Drug Receptors Flashcards
(101 cards)
1
Q
What is formed when a drug (D) and a receptor (R) interact? (2)
A
- Drug receptor complex (DR)
- Association of drug with binding site
2
Q
What are the two types of drug that act on receptors?
A
- Agonist
- Antagonist
3
Q
How do agonists work on receptors?
A
Stimulate G protein coupled receptor to evoke a response
4
Q
How do antagonists work on receptors?
A
Bind to G protein coupled receptor and stop it working, preventing biological response
5
Q
Give 2 examples of endogenous agonists
A
- Hormones
- Neurotransmitters
6
Q
What type of drug that acts on receptors is normally prescribed?
A
Antagoist
7
Q
What is drug affinity? (2)
A
- Ability of a drug to be agonist/antagonist
- How well it binds to a receptor to evoke/prevent a response
8
Q
What does drug affinity show about the relationship of a drug to the receptor?
A
How attracted a drug is to its receptors
9
Q
What is drug efficacy? (2)
A
- A drug’s ability to effectively activate the receptor once it has bound to it
- The strength of a single drug-receptor complex in evoking a response
10
Q
What type of drug does drug efficacy apply to?
A
Agonists only
11
Q
What law does drug binding obey?
A
Law of mass action
12
Q
Why is drug binding reversible?
A
- Drug in blood = two forms: bound and unbound
- Proportion of the drug may become bound to plasma proteins and form DR complexes
- Remainder = unbound
- A chemical equilibrium exists between the bound and unbound states
13
Q
What two drug rates are equal at equilibrium?
A
- Rate of association
- Rate of dissociation
14
Q
What is the formula for rate of association?
A
k+1 [D][R]
15
Q
What is the formula for rate of dissociation?
A
k-1[DR]
16
Q
What does k represent in the formula of drug binding?
A
Rate constant
17
Q
Give the formula for drug binding
A
D+R –(k+1) ->
18
Q
Give the formula that shows drug-receptor equilibrium
A
k+1 [D][R] = k-1 [DR]
19
Q
What is the formation of the drug complex determined by?
A
- How fast its formed (rate constant)
- Multiplied by concentration of free drug and free receptor
20
Q
What is the breakdown of the drug complex determined by?
A
- How fast its formed (rate constant)
- Multiplied by concentration of drug receptor complex
21
Q
Why do concentrations of free drugs and free receptor ([D][R]) and drug-receptor complex not change?
A
As complexes are formed they are broken down
22
Q
What is the binding of a drug to a receptor governed by?
A
Drug affinity
23
Q
What does Kd stand for?
A
Dissociation constant
24
Q
Give the equation for Kd
A
[D][R]/[DR]
25
What are the units for Kd and why?
Molar as it is a concentration
26
What is Kd?
The concentration of the drug that occupies 50% of the receptors since at 50% occupancy [R} equals [DR]
27
What is the relationship between Kd and affinity?
The lower the Kd, the higher the affinity
28
Explain the relationship between Kd and affinity (2)
= Drugs with high affinity=good at binding
| - Achieve a significant degree of receptor occupancy (occupy 50% binding sites) at low concentrations
29
Does the bound/unbound drug fraction exhibit pharmacological effects?
Unbound
30
What is the total number of receptors (RT)?
The sum of the receptors in DR complex + free receptors (R)
31
Give the equation for calculating RT
Receptors in DR complex + free receptors (R)
| RT = [DR] + [R]
32
What does RT mean?
Total number of receptors
33
What is P?
Fractional receptor occupancy
34
Give the equation for P that incorporates RT
P = [DR]/[RT]
35
Give the equation for P that incorporates Kd
P = [D]/[D]+Kd
36
What is important to remember in fractional occupancy questions?
If occupancy is given in percentage in the question, this needs to be converted to a FRACTION for the equation
37
What conditions is the receptor occupancy equation valid under? (5)
- Equilibrium
- Drug concentration at receptors same as applied to system
- 1 drug molecule combines with 1 receptor molecule
- Neg. amount of drug added is already bound (this would alter free drug conc)
- Binding of 1 drug molecule doesn't influence binding of another (no-co-operativity)
38
Explain why drug binding is saturable?
Once all binding sites are occupied no more drug can bind to receptors
39
What is the shape of a binding curve?
Rectangular hyperbole
40
What is a binding curve?
Graph of [P] on y axis vs [Drug] conc on x axis
41
How can RT be found from a binding curve?
Asymptote on y axis (i.e maximum top bit of curve)
42
How can Kd be found from a binding curve?
Draw a line across from 0.5 P to binding curve, then line down to [drug]
43
What are the issues with a linear binding curve? (2)
- Large changes in P with small changes in drug concentration= errors can be made at low concentrations
- Real max at top of curve hard to determine, needs lots of extension
44
How can the issues with a linear binding curve be fixed?
- Doing a semi log of the curve
| - x axis=log10 [Drug]
45
What shape is a semi log of a binding curve turned into?
Sigmoid curve
46
How does doing a semi log of a binding curve fix the issues?
- Logging small numbers stretches them out, less error at small concs
- Logging large numbers makes them smaller, shortens max, no need to extend top of curve
47
What is the position of a drug's saturation curve along the horizontal axis determined by?
Kd
48
How does drug affinity affect the position of a drug's saturation curve along a horizontal axis?
The higher the affinity, the lower the Kd value and so the more leftward the curve
49
What is a saturation curve?
Graph of log [D] on X axis
| [DR] Y axis
50
How does increased drug affinity make a drug's saturation curve more left along the horizontal axis?
Less drug needed for a high [DR]
51
What does the ability of an agonist to produce a pharmacological effect in a tissue depend on? (2)
- Binding of drug to receptor (affinity)
| - Following binding, activation of receptor and production of response (efficacy)
52
What part of the process of forming an active DR complex does affinity affect?
Combination of free drug and receptor to form an inactive DR complex
53
What part of the process of forming an active DR complex does efficacy affect?
Configuration: DR complex changing shape to become active
54
If a drug has a high efficacy what does this mean for the DR complex?
Higher efficacy, more time DR complex sits in the active configuration
55
Why is the activation of DR complexes a reversible process?
Involves shape change which is reversible
56
Give the formula for the activation of the drug receptor complex
[DR] ---- (beta) ---->
57
If a drug has a high efficacy what are the values of alpha and beta like? (2)
- Large alpha value
- Small beta value
(or both)
58
If a drug has a low efficacy what are the values of alpha and beta like? (2)
- Small alpha value
- Large beta value
(or both)
59
What are the problems with the definition of efficacy?
- Suggests proportionality between occupancy and response
| - Suggests the more DR complexes that exist the more the response
60
What other than intrinsic efficacy affects the response from an active DR complex?
Tissue efficacy
61
What does a drug response depend on?
- Intrinsic efficacy
- Tissue efficacy/scaling factor
- Initial concentration of total active receptors (determined by drug conc)
- Kd
- Total number of effectors
62
What is tissue efficacy/scaling factor determined by? (2)
- Amplification - the secondary messenger cascade active DR complex produces - type
- Amplification - amount
63
What is intrinsic efficacy?
The ability of a drug receptor complex to evoke a response (agonist dependant)
64
What aspects of drug response are drug dependant? (3)
- Drug concentration
- Intrinsic efficacy
- Kd
65
What aspects of drug response are tissue dependant?
- Total number of receptors (Rt)
| - Tissue efficacy/scaling factor (F)
66
From what point does the response change from drug dependant to tissue dependant?
From activation of the DR complex
67
Give the equation for drug response
f E [Rt][D]/[D]+Kd
68
How does a concentration response curve compare to occupancy?
Similar in shape but not super-imposable
69
What are more useful curves to plot than concentration-response curves?
Log concentration - response curve
70
What shape is a log concentration-response curve?
Sigmoidal
71
What is a log concentration-response curve defined by?
- A max response
| - An effective concentration (EC50) value
72
What is EC50?
The concentration of drug that gives 50% of maximum response
73
What is the difference between EC50 and Kd?
EC50 incorporates binding AND response so takes into account tissue efficacy (i.e cascade)
74
Why is occupancy not linear with response?
Multiple steps involved in tissue between occupancy and response amplifying signal several fold
75
How does non - linearity of response with occupancy affect EC50 value?
EC50 value well to the left of Kd
76
What are the multiple steps involved in tissue between occupancy and response? (7)
- Drug binds
- Receptor activation
- Membrane protein effect
- Tissue chemical changes
- Ion fluxes
- Actin/myosin changes
- Muscle contraction
77
Why is the response curve to the left of a binding curve on the horizontal log drug concentration axis?
Lower drug conc needed to activate a few receptors to get a response
78
How does agonist efficacy affect the separation of the response curve to the binding curve?
Higher efficacy = greater separation of curves
79
How does increased agonist efficacy/strength cause a greater separation between the response curve from the binding curve? (3)
- Further kd value is from EC50
- DR complex mostly in DR* (active) form
- Maximum response with only low occupancy
- Larger proportion of spare receptors
80
What is receptor reserve?
The spare receptors in a cell in excess of those necessary to produce a maximum response when occupied by an agonist
81
What type of efficacy is receptor reserve related to?
Intrinsic efficacy
82
Why is magnitude of response not proportional to receptor occupancy?
Receptor reserve
83
What is a rough measure ofreceptor reserve?
Extent of KD/EC50 seperation
84
What does receptor reserve vary between?
Different agonists that act on the same receptor
85
What are useful advantages of receptor reserve? (3)
- Safety margin for receptor activation, needed for disease states and different drugs
- Economy
- Potential of low efficacy drugs for therapy
86
How does having a large receptor reserve help economy?
Less endogenous hormone/neurotransmitter
| required to produce same effect
87
How does high receptor reserve make a drug more safe?
Safer to have lower drug dosages for therapeutic effect
88
How does reduction in receptor number affect concentration response curve?
Shifts it to the right
89
Why does reduction in receptor number shift concentration response curve to the right? (3)
- Lower efficacy
- EC50 gets larger
- Reduces receptor reserve
90
What is drug potency?
How much drug is needed to produce a particular response
91
How does drug potency affect the position of a concentration response curve?
The more potent the drug, the more the curve shifts to the right
92
When testing different agonists on the same preparation what is the relative position of an agonist conc-response curve dependant on? (2)
- Agonist affinity
| - Agonist efficacy
93
When the same agonists on the different preparations what is the relative position of an agonist conc-response curve dependant on?
Receptor number
94
What are the constants when testing different agonists on the same preparation? (3)
- Receptor type
- Receptor number
- Tissue efficacy (F)
95
What are the differences when testing different agonists on the same preparation? (2) And what is the issue with this?
- Drug binding ability (kd)
- Intrinsic efficacy
(Issue=Unclear which one different potency caused by)
96
What is the difference when testing the same agonists on different preparations?
Receptor number
97
What are the constants when testing the same agonists on different preparations? (3)
- Binding ability (kd)
| - Intrinsic efficacy
98
Why is tissue efficacy (F) a constant when testing on the same preparation?
Same receptor once activated gives the same cascade
99
When an agonist produces a maximal response upon occupying 14% receptors, what is receptor reserve? What proportion would need to be lost/inactivated to see decrease in the max?
86%
| >86%
100
How would a loss in receptor population affect the DR curve? Why? (5)
- Less receptors available
- Probability of interaction decreases
- Decrease in affinity
- Increase in Kd
- Curve shifts to the right
101
Why is EC50 not relevant in a question asking for fractional receptor occupancy?
Occupancy is not the same as response
