Agonists and dose response curves L2

Question 1

what is the sequence of events that agonists cause and give example

Answer 1

1. bind to receptor forming agonist-receptor complex
   - salbutamol binds to B2 adrenoceptor
2. causes an action
   - increases cAMP levels
3. causes an effect
   - bronchodilation

Question 2

what are dose-response curves used for

Answer 2

to determine correct dose

Question 3

describe dose-response curves

Answer 3

Y: biological response
X: log of agonist concentration
-semi log as only one factor is in log

Question 4

describe the two dose-response relationships

Answer 4

1. graded
   - response of a particular (individual) system
   - measured against agonist concentration
2. quantal
   - drug dose required to produce specific response determined in each member of population
   - tend to look like bell curve

Question 5

what does a dose-response curve tell us

Answer 5

1. estimation of Emax
2. estimation of concentration or dose required to produce 50% of maximal response (EC50 or ED50)
3. Allow efficacy to be determined
4. potency to be determined

Question 6

what is Emax

Answer 6

maximum effect of agonist

Question 7

what is EC/ED50

Answer 7

estimation of concentration or dose required to produce 50% of maximal response

Question 8

what is efficacy

Answer 8

the size of the effect
- uses Emax to be determined

Question 9

if there is a high Emax, what is efficacy like

Answer 9

high efficacy

Question 10

what is potency

Answer 10

The drug which can produce an effect at lower drug concentrations is “more potent”
use EC50 to work out

Question 11

if an agonist has lower EC50, what kind of potency does it have

Answer 11

high potency

Question 12

what is affinity

Answer 12

the strength with which an agonist/drug binds to a receptor

Question 13

in the formation of agonist receptor complex, what does K1 and K-1 represent

Answer 13

K1: association constant
K-1: dissociation constant
one agonist receptor complex is formed, it either dissociates or produced biological response

Question 14

how is receptor saturation easily measured

Answer 14

Bmax
maximum number of binding sites

Question 15

what is difficult to get a measure of in terms of receptor saturation

Answer 15

how avidly the drug binds – affinity (KD)

Question 16

how can affinity be determined

Answer 16

K1/K-1
- rate of association/ rate of dissociation

Question 17

what does a large value of K1 and a small value of K-1 mean

Answer 17

high affinity and low dissociation rate

Question 18

what is Kd

Answer 18

equilibrium dissociation constant

Question 19

what does equilibrium dissociation (Kd) show

Answer 19

The KD is a physiochemical constant like Avogadros number and is the same for a given receptor and drug combination in any tissue, in any species (as long as the receptor is the same).
can be used to determine
1. unknown receptor
2. quantitatively compare the affinity of different drugs on the same receptor.
Kd is EC50

Question 20

Kd and affinity are inversely proportional
what does a low Kd suggest

Answer 20

high affinity

Question 21

on a binding-dose curve there are two curves
- one to the right and one to the left
which curve has the highest affinity

Answer 21

the one to the left as it has lower Kd so less agonist needed to get EC50 as it dissociates less readily

Question 22

which will have the higher potency

Answer 22

the one to the left

Question 23

what are potent drugs

Answer 23

Potent drugs are those which elicit a response by binding to a critical number of receptors at low concentration (high affinity) compared with other drugs acting on the same system with lower affinity
high affinity at low concentrations

Question 24

what 4 factors is potency dependant on

Answer 24

1.affinity of drug
2. efficacy of drug
3. receptor density
4. Efficiency of stimulus-response mechanisms used

Question 25

how does EC50 relate to potency

Answer 25

lower EC50, higher potency - lower concentration needed to achieve half of the maximum biological response agonists which are potent tend to have high affinity

Question 26

why may only a fraction of total receptors may be needed to be stimulated to get maximum response

Answer 26

Many receptors can amplify signal duration and intensity Systems that exhibit this behaviour are said to have spare receptors

Question 27

what is efficacy

Answer 27

ability of agonist to activate receptor and evoke an action determined by the nature of the receptor-effector system refers to the maximum effect an agonist can produce regardless of dose

Question 28

what are the two types of agonists and what is their efficacy

Answer 28

1. full agonist: high efficacy - the maximum response produced corresponds to the maximum response that the tissue can give. 2. partial agonist: low efficacy - maximal response which falls short of the maximal response that the system is capable of producing

Question 29

what is the relationship between type of agonist, efficacy and forming active agonist-receptor complex

Answer 29

full agonist mean active complx is likely - produce a maximum response while occupying only a small % of receptors available parital agonist means active complex is less likely - unable to produce a maximum response even when occupying all the available receptors

Question 30

give 3 examples of partial agonists

Answer 30

1. Varenicline -Nicotine receptor partial agonist for smoking cessation. 2. Tamoxifen - Estrogen receptor partial agonists for use in estrogen dependent breast cancer. 3. Aripiprazole - Antipsychotic – partial agonists at selected dopamine receptors.

Question 31

describe inverse agonists

Answer 31

Have higher affinity for the AR (inactive) state than for AR* (active) state of the agonist receptor complex Many ‘classical’ competitive antagonists display inverse agonist activity

Question 32

give an example of inverse agonists

Answer 32

β-carbolines on GABAA receptors – anxiogenic rather than anxiolytic

Question 33

what effect does the allosteric modulator Benzodiazepines have on GABA receptors

Answer 33

Increases KA for GABA Increase efficacy of GABA

Question 34

what are the two types of allosteric modulators and give examples

Answer 34

1. Positive (PAM) Not active alone but increase affinity and/or efficacy of endogenous agonist Examples: Diazepam, Propofol, Isoflurane 2. Negative (NAM) Not active alone but decrease affinity and/or efficacy of endogenous agonists mGluR5 dipraglurant

Question 35

describe desensitization of receptors

Answer 35

Effect of the drug reduces with continual/repeated administration.

Question 36

what term is given to desenitization of receptors

Answer 36

tachyphylaxis

Question 37

how does desentisation of receptors happen

Answer 37

Conformational changes in receptor Internalisation of receptors Depletion of mediators Altered drug metabolism Other physiological responses (homeostatic).