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ICPP 2023 > Pharmacodynamics > Flashcards

Pharmacodynamics Flashcards

1
Q

How do endogenous and exogenous ligands exert their effects?

A

By binding to targets
Usually proteins

(some exceptions antimicrobial/antitumour bind to DNA)

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2
Q

Molecular targets for drugs (5)

A 
GPCR
Other e.g. Enzymes, DNA, Integrins, transporters
Ion channels
Nuclear receptors
Kinases
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3
Q

What are gpcr regulated by? (5)

A

Light, odorants, hormones, neurotransmitters, ions

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4
Q

What receptors do not have identified ligands?
What do they act as?

A

Orphan receptors - potential drug targets

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5
Q

Most GPCR’s are

A

Olfactory receptors (smell)

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6
Q

Examples of Therapeutic ligands targeting GPCRs (3)

A

Bisoprolol fumarate (hypertension, angina - B1 antagonist)
Salbutamol (Asthma, B2 agonist)
Co-codamol (u-opioid receptor, pain relief)

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7
Q

Top prescribed drug targeting protein (not a GPCR ligand)

A

Atorvastatin (HMG CoA reductase inhibitor - lower cholesterol)

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8
Q

What determines drug action?

A

Concentration (molarity) of drug molecules surrounding receptor

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9
Q

What is molarity?
How do you work it out?

A

Moles per litre of solution

g/L divided by Molecular weight

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10
Q

g/L =

A

Molecular weight x molarity

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11
Q

Different useful prefixes for concentrations (5)

A 
Molar
Millimolar (10^-3) mM
Micromolar (10^-6) µM
Nanomolar (10^-9) nM
Picomolar (10^-12) pM
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12
Q

Why is molarity important?

A

Can have less molecules than another chemical but same concentration

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13
Q

Why do we need to consider drug concentrations in molarity?

A

Concentration of drug molecules around receptor is critical in determining action

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14
Q

What is binding governed by?
How do most drugs bind to receptors?

A

Association and disassociation (most bind reversibly)

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15
Q

What law does binding obey?

A

Law of mass action

velocity of reaction depends on concentration of reactants

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16
Q

How do drugs work?

A

Agonist - activate receptor

Antagonist - Block binding of endogenous agonist

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17
Q

How do ligands bind to receptors?

A

Must have affinity
Binding is governed by affinity
(high = stronger binding)

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18
Q

What do antagonists do?

A

They do not cause receptor to do anything:

JUST BLOCK AGONIST from binding

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19
Q

What is receptor activation governed by?

A

Intrinsic efficacy

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20
Q

What is intrinsic efficacy?

A

Ability of a agonist to generate active form of receptor via conformational change
Active form = R*

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21
Q

How is an active receptor represented?

A

R*

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22
Q

What do agonists have to have to be effective? Vs what antagonists have to have?

A

Agonists need affinity and efficacy (have to activate)

Antagonists need affinity ONLY

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23
Q

What happens after intrinsic efficacy?

A

Cell/tissue dependent factors to evoke response

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24
Q

Lock and key affinity and efficacy

A

Affinity is key fitting in lock

Efficacy is key being able to turn lock and unlock door

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25
Q

What determines overall efficacy (NOT intrinsic)

A

Intrinsic efficacy and cell/tissue dependent factors

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26
Q

Pharmacological efficacy vs clinical efficacy

A

Pharmacological: intrinsic efficacy and cell/tissue dependent factors

Clinical: how well does treatment succeed? ie Does it lower blood pressure

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27
Q

How do we measure binding?

A

Radioactively labelled ligand
Incubate radioligand and receptors
Separate bound and free and measure BOUND

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28
Q

Binding graph

A

proportion of bound receptors over drug concentration
Bmax - max binding capacity
Kd - disassociation constant

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29
Q

What is Kd?

A

Disassociation constant
Concentration of ligand required to occupy 50% of receptors

Index of affinity
Low value = high affinity as not much drug needed for 50% binding

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30
Q

How else can affinity be determined?

A

Ka

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31
Q

How is affinity important for ligands?

A

Naloxone is used in drug overdose (heroin/morphine)
Naloxone has higher affinity to µ-opioid receptor
Out competes opioid = no respiratory depression/death

32
Q

Problems with affinity

A

If drug has high affinity (eg fentanyl) drives opioid crisis as there is no longer ligand to out compete

33
Q

How are drug concentrations usually represented on graphs?

A

Logarithmic (not linear) eg -11 Log10 = 10^-11

Scale = -11 –> -7 (Log10)
= 10^-11 –> 10^-7

34
Q

What can response be measured as?

A

Change in signalling pathway
Change in cell/tissue behaviour

requires drug efficacy

35
Q

Response graph

A

Response % over drug concentration
EC50
Emax

36
Q

What is EC50?

A

Effective concentration giving 50% of the maximal response

DRUG POTENCY

37
Q

What does potency depend on?

A

Affinity and intrinsic efficacy AND cell/tissue specific components

38
Q

What is concentration vs dose?

A

Concentration - known concentration of drug at site of action

Dose - concentration at site is usually UNKNOWN

39
Q

Functional antagonism example

A

B2 adrenoreceptors targeted for asthma treatment

Binding causes relaxation of bronchioles

40
Q

Where else do B adrenoreceptors work? Why is this a problem?

A

B1 adrenoreceptors in heart - cause increase HR and contractility when stimulated

Need selective/specific activation of B2 receptors if treating asthma to minimise side effects

41
Q

Salbutamol explained

A

Poor selectivity affinity for B2 receptor
BUT very good B2 selective efficacy

so get selective response (based on efficacy and route of administration)

42
Q

Salmeterol explained

A

Really good selective affinity for B2
No selective efficacy

so get selective response too (based on affinity)

43
Q

What things are fixed in ligand receptor combination?

A

Affinity and intrinsic efficacy are FIXED

44
Q

What things are not fixed in ligand receptor combination?

A

Potency is VARIABLE

Cell/tissue dependent factors effect

45
Q

What relationship do we see between affinity and potency?

A

Often only need 50% binding for 100% response due to ‘spare receptors’
Response is limited by other factors within tissue (muscles can only contract so much)

46
Q

Graph binding and response?

A

Response shifted left as not needing 100% binding to get 100% response

47
Q

Where do we often see spare receptors?

A

Tyrosine kinase

G protein coupled receptor

48
Q

Why do spare receptors exist?

A

amplification in signal transduction
response is limited by post receptor event
INCREASE SENSITIVITY/POTENCY

49
Q

How do spare receptors increase sensitivity/potency?

A

Allow responses when there is only minimal agonist

(eg if full response requires 10,000 activated receptors, a cell with 20,000 receptors only requires 50% occupancy for full response)

50
Q

What does receptor number influence?

A

Agonist sensitivity and potency
AND MAXIMAL RESPONSE

(more receptors = more sensitive)

51
Q

What happens if you have too little receptors?

A

100% occupancy but insufficient receptors to illicit 100% response

52
Q

Receptor numbers are not fixed, what do they vary with?

A

Cell type
Increase with low activity (up-regulation, more sensitive)
Decrease with high activity (down regulation, less sensitive)

53
Q

Analogy down regulation receptors

A

Receptor number decreases when highly stimulated by drugs for example
This is what contributes to tolerance and withdrawal

54
Q

Are all agonists equal at same receptor?

A

NO

Different affinities and efficacies

55
Q

What are partial agonists vs full agonists?

A

Full agonists will elicit full response (+/- spare receptors)
Partial agonists will have no spare receptors but only illicit 50% response

56
Q

EC50 and Kd full agonist and partial agonist

A

Full agonist:
EC50 < or equal to Kd
(half receptors bound is greater than receptors needed to illicit 50% response - spare receptors)

Partial agonist
EC50 SIMILAR or equal Kd

57
Q

What does height of graph show on response graph?

A

Intrinsic activity (full vs partial response)

Partial agonist = lower intrinsic activity as lower efficacy

58
Q

Why are partial agonists good?

A

Allow for a more controlled response
Work if there is low levels (or none) of endogenous ligand
Act as antagonist if high levels of full agonist

59
Q

Use of partial agonists

A

Opioids:
Provide pain relief but high levels can result in respiratory depression (100% response)
Partial agonists (eg buprenorphine/methadone) occupies receptors and limits danger response (only 50% response)

Used to treat addiction

60
Q

What are partial agonists often referred to as?

A

Mixed agonist/antagonist

61
Q

How can antagonism be achieved?

A 
Functional antagonism (asthma treatment stimulating B2 receptors)
Antagonist AT ITS RECEPTOR (using ligand)
62
Q

3 Receptor antagonists

A

Reversible competitive antagonism
Irreversible competitive antagonism
Non-competitive antagonism

63
Q

Reversible competitive antagonism

A

Relies on dynamic equilibrium between ligands and receptors

More antagonists = out completes agonists (greater inhibition)

64
Q

What is IC50?

A

Concentration of antagonist giving 50% inhibition

65
Q

What does IC50 give an indication of?

A

Some antagonist affinity

But this also is influenced by antagonist and strength of stimulus (agonist)

66
Q

What type of inhibition is competitive?

A

Surmountable

Adding more agonist can overcome antagonists actions

67
Q

What does reversible competitive antagonists cause?

A

Parallel shift to right of agonist response curve (Maximal response is just achieved at higher concentrations)

68
Q

Example of reversible competitive inhibition

A

Naloxone - out competes heroin

69
Q

Irreversible competitive antagonist

A

With increased antagonists or time more and more receptors are permanently blocked by ligand (glued on)
NOT SURMOUNTABLE

70
Q

Graph of irreversible competitive agonist

A

Decrease in size of response even when increasing antagonist even if increasing concentration of agonist

SUPPRESS MAXIMAL response

71
Q

Example of irreversible competitive agonist

A

Phaechromocytoma = tumour of chromaffin
Lots of excreted adrenaline
acts on A1 adrenoreceptors

Irreversible competitor must be used as otherwise VERY high concentrations of competitor would have to be used

72
Q

Clopidogrel antagonist example

A

Irreversible binds
P2Y12 antagonist
Reduced platelet activation so reduces risk of thrombosis

73
Q

Where do non competitive antagonists bind?

A

allosteric site

74
Q

What can allosteric sites provide binding sites for?

A

Agonists (potential drug targets)
Molecules that enhance or reduce effects of agonists (non competitive antagonists)

= negative allosteric modulation

75
Q

What effect do non competitive antagonists have?

A

Similar to irreversible competitive antagonism

Need additional experiments to distinguish

76
Q

Allosteric compounds example

A

Maraviroc
Negative allosteric modulator of chemokine receptor 5
Usually used by HIV to enter cells
Allosteric antagonist prevents HIV from entering

ICPP 2023 (31 decks)

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