperbola

18
Q

What is the Kd?

A

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

19
Q

What is Bmax?

A

The maximum binding capacity receptors

20
Q

The Bmax gives us information about what?

A

The receptor number

21
Q

The Kd gives us information about what?

A

The affinity of the drug for the receptor

22
Q

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

A

Lower

23
Q

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

A

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

24
Q

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

A

On a logarithmic scale

A sigmoidal shape curve

25
Q

Give two examples of what the “response” of an agonist could be

A

Change in a signalling pathway

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

26
Q

In a concentration-response curve, what is EC50?

What is it a measure of?

A

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

27
Q

What is the difference between concentration and dose?

A

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

28
Q

EC50 (Agonist potency) depends on what three things?

A

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

29
Q

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

A

True

30
Q

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

A

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

31
Q

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

A

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

32
Q

Salmeterol has selective _________ for beta2 adrenoceptors

This mean what?

A

Affinity

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

33
Q

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

A

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

34
Q

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

A

Salbutamol is short-acting

Salmeterol is long-acting

35
Q

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

A

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)

36
Q

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

A

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

37
Q

When are spare receptors often seen?

Give examples

A

When receptors are catalytically active

GPCRs or tyrosine kinase

38
Q

Why do spare receptors exist?

A

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

39
Q

Give an example of an area of the body with abundant “spare” receptors

A

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

40
Q

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

A

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

41
Q

Changing the number of receptors changes what?

It can also affect what?

A

Agonist potency

It can also affect the maximal response

42
Q

Receptor number tends to increase with what?

A

Low activity (Up-regulation)

43
Q

Receptor number tends to decrease with what?

A

High activity (Down-regulation)

44
Q

Down-regulation of receptors can contribute to what?

A

Tachyphylaxis (Drug tolerance)

45
Q

True or false: receptors are on-off switches

A

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

46
Q

Maximal response indicates _______ activity

A

Intrinsic

47
Q

Full agonist is often what kind of ligand?

A

Endogenous

48
Q

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

A

Lower

Efficacy

49
Q

Partial agonists allow what kind of response?

A

Controlled

50
Q

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

A

Ligand (endogenous)

51
Q

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

A

Antagonists

52
Q

What is a partial agonist?

A

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

53
Q

What is intrinsic activity?

A

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

54
Q

What is an antagonist?

A

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

55
Q

What is functional antagonism?

A

Where two agonists interact with different receptors to produce opposing effects

56
Q

What is reversible competitive antagonism?

A

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

57
Q

What is irreversible competitive antagonism?

A

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

58
Q

What is non-competitive antagonism?

A

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

59
Q

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

A

The number of receptors

60
Q

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

A

The number of receptors

61
Q

Partial agonists have lower _______ than full agonists

A

efficacy

62
Q

Full agonists with identical intrinsic activities may have different what?

A

efficacies

63
Q

Full agonists with identical intrinsic activities may have different what?

A

efficacies

64
Q

Efficacy in a clinical setting means what?

A

How good a drug is at producing a response

65
Q

What are the three types of antagonism?

A

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

66
Q

Reversible antagonism relies on what?

Greater antagonist concentration means?

A

Dynamic equilibrium between ligands and receptors

Greater inhibition

67
Q

Reversible antagonist inhibition of agonist is ___________ with increased agonist concentration

A

Surmountable

68
Q

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

A

Right

69
Q

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

A

Right

70
Q

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

A

Naloxone

71
Q

Why might Naloxone be clinically useful?

A

In reversal of opioid-mediated respiratory depression

The high affinity of Naloxone means that it will compete with heroin (or other opioids) for receptors

72
Q

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

A

Antagonist concentration

Time

73
Q

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

A

Non-surmountable

74
Q

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

A

Right

Suppress

75
Q

What is pheochromocytoma?

A

Rare tumour of the adrenal gland tissue

76
Q

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

A

Phenoxybenzamine

77
Q

Where does phenoxybenzamine act?

How does it cause it’s therapeutic affect here?

A

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

78
Q

Name a common irreversible competitive antagonist

A

Clopidogrel

79
Q

What is an orthosteric site?

A

The site on a receptor where the endogenous ligand will bind

80
Q

What is an allosteric site?

A

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

81
Q

What disease is negative allosteric modulation potentially a treatment for?

A

HIV (Maraviroc)