Agonists & dose response curves (L3)

Question 1

what is an agonist?

Answer 1

a ligand that combines with receptors to elicit a cellular response

• receptor
• agonist-receptor complex
• action
• effect

Question 2

what are the 2 types of dose response curves?

Answer 2

concentration-effect curves

semi-logarithmic plot of agonist concentration against response

Question 3

why do we use a semi-logarithmic plot of agonist concentration against response curve

Answer 3

linear scale would need to be massive

we log the scale to see the full rage of concentrations

changes graph to a sigmoid shape

Question 4

what are the 2 types of dose-response relationships?

Answer 4

graded

quantal

Question 5

what is a graded response?

Answer 5

response of a particular system
• isolated tissue
• animal
• patient

measured against concentration

Question 6

what is a quantal response?

Answer 6

required to produce a specified response determined in each member of a population

population based data

tend to form a bell shaped curve in log form

Question 7

why plot a dose response curve?

Answer 7

allow estimation of Emax

allow estimation of EC50/ED50

allow efficacy to be determined

allow potency to be determined

Question 8

what is Emax?

Answer 8

concentration when we get 100% response

Question 9

what is EC50/ED50?

Answer 9

dose required to produce 50% of maximal response

Question 10

what is the 2 state hypothesis?

Answer 10

1) agonist binds to receptor
2) agonist-receptor complex made
3) if complex is activated then theres a response

Question 11

what is affinity?

Answer 11

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

affinity = K1 / K-1 
K1 = rate of association of the agonist with receptor 
K-1 = rate of AR complex dissociation

Question 12

what is Bmax?

Answer 12

the maximum number of binding sites - receptor saturation

Question 13

what is Kd?

Answer 13

equilibrium dissociation constant
a physiochemical constant

concentration of ligand at which 50& of the available receptors are occupied

it is the same for a given receptor & drug combination in any tissue, in any species

Question 14

what can Kd tell us?

Answer 14

• can be used to identify an unknown receptor
• can be used to qualitatively compare the affinity of different drugs on the same receptor
• a lower Kd indicates a tighter ligand-receptor interaction
• curve moves to the left when Kd is lower
• tells you more about potency

Question 15

what is potency dependent on?

Answer 15

affinity of drug

efficacy of drug

receptor density

efficiency of stimulus-response mechanism used

Question 16

what is potency?

Answer 16

the amount of drug needed to produce a given effect

Question 17

what is efficacy?

Answer 17

describes the ability of an agonist to activate a receptor - to evoke an action at cellular level

Question 18

what are full agonists?

Answer 18

high efficacy - AR* very likely

produce a maximum response while occupying only a small % if receptors available

maximum response corresponds to the maximum response of the tissue

Question 19

what are partial agonists?

Answer 19

low efficacy - AR* less likely

unable to produce a maximum response even when occupying all available receptors

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

drop in Emax

Question 20

examples of partial agonists?

Answer 20

varenicline
tamoxifen
aripiprazole

Question 21

what are inverse agonists?

Answer 21

have higher affinity for the AR state than the AR* state

~85% of competitive antagonists are actually inverse agonists

Question 22

what are the types of allosteric modulators?

Answer 22

positive (PAM)

negative (NAM)

Question 23

what are PAMs?

Answer 23

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

Question 24

what are NAMs?

Answer 24

not active alone but decrease affinity and/or efficacy of endogenous agonists

Question 25

what happens in the desensitisation of receptors?

Answer 25

effect of the drug reduces with continual/repeated administration

termed tachyphylaxis

Question 26

what are contributing factors to the desensitisation of receptors?

Answer 26

• conformational changes in receptor
• internalisation of receptors
• depletion of mediators
• altered drug metabolism
• other physiological responses