drug receptor interactions

Question 1

what is an agonist ?

Answer 1

a drug or molecule which binds to the receptor will induce a pharmacological response.
◦ on the graph, as the concentration of the agonist increases, the pharmacoloigcal response increases, as agonists bind to the receptor inducing a response, and the more you increase the agonist the greater the pharmacolgical response.
◦ it will plateu . ie even if you continue to increase the agonists, the pharmacaological response will not increase.

Question 2

what is an antagonist ?

Answer 2

the drugs will bind to the receptors, but will not induce a pharamacoloigcal response
◦ on the graph, even if you start increasing the concentration of the antagonist, the response will remain zero.

Question 3

what is an antagonist + agonist ?

Answer 3

the antagonist will reduce the pharmacological activity of the agonist.
◦ ie if there is an agonist that binds to the receptor to induce a pharmocological response, and you start adding the antagonist, the antagonist will bind to the receptor and displace the agonist. since the antagonist doesnt induce activation, it will reduce the activity of the agonist. it blocks the effect of the agonist.

Question 4

what is an inverse agonist

Answer 4

a drug that produces an opposing pharmacological response to that observed by a full agonist.
◦ e.g instead of contraction of the muscle, it will relax the muscle.

Question 5

define affinity

Answer 5

• affinity is the measure of how tightly or loosely the drug binds to the receptor. does not affect the pharmocoloigcal response.
• some drugs can bind really tightly but does not induce a pharmocological response, e.g an antagonist.

Question 6

define efficacy

Answer 6

• the ability of a drug to induce a pharmocological response

Question 7

describe the affinity and efficacy of antagonist ?

Answer 7

• anatgonists have a high affinity but low efficacy.

Question 8

how do drugs bind to receptor

Answer 8

• the drug will interact and bind to a specific pocket of the receptor. this interaction can have a high or low affinity.
• often have weak affinity so agonists often dissociate from the receptor. so there is binding to the receptor and then they dissociate.
• affinity depends on the bonds formed between the receptor and agonist. strong bonds - binding strong, weak bonds - binding weak.
• weak bonds
◦ hydrogen bonds, ionic bonds and van der waals forces.
◦ most common and there is reversible binding dissociation. ie the agonist will dissociate from the receptor.
• stable strong bonds
◦ covalent bonding
◦ irreversible binding, poor dissociation. binds for a long period of times. rare
• this explains why binding is reversible.

Question 9

why is a drug receptor interaction reversible ?

Answer 9

his interaction is reversible because there are usually weak bonds between the agonist and receptor and so will dissociate.

Question 10

what is the reversible binding of an agonist governed by ?

Answer 10

law of mass action

Question 11

what does the law of mass action mean

Answer 11

low a conc - low ar interactions
as drug concentration increases, more receptors will be occupied so more drug-receptor complexes are being formed. it will eventually reach saturation.
free free receptors, so the reaction reaches maximal.

There is a maximum number of AR interactions due to finite number of receptors. Even if you increase the concentration of drugs, no more receptors will be occupied

Question 12

what kind of plot can you identify Bmax and kd from

Answer 12

saturation binding curve

Question 13

define Bmax

Answer 13

Bmax is the maximum amount of receptors bound by the drug.

Question 14

define Kd

Answer 14

Kd is the amount of drug required to occupy half the receptors, its inversely coordinated with affinity. measurement of concentraion.

Question 15

what does a small kd mean

Answer 15

• if there is a smaller Kd, the drug binds tightly to the receptor, and will require a smaller amount of the drug to achieve 50% of the Bmax.

Question 16

what does a large kd mean

Answer 16

• if there is a larger Kd, the drug binds weakly to the receptor and so will require larger amounts of the drug to achieve 50% of the the Bmax.

Question 17

why are there a maximal number of AR interactions ?

Answer 17

• There’s a maximal number of AR interactions due to a finite number of receptors.

Question 18

what is kd a measure of

Answer 18

• kd is inversely correlated with affinity. the lower the kd, the higher the affinity.

Question 19

what are the 3 characteristics given by a dose response curve?

Answer 19

• threshold conc is the minimum concentration of drug required to induce any pharmacological response.

ec50 - effective concentration giving 50 percent of the max biological response. depicts potency of the drug, the higher it is, the lower the potency

• The maximal biological effect : all drugs have a maximum pharmocological response that they can induce even if increase the concentration of the drug. this is known as efficacy

Question 20

if drugs have the same efficacies what does this mean

Answer 20

they have the same max biological effect

Question 21

draw a graph with 4 drugs that have the same efficacies and different potencies. explain why

Answer 21

x

Question 22

do you need full occupancy to give a maximum response ? explain your answer

Answer 22

You do not need full occupancy to give a maximum response.

remember : receptors amplify signals, so only a small number of drug-receptor interactions can produce biogical effects.

Question 23

give an example of a partial agonist

Answer 23

buprenorphine for opioid addiction

◦ present at receptors - high affinity but less efficacy 
◦ reduces withdrawal effects
◦ reduces additive highs 
◦ heroin-induced highs are reduced in presence of partial agonist.

Question 24

describe the action of buprenorphine

Answer 24

◦ Heroine is really addictive because it binds to the opioid receptor with high efficacy and induces a sense of reward.
◦ if you take people of heroine they will go through withdrawal e.g pain
◦ solution : buprenorphine another opioid drug.
◦ it is a partial agonist with high affinity to the opioid receptor and because it has a higher affinity than heroine, so it will displace heroine from its bindng site. instead of heroine binding to the opioid receptor, there is the buprenorphine binding to the receptor.
◦ it is a partial agonist so it will induce a pharmacological effect ( rewarding) but the pharmocological effect is not as high as heroine. not as rewarding
◦ it is important that buprenorphine has a rewarding effect to reduce any withdrawal symptoms. the partial efficacy is enough to reduce withdrawal symptoms. an antagonist would have percipitated withdrawal symptoms whereas bphine would reduce.

Question 25

what is a competitive antagonist ?

Answer 25

competitve antagonists: drugs that will compete for the same active site as the agonists. the antagonist will eventually displace the agonist, so that there is an antagonist b

Question 26

what is a non competitive antagonist >

Answer 26

non competitive antagonists : antagonists that will bind to the receptor but on a different binding site to the agonist binding site. The agonist is still able to bind to the binding site but because the antagonist binds to a different binding site, it will block the receptor from functioning.

Question 27

what are non competitve allosteric antagonist?

Answer 27

Non competitive, allosteric antgonist : drugs that will act on a different binding site to the agonist, and this interaction will change the 3D conformation of the agonist binding site. as a result, the agonist is unable to bind to its binding site because the 3d shape has changed and so the receptor will become inactive.

Question 28

draw a graph of an agonist + agonist+antagonist. explain it

Answer 28

• the competitive antagonist will compete with the agonist for the same binding site, and eventually displacing the agonist. resulting in the antagonist binding to the binding site on the receptor. this means that the receptor is inactive and will not induce a pharmacological response.
• [A] must increase to overcome ANT binding to receptors. so increasing the concetration of the agonist, eventually the agonist will start competing with the antagonist for the same active site. eventually the agonist will outcompete the antagonist for the binding site. restoration. can reveal that the agonist is a competitve agonist.

Question 29

describe the dose response curve in the presence of a competitive antagonist.

Answer 29

• in the presence of the competitve Ant concentration - effect of curve is shifted to the right
• shift to right is linearly related to [Ant]
• linear part of curve is parallel.
• same maximal response is obtained- if you increase [A] you will outcompete anatagonist.
• sumountable antagonism.
• experiments measuring % of response of agonists with and without antagonists are done to determine whether a molecule is a competitive or not competitive antagonist. if your graph has a shift to the right with the same maximum pharmacological response, ie max efficacy, then antagonist is competitve.
• there is a big shift in ec50. higher cocentration of agonist is required to induce 1/2 max pharmacoligcal response when there is the competitve antagonist, compared to the agonist alone. remember max efficacy is the same

Question 30

draw and describe the graph of a non competitve antagonist

Answer 30

• the dose response curve of agonist and agonist + competitve antagonist, there is a shift of the dose response curve downwards. why?
• even if you increase the concentration of the agonist, it will not be able to outcompete the antagonist. this is because the non -competitve antagonist is not competing with the agonist for the same binding site.
• no competition for the same active site.
• EC50 remains same because the non competitive antgonist does not compete with the same binding site.
• max efficacy reduced.
• ant binds to a different site from the agonist