1.3 Agonists and dose response curves

Question 1

What is an agonist?

Answer 1

a ligand (drug, hormone or neurotransmitter) that combines with receptors to elicit a cellular response

Question 2

Give an example of an agonist:

Answer 2

salbutamol

Question 3

How does salbutamol effect beta2-adrenorecptors?

Answer 3

binds to form salbutamol-beta2-adrenoceptor complex

2) increased cAMP
3) bronchodilation

Question 4

Why are dose-response curves presented as a semi-logarithmic plot?

Answer 4

as concentration is a very big number so you can identify the concentration required to have an effect without negative side effects.

Question 5

What is a graded dose-repsonse curve?

Answer 5

response of a particular system: isolated tissue, animal or patient. measure against agonist concentration.

Question 6

What is a quantal dose response curve?

Answer 6

– Drug doses • (agonist or antagonist) – required to produce a specified response determined in each member of a population, using absolute measures so we quantify where the vast majority is effected, therefore if its per a number of people its quantal, usually a bell shaped curve

Question 7

Dose response curve vs concentration-effect curve

Answer 7

Dose is the amount you take, concentration is the amount that actually enters the body.

Question 8

Whats the easiest way to differ between graded and quantal response?

Answer 8

quantal response involves looking at response determined in each member of the population, usually bell shaped curve. There is a yes or no reponse. While in graded the response has different levels/grades, and doesn’t look at a population but how extreme that reponse is

Question 9

what is the 2 state hypothesis of receptor drug interactions?

Answer 9

receptor has 2 states, active or rested.

Question 10

When will more receptors be in rested state?

2) When will more receptors be in active state?
3) Why does this change occur?

Answer 10

1) when there is less drug agonist
2) when drug agonist is added
3) If we add a drug agonist it will shift the equilibrium to the right and more drug will bind to receptor dependent on affinity, then receptor will be activated.

Question 11

1) What is another way of describing receptor saturation?

2) How do you find it??

Answer 11

1) Receptor saturation is easily measured i.e. maximum number of binding sites (Bmax)
2) do total drug bound-non specific= specific
non-specific is when a drug binds to another receptor you are no interested in

Question 12

What is Bmax?

Answer 12

binding saturation

Question 13

What 2 properties must a drug have to have a high affinity?

2) what constant can tell you this?

Answer 13

bind more relative to dissociate determined by

a) the number of bonds
b) the “level of fit” between ligand and receptor
2) Kd (equilibrium dissociation constant)

Question 14

What does affinitiy desribe?

Answer 14

the strength at which a drug binds to receptor

Question 15

1) what is Kd the inverse of??
2) What would a low Kd indicate?
3) the formula is k-1 over k1. what does
a) k1
b) k-1
mean?

Answer 15

1) affinity
2) a tighter ligand-receptor interaction (high affinity)
3) a) is the rate of association of the agonist with receptor
b) is the rate of AR complex dissociation

Question 16

a) What is the 2 state hypothesise?

b) What properties determines if a drug causes a response in receptor?

Answer 16

a) 1. Drug occupies receptor
2. complx causes acitvation of receptor
3. response occurs
b) the affinity (1) and ht efficacy (2)

Question 17

The KD is the same for a given receptor and drug combination in any tissue, in any species (as long as the receptor is the same), anywhere in the universe.
A) What can Kd be used for? (2)

Answer 17

A) 1) The KD can therefore be used to identify an unknown receptor.
2)The KD can be used to quantitatively compare the affinity of different drugs on the same receptor.

Question 18

How do you compare affinities of 2 different drugs?

Answer 18

1. read dose-dependent graph (y axis reads % receptors occupied, x axis reads drug concentration)
2. find the value of Kd, by reading drug concentration at 50% occupancy
3. The one with a lower Kd value has a greater affinity

Question 19

How do you find

a) Emax
b) EC50

Answer 19

1. read dose-response graph (y axis= percentage response, x axis is concentration )
   a) read value of drug concentration at 100% response
   b) read value of drug concentration at 50% response

Question 20

What value do you use to find out

a) efficacy
b) potency

Answer 20

a) Emax

b) potency

Question 21

What is potency dependent on? (4)

Answer 21

Affinity of drug
Efficacy of drug
Receptor density
Efficiency of stimulus-response mechanisms used

Question 22

If there is a linear relationship between receptor occupation and biological effect then Kd and EC50 are equal
TRUE OR FALSE

Answer 22

TRUE

Question 23

Why may Kd and EC50 not always be equal?

2) When are they equal?

Answer 23

1) Many receptors can amplify signal duration and intensity
Because of this amplification only a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell

2) when there is a linear relationship between receptor occupancy and biological effect.

Question 24

what behaviour doe spare receptor systems exhibit?

Answer 24

Many receptors can amplify signal duration and intensity
Because of this amplification only a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell

Question 25

describe efficacy

2) What determines efficacy?

Answer 25

the ability of an agonist to activate a receptor i.e. to evoke an ‘action’ at the cellular level
2) the nature of the receptor-effector system

Question 26

the ability of an agonist to activate a receptor i.e. to evoke an ‘action’ at the cellular level
What word describes this?
2) What is it used in reference to?

Answer 26

efficacy

2) the maximum effect an agonist can produce regardless of dose

Question 27

Describe the efficacy of full agonists?

2) what is the probability of a drug and receptor complex that causes a response?

Answer 27

1) high efficacy

2) very likely

Question 28

Describe the efficacy of partial agonists?

2) what is the probability of a drug and receptor complex that causes a response?
3) is it able to produce a maxium response if all receptors are occupied?

Answer 28

1) low efficacy
2) less likely
3) no

Question 29

With full agonists, the maximum response produced corresponds to ….

Answer 29

the maximum response that the tissue can give.

Question 30

A partial agonist is a ligand that combines with receptors to elicit a maximal response which ….

Answer 30

falls short of the maximal response that the system is capable of producing

Question 31

name:

Nicotine receptor partial agonist for smoking cessation.

Answer 31

varenicline

Question 32

what is varenicline

Answer 32

Nicotine receptor partial agonist for smoking cessation.

Question 33

what is tamoxifen?

Answer 33

Estrogen receptor partial agonists for use in estrogen dependent breast cancer.

Question 34

Name:

Estrogen receptor partial agonists for use in estrogen dependent breast cancer.

Answer 34

tamoxifen

Question 35

what is aripiprazole?

Answer 35

Antipsychotic – partial agonists at selected dopamine receptors.

Question 36

Name:

Antipsychotic – partial agonists at selected dopamine receptors.

Answer 36

aripiprazole

Question 37

What is the significance of spare receptors or receptors reserve systems in medicine?

Answer 37

you only need to bind to some of the receptors so maximum dose is not required to have max effect.

Question 38

is there ever a situation where the response to a partial agonist and full agonist is the same

Answer 38

yes, growing body of data

e.g. some ion channels

Question 39

what are inverse agonists?

Answer 39

some receptors are active without even been bound to. inverse agonists binds to a receptor and reduces activity,

Question 40

what is a positive allosteric modulator?

Answer 40

Not active alone but increase affinity and/or efficacy of endogenous agonist

Question 41

What is a negative allosteric modulator?

Answer 41

Not active alone but decrease affinity and/or efficacy of endogenous agonist

Question 42

1) what is traphylaxis?

2) What a contributing factors? (5)

Answer 42

desensitisation to a drug from continous binding to receptors over a long period of time
2) Conformational changes in receptor
Internalisation of receptors
Depletion of mediators
Altered drug metabolism
Other physiological responses (homeostatic).