Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

ICPP 2023 > Pharmacodynamics > Flashcards

Pharmacodynamics Flashcards

(76 cards)

Start Studying
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Molecular targets for drugs (5)

A 
GPCR
Other e.g. Enzymes, DNA, Integrins, transporters
Ion channels
Nuclear receptors
Kinases
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are gpcr regulated by? (5)

A

Light, odorants, hormones, neurotransmitters, ions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

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

A

Orphan receptors - potential drug targets

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Most GPCR’s are

A

Olfactory receptors (smell)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Top prescribed drug targeting protein (not a GPCR ligand)

A

Atorvastatin (HMG CoA reductase inhibitor - lower cholesterol)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What determines drug action?

A

Concentration (molarity) of drug molecules surrounding receptor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is molarity?
How do you work it out?

A

Moles per litre of solution

g/L divided by Molecular weight

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

g/L =

A

Molecular weight x molarity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Why is molarity important?

A

Can have less molecules than another chemical but same concentration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Why do we need to consider drug concentrations in molarity?

A

Concentration of drug molecules around receptor is critical in determining action

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

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

A

Association and disassociation (most bind reversibly)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What law does binding obey?

A

Law of mass action

velocity of reaction depends on concentration of reactants

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How do drugs work?

A

Agonist - activate receptor

Antagonist - Block binding of endogenous agonist

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

How do ligands bind to receptors?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What do antagonists do?

A

They do not cause receptor to do anything:

JUST BLOCK AGONIST from binding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is receptor activation governed by?

A

Intrinsic efficacy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is intrinsic efficacy?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How is an active receptor represented?

A

R*

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What happens after intrinsic efficacy?

A

Cell/tissue dependent factors to evoke response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
What determines overall efficacy (NOT intrinsic)
Intrinsic efficacy and cell/tissue dependent factors
26
Pharmacological efficacy vs clinical efficacy
Pharmacological: intrinsic efficacy and cell/tissue dependent factors Clinical: how well does treatment succeed? ie Does it lower blood pressure
27
How do we measure binding?
Radioactively labelled ligand Incubate radioligand and receptors Separate bound and free and measure BOUND
28
Binding graph
proportion of bound receptors over drug concentration Bmax - max binding capacity Kd - disassociation constant
29
What is Kd?
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
30
How else can affinity be determined?
Ka
31
How is affinity important for ligands?
Naloxone is used in drug overdose (heroin/morphine) Naloxone has higher affinity to µ-opioid receptor Out competes opioid = no respiratory depression/death
32
Problems with affinity
If drug has high affinity (eg fentanyl) drives opioid crisis as there is no longer ligand to out compete
33
How are drug concentrations usually represented on graphs?
Logarithmic (not linear) eg -11 Log10 = 10^-11 Scale = -11 --> -7 (Log10) = 10^-11 --> 10^-7
34
What can response be measured as?
Change in signalling pathway Change in cell/tissue behaviour requires drug efficacy
35
Response graph
Response % over drug concentration EC50 Emax
36
What is EC50?
Effective concentration giving 50% of the maximal response | DRUG POTENCY
37
What does potency depend on?
Affinity and intrinsic efficacy AND cell/tissue specific components
38
What is concentration vs dose?
Concentration - known concentration of drug at site of action Dose - concentration at site is usually UNKNOWN
39
Functional antagonism example
B2 adrenoreceptors targeted for asthma treatment | Binding causes relaxation of bronchioles
40
Where else do B adrenoreceptors work? Why is this a problem?
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
Salbutamol explained
Poor selectivity affinity for B2 receptor BUT very good B2 selective efficacy so get selective response (based on efficacy and route of administration)
42
Salmeterol explained
Really good selective affinity for B2 No selective efficacy so get selective response too (based on affinity)
43
What things are fixed in ligand receptor combination?
Affinity and intrinsic efficacy are FIXED
44
What things are not fixed in ligand receptor combination?
Potency is VARIABLE | Cell/tissue dependent factors effect
45
What relationship do we see between affinity and potency?
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
Graph binding and response?
Response shifted left as not needing 100% binding to get 100% response
47
Where do we often see spare receptors?
Tyrosine kinase | G protein coupled receptor
48
Why do spare receptors exist?
amplification in signal transduction response is limited by post receptor event INCREASE SENSITIVITY/POTENCY
49
How do spare receptors increase sensitivity/potency?
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
What does receptor number influence?
Agonist sensitivity and potency AND MAXIMAL RESPONSE (more receptors = more sensitive)
51
What happens if you have too little receptors?
100% occupancy but insufficient receptors to illicit 100% response
52
Receptor numbers are not fixed, what do they vary with?
Cell type Increase with low activity (up-regulation, more sensitive) Decrease with high activity (down regulation, less sensitive)
53
Analogy down regulation receptors
Receptor number decreases when highly stimulated by drugs for example This is what contributes to tolerance and withdrawal
54
Are all agonists equal at same receptor?
NO | Different affinities and efficacies
55
What are partial agonists vs full agonists?
Full agonists will elicit full response (+/- spare receptors) Partial agonists will have no spare receptors but only illicit 50% response
56
EC50 and Kd full agonist and partial agonist
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
What does height of graph show on response graph?
Intrinsic activity (full vs partial response) Partial agonist = lower intrinsic activity as lower efficacy
58
Why are partial agonists good?
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
Use of partial agonists
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
What are partial agonists often referred to as?
Mixed agonist/antagonist
61
How can antagonism be achieved?
``` Functional antagonism (asthma treatment stimulating B2 receptors) Antagonist AT ITS RECEPTOR (using ligand) ```
62
3 Receptor antagonists
Reversible competitive antagonism Irreversible competitive antagonism Non-competitive antagonism
63
Reversible competitive antagonism
Relies on dynamic equilibrium between ligands and receptors | More antagonists = out completes agonists (greater inhibition)
64
What is IC50?
Concentration of antagonist giving 50% inhibition
65
What does IC50 give an indication of?
Some antagonist affinity | But this also is influenced by antagonist and strength of stimulus (agonist)
66
What type of inhibition is competitive?
Surmountable | Adding more agonist can overcome antagonists actions
67
What does reversible competitive antagonists cause?
Parallel shift to right of agonist response curve (Maximal response is just achieved at higher concentrations)
68
Example of reversible competitive inhibition
Naloxone - out competes heroin
69
Irreversible competitive antagonist
With increased antagonists or time more and more receptors are permanently blocked by ligand (glued on) NOT SURMOUNTABLE
70
Graph of irreversible competitive agonist
Decrease in size of response even when increasing antagonist even if increasing concentration of agonist SUPPRESS MAXIMAL response
71
Example of irreversible competitive agonist
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
Clopidogrel antagonist example
Irreversible binds P2Y12 antagonist Reduced platelet activation so reduces risk of thrombosis
73
Where do non competitive antagonists bind?
allosteric site
74
What can allosteric sites provide binding sites for?
Agonists (potential drug targets) Molecules that enhance or reduce effects of agonists (non competitive antagonists) = negative allosteric modulation
75
What effect do non competitive antagonists have?
Similar to irreversible competitive antagonism | Need additional experiments to distinguish
76
Allosteric compounds example
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)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions