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BMS242 Core Phys Pharm > L5-8 Receptor Theory > Flashcards

L5-8 Receptor Theory Flashcards

1
Q

What is the major target of drugs

A

Proteins

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2
Q

What is a target of a select group of drugs, what type of drugs target this

A

DNA

Chemotherapy drugs

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3
Q

Define a receptor

A

Proteins whose function it is to recognise and respond to endogenous chemical signals

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4
Q

What are some examples of protein targets of drugs

A

Receptors
Enzymes
Transporters and Carriers
Ion channels

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5
Q

Define a drug target

A

Other macro molecules which drugs interact with in order to produce their effects

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6
Q

Receptors are classified by

A

Strucuture, pharmacology and signalling

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7
Q

Receptors show _______ in the classes of drugs which they recognise

A

Specificity

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8
Q

Are drugs 100% efficient

A

No, no drug is 100% specific

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9
Q

What arises as a result of a loss of receptors

A

Disease

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10
Q

Location of ligand gated ion channels

A

Membrane

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11
Q

How many tm domains in ligand gated ion channels

A

Variable

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12
Q

Where is the c’ term in ligand gated ion channels

A

Extracellular

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13
Q

Where is the n’ term in ligand gated ion channels

A

EC

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14
Q

What is the effector for a ligand gated ion channels

A

Ion channel

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15
Q

What type of coupling involved in ligand gated ion channels

A

Direct

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16
Q

Structure of ligand gated ion channels

A

Oligomeric assembly of subunits around a central pore

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17
Q

Location of GPCRs

A

Membrane

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18
Q

How many TM domains in GPCRs

A

7

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19
Q

Where is the c’ term in GPCRs

A

IC

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20
Q

What is the effector for GPCRs

A

Channel or enzyme

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21
Q

Where is the n’ term for GPCRS

A

EC

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22
Q

Coupling GPCRs

A

Via a G-protein

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23
Q

Structure of a GPCR

A

Mon/oligomeric assemblt of 7 TM helicies with an IC G-protein coupling domain

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24
Q

Location of kinase-linked receptors

A

Membrane

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25
Q

How many TM domaiins kinase-linked receptors

A

1

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26
Q

Where is c’ term kinase-linked receptors

A

IC (catalytic domain)

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27
Q

Where is the n’ term. kinase-linked receptors

A

EC (binding ligand domain)

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28
Q

Effector for kinase-linked receptors

A

Protein kinases

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29
Q

Coupling in kinase-linked receptors

A

Direct

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30
Q

Structure of kinase-linked receptors

A

Single Tm domain linked to EC receptor domain and IC catlytic domain

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31
Q

Location of nuclear receptors

A

Cytosol

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32
Q

Effector for nuclear receptors

A

Gene transcription via the DNA

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33
Q

Structure of a nuclear receptor

A

Monomeric structure with separate receptor and DNA binding domain

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34
Q

As downstream pathway

A

With GTP bound
Activation of adenylyl cyclases
Prod of cAMP
Act of PK-A

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35
Q

Ai downstream pathway

A

Inhibition of adenylyl cyclase

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36
Q

Aq downstream pathway

A

Act of PLC-B

Breakdown of PIP(4,5)2 to IP3 and DAG

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37
Q

Occupation is governed by

A

Affinity

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38
Q

Activation is governed by

A

Efficacy

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39
Q

What does high specifity mean for the binding of drug to receptor

A

Binding will be strong

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40
Q

What does high specifity mean for the rate of the forward and reverse reaction

A

Rate forward will be high

Rate backward will be low

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41
Q

A full agonist will have an efficacy of

A

E>0

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42
Q

An antagonist will have an antagonist of

A

E=0

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43
Q

Define occupancy

A

How many receptors are occupied by the drug and are forming the drug receptor comple

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44
Q

Occupancy will vary with

A

Drug concentration

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45
Q

Formula for occupancy

A

No receptors occupied / Total no. receptors

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46
Q

What scale is occupancy measure on

A

0 -1
0 no drug
1 fully occupied

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47
Q

Why is response NOT a good measure of occupancy

A

Response will vary with efficacy

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48
Q

Is occupancy directly proportional to occupancy

A

NO proportional - but not a 1:1 realationship

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49
Q

Define efficacy

A

The ability of the active form of the drug receptor complex to induce further downstream signalling

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50
Q

What is the method used to measure occupancy

A

A radioligand bidning assay

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51
Q

Method for accounting for non-specific binding in a radioligand binding assay

A

Two experiments in parrallel
In one - excess of cold ligand to displace the hot ligand from the specific bidning sites.
So any flourescence seen will be non specific binding (infinite number of binding sites)
So then specific binding = total bound - non specific binding

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52
Q

Conditions for purity in a radioligand binding assay

A

100% pure

Free from chirality (optical isomerism)

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53
Q

Methods to prevent degredation in a radioligand binding assay

A

Free radical scavenger
Store at low temps
Avoid light
Incorporation of an anti-oxidant

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54
Q

Example of a free radical scavenger

A

Ethanol

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55
Q

Example of an anti-oxidant

A

Ascorbic acid

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56
Q

Characteristics of a good lable in a radioligand binding assay

A

High specifity
Low concentration of tracer (safe)
Does not impact on normal fucntion

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57
Q

3H is

A

Tritium

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58
Q

Advantages of using tritium as a radiolable

A

Radioactive form is indistinguishable from the natural form
High specific activities
Good stability
Long half life (~67 years)

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59
Q

Disadvantages of using tritium as a radiolabel

A

Hard to get homogenus group (i.e. getting the sam number of Hs labelled on each compound)
Specialist labs are required
Labelling is expensive and difficult

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60
Q

Advantages of using 125 I

A

If aromatic hydroxyl group (tyrosine residues in peptides) can be incorporated at high specific activities
Easy to use in labs
Cheap

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61
Q

Disadvantages of 125 I

A

More readily degraded
Biological activity of the ligand can be reduced
Short half-life (~67 years)

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62
Q

Characteritics of the tissue selected

A

Selected to contain the recog sites
Can be isolated membrane or whole organ
Dependent on the receptor and hypothesis

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63
Q

Incubation conditions for a radioligand binding assay

A

Preserve the integrity of the ligand and receptor
High enough protein content for assay volume
Additives added for protection
Temp close to 0

64
Q

Why must temp be close to 0 during incubation

A

When cells homogenated, lysosomes ruptured, lysozyme enzyme released which would breakdown proteins
At a low temperature activity is low enough to protect the proteins

65
Q

Two techniques usually used for spearation of bound from free

A

Filtration or centrifugation

66
Q

What soluble binding techniques may be used to separate bound from free

A

Dialysis
Column chromatography
Precipitation/adsorption

67
Q

The time available to separate depends on what

A

The KD

68
Q

A low KD means

A

High affinity

69
Q

A high KD means

A

Low affinity

70
Q

If KD is low will you have long to separate

A

Yes

71
Q

If the KD is high will you have long to separate

A

No

72
Q

How to calculate specific binding from total bound and non specific

A

Specific = total - non specific

73
Q

What is the shape o the total bound curve

A

Rectangular hyperbola

74
Q

Why is specific binding saturable

A

Only a certain number of binding sites, eventually these will be full

75
Q

How many non specific binding sites

A

Infinite

76
Q

What is Bmax

A

The maximum occupancy

77
Q

What is Kd

A

The disociation constant - concentration required for 50% occupancy

78
Q

What is the equation linked to occupancy

A

Langmuir equation

79
Q

Kd is a measure of

A

Affinity

80
Q

Kd =

A

(k-1)/(k+1)

81
Q

Lower KD means a

A

Higher affinity

82
Q

Give the equation for bound drug at X concentration

A

(Bmax X Xa) // (Xa + Kd)

83
Q

Give the equation for b/f from a scatchard plot

A

(Bmax - B) // Kd OR

B/F = 1/KD . (B-Bmax)

84
Q

What does B represent

A

Bound radioligand

85
Q

What does F represent

A

Free radioligand

86
Q

What is the free radioligand equvilant to?

A

The ammount of drug added, concentration change due to some binding will be neglidgeable

87
Q

What is Kd

A

The dissociation constant, concentration at which there is 100% occupancy

88
Q

Bmax

A

Maximum ammount of drug which can specifically bind if one drug molecules binds to each receptor

89
Q

Low Kd means

A

High affinity

90
Q

High Kd mean

A

Low affinity

91
Q

On a scatchard plot what is given by the slope of the graph

A

-1/KD

92
Q

On a scatchard plot what is given by the x intercept

A

A ratio of B/F of zero => no bound

93
Q

What is known if Kd is different

A

Must be a different receptor

94
Q

Kd can be used to ___________ the ___________ of receptors

A

Quantify number

95
Q

What disease involves a loss of receptors

A

Myasthenia gravis

96
Q

What would be used to measure efficacy

A

A bioassay

97
Q

Define EC50

A

Drug concentration which gives half of the maximum response capable of a tissue

98
Q

Describe how Kd and EC50 values differ, why>

A

EC50 lower than Kd ==> 50% of the response is seen which less than 50% occupancy of the receptors
Due to receptor reserve or spare receptors

99
Q

Why is there a receptor reserve

A

Signal amplification –> 1 activated receptor causes activation of many second messengers
MAX response may have been achieved - i.e. a muscle will only be able to contract to a certain degree

100
Q

What is the hill equation used to determine

A

Response of a tissue to an agonist

101
Q

What is the hill equation

A

(MAX . [Xa]^n) // ([Xa] + [EC50]^n)

102
Q

What is MAX

A

Max response of a tissue

103
Q

Xa =

A

Concentration of agonist

104
Q

What is n

A

The slope factor -

Determined by how many molecules of agonist need to bind to a receptor in order to activate it

105
Q

What would the n number of a muscarinic receptor be

A

1

106
Q

What would the n number of a nicotinic receptor be

A

2

107
Q

EC50 is a measure of a drugs

A

Potency

108
Q

What are the three things that potency depends on

A

Affinity, efficacy and the receptor reserve

109
Q

What does a lower EC50 indicate

A

A greater potency

110
Q

What does a higher EC50 indicate

A

A lower potency - more receptors need to be activated to induce 50% of the MAX response

111
Q

What can be said about agonists A B and C in respect to their maximum responses and their EC50 value

A

Different maximum responses

Same EC50 values

112
Q

What is efficacy a measure of

A

A single agonist-receptor complexes ability to cause a response

113
Q

What can be said about the occupancy for a partial agonist to elicit it’s maximum response

A

All of the receptors have to be occupied

114
Q

What are the three properties that determine the effect of a drug

A

Specificty
Affinity
Efficacy

115
Q

Define specificity

A

The ability of a drug to interact with a structurally defined site/receptor

116
Q

Define affinity

A

The ability of a drug to bind to a receptor

117
Q

Define efficacy

A

The ability of a drug to cause activation of a receptor

118
Q

What is the efficacy of a full agonist

A

E = 1

119
Q

What is the efficacy of an antagonist

A

E = 0

120
Q

What is an inverse agonist

A

A drug that when it binds to the receptor stabilises the resting state of that receptor reducing any constitutive activity

121
Q

What is constitutive activity of a receptor

A

Where no agonist is bound but the receptor becomes spontaneously active

122
Q

Define antagonist

A

A drug which prevents the response of an agonist - there are many types

123
Q

Describe chemical antagonism

A

Substances which can combine in solution to chemically alter the agonist so that the active drug is lost

124
Q

Example of a chemical antagonist

A

Heavy metal poisoning treating with chelating agents

125
Q

What is a pharmacokinetic antagonist

A

Drug that causes a change in rate of metabolism, rate of absoprtion or rate of excretion

126
Q

How do opiates act as pharmacokinetic antagonists

A

Affect GI tract motility, will reduce the effectiveness of any drugs which are taken by the oral route

127
Q

What is warfarin used to treat, how does it show pharmacokinetic antagoism and why is this dangerous

A 
Blood thinner (anti-coagulant) - taken in order to prevent heart attacks 
Care must be taken when treated with some a.biotics as stimulate the metabolism of warafin and all of the effects are lost
128
Q

What is physiological antagonism

A

Two drugs which act on different receptors to cause opposing effects within the body

129
Q

How is arterial BP affected by physiological antagonism

A

NA –> Increases arterial BP

Histamine –> Causes vasodilation thus lowering arterial BP

130
Q

What is a non competitive antagonist

A

Substances which cause a block between receptor activation and response so no response is seen

131
Q

How do dihydropyridines show non competitive antagonism

A

By blocking voltage gated calcium channels, preventing smooth muscle contraction

132
Q

Define competitive antagonism

A

Directly compete with the agonist for occupancy of the receptor

133
Q

What are the two types of competitive antagonists

A

Reversible and irreversible

134
Q

What would happen to the dose response curve if reversible antagonist added, what about if more agonist was added ontop of this

A

Curve would shift (translate) right

135
Q

What would happen to the max response and EC50 values if reversible antagonist added, what about if more agonist was added ontop of this

A

Max response would remain the same but ammount of agonist required would increase
EC50 would also increase

136
Q

FOR COMP REVERSIBLE ANTAG
If concentration of agonists is ______ sufficiently the ______________________ increases and the effect of the antagonist ___________. This type of antagonism is _____________

A

Increased
Probability of an agonist binding specifically
Decreases
Surmountable

137
Q

Define dose ratio

A

How many more times agonist is needed in the presence of an antagonist for the same response to be seen

138
Q

Equation of dose ratio (DR)

A

[Agonist in presence of antagonist] // [Agonist without the antagonist]

139
Q

A shild analysis is used to measure

A

Antagonist affinity

140
Q

In a schild analysis what is DR given by

A

DR = (Xb/Kd) + 1

141
Q

What is Xb

A

Concnetration of antagonist

142
Q

What is Kd

A

Antagonist affinity contastnt

143
Q

Whar is the equation of the line in a schild analysis

A

log(DR-1) = Log[Xb] - Log(Kd)

144
Q

In a shild analysis what is plotted on the y axis

A

Log(DR-1)

145
Q

In a schild analysis what is plotted on the x axis

A

Log(Xb)

146
Q

The x intercept of a schild analysis is

A
  • log(Kd)
147
Q

Define Pa2

A

The negative log of molar concentration od the antagonist which will reduce the effect of double dose of the agonist drug to that of a single dose or -1*logKd

148
Q

What can be said when DR

A

Double ammount of the receptor agonist is required for the same response to be seen

149
Q

Pa2 =

A

logKd

150
Q

What can be said about a higher Pa2 value

A

Higher the affintiy of the antagonist

151
Q

If Pa2 is 9 what is KD

A

10^-9

152
Q

Can irreversible competivie antagonism be reversed by washing

A

No

153
Q

irreversible competivie antagonism is

A

Time dependent

154
Q

Give an example of irreversible competitive antagonism

A

The effects of the alkylating drug bidenamine on histamine receptors in the guinea pig ileum

155
Q

What condition cause desensitisation

A

When a drug is given continuously or repeatedly over a period of time

156
Q

Desensitiation occurs due to

A

Loss of receptors from the cell surface
Change in the receptor - e.g. due to phosphorylation
Exhaustion of mediators
Increased metabolic degredation or extrusion of the drug
Physiological adapation

BMS242 Core Phys Pharm (9 decks)

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