Pharmodynamics : Receptor Theory

Question 1

How to calculate g/L of acetylcholine that has a molecular weight of 146 in 1M solution ?

Answer 1

MWt x Molarity = g/L

146 x 1 = 146g/L

• molecular weight means molecular weight in GRAMS.

Question 2

How does binding of a ligand obey the law of mass action ?

Answer 2

L + R = RLIgand receptor complex

• reversible reaction
• as you add more ligand or more receptor the eq would shift to the right and more ligand -receptor complexes would be made.

Question 3

Define affinity

Answer 3

Measure of strength of interaction between a ligand and a receptor

Question 4

How does an agonist work ?

Answer 4

• an agonist binds to a receptor.
• binding of the agonist depends on AFFINITY
• an agonist-receptor complex is made
• receptor activation is governed by intrinsic efficacy which results in the receptor being activated conformation.
• to generate a biological response EFFICACY is required

Question 5

Explain how an antagonist works ?

Answer 5

• antagonist binds to receptor
• this requires AFFINITY
• an antagonist blocks the binding of the agonist which prevents the receptor being activated.
• they have NO intrinsic efficacy which explains why there is no response

Question 6

How can we measure binding of a ligand to a receptor experimentally ?

Answer 6

• often by binding of a radioactively labelled ligand to cells or membranes
• incubate radioligand and receptors
• we separate the ligands that are bound and free and then measure the ligands that are bound.

Question 7

What is kd?

Answer 7

The concentration of drug at which 50% of receptors are occupied.

• gives a measure of affinity

Question 8

The lower the kd the ….. greater/lower the affinity ?

Answer 8

Greater the affinity because the lower the kd the less concentration required to occupy all 50% of receptor sites

Question 9

How can we treat heroin or morphine overdose ?

Answer 9

Naloxone is used to treat overdose

• it has a very high affinity ( thus lower kd) than heroin
• high affinity antagonist of u-opioid receptors
• and eventually outcompetes heroin in the body

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Question 10

What is fentanyl and why is it very difficult to treat overdose in it ?

Answer 10

• fentanyl is an opioid that causes euphoria
• it has an agonist which has an extremely high affinity towards opioid receptors
• often medications like naloxone cannot outcompete fentanyl.

Question 11

Log10 of number =

Answer 11

Power by which 10 has to be raised to get that number

Eg log10 ( 1000) = 3 because 10^3 = 1000

Question 12

What does a response require in order to happen ?

Answer 12

EFFICACY

Question 13

Define EC50

Answer 13

Effective concentration giving 50% maximal response

Question 14

What is intrinsic efficacy ?

Answer 14

Ability to activate receptor

Question 15

Define potency

Answer 15

Effective concentration that gives 50% of the maximal response

Question 16

What does potency depend on ?

Answer 16

• BOTH AFFINITY
• intrinsic efficacy
• PLUS cell/tissue components eg number of receptors

Question 17

Define concentration and dose

Answer 17

Concentration - known concentration of drug at site of action

• dose : concentration at site of action generally unknown eg dose to a patient in mg or mg/kg

Question 18

Why when treating asthma we need a highly selective drug ?

Answer 18

-drugs that act as agonists tend to target b2-adrenoreceptors in the airways , however because b-adrenoreceptors are elsewhere in the body eg b1-adrneoreceptors are found in the heart , non-selective drugs may increase force and rate of contraction!

Question 19

How does Salbutamol achieve selective specificity ?

Answer 19

Kd for b2- 1micromoles
Kd for b1- 20micromoles

• this shows that there is only a 20 fold difference between the affinity towards beta1 and beta2 adrenoreceptors. Which suggests that selectivity is not that great. HOWEVER…
• when salbutamol binds to beta2- adrenoreceptors, the receptors are activated very well compared to beta1-adrenoreceptors which suggests that salbutamol is enhanced by b2-selective efficacy.

Question 20

How does salmeterol achieve selective specificities

Answer 20

• long acting drug
• kd b1- 1900nm
• kd b2- 0.5nm

= there is a 3455 fold difference in affinity which suggests that salmeterol selectivity is based on affinity , not selective efficacy

Question 21

What are the problems with salbutamol in people who have cardiovascular disease ?

Answer 21

the b1-adrenoreceptors are also activated resulting in heart rate increasing.

• this could lead to problems such as angina
• hypertension

Question 22

Give an example of one cell/tissue dependant factors that influence agonist potency ?

Answer 22

Number of receptors

Question 23

How does an increase in the number of receptors increase agonist potency ?

Answer 23

• because we often have spare receptors left over
• for example : if there were no spare receptors ( there were 10,000 receptors in a cell ) , a full response requires 100% occupnacy . This would mean it requires&raquo_space;»> kd concentration of drug. Eg if kd of drug is 1nm it would need 10-100 Nm of drug instead.
• HOWEVER, with spare receptors ( if we have 20,000) . Only 50% occupancy required for full response (10,000). So it requires kd of drug. Eg if kd=1nm, it requires 1nm.

Question 24

Does changing receptors number affect maximal response ?

Answer 24

Yes it can

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Question 25

How does receptors numbers vary in the body ?

Answer 25

• they vary with cell type
• they tend to increase with low activity in the cell , to up regulation
• they tend to decrease with high activity to down regulation

Question 26

Define a partial agonist

Answer 26

• a- binds to receptors , however has insufficient intrinsic efficacy for maximal response to be evoked. Thus , EMAX decreases.

Question 27

Give an example of a partial agonist that can be used to treat heroin addictions

Answer 27

Buprenorphine

Question 28

Outline how the partial agonist buorenorphine acts as an agonist but also an antagonist at the same time

Answer 28

1) buprenorphine has a higher affinity for the u-opioid receptors than heroin so would bind to the receptors preventing the binding of heroin thus acting as an antagonist
- at the same time it activates the receptors , but not enough to evoke a maximal response.

Question 29

Why can a heroin addict become very ill if they administered buprenorphine ?

Answer 29

Addict experiences withdrawal symptoms because buprenorphine is a partial agonist which means it would not evoke a maximal response at the opioid receptors which the body is not used to,

Question 30

What are the three types of antagonists?

Answer 30

1( reversible competitive antagonist

2) irreversible competitive antagonist
3) non competitive antagonist

Question 31

Define IC50

Answer 31

Concentration of antagonist giving 50% inhibition

Question 32

Reversible competitive antagonist

Answer 32

Competitive antagonists compete with agonist for binding

• the inhibition is surmountable
• causes a parallel shift to the right of the agonist - concentration response curve because more agonist concentration is required to outcompete the competitive antagonist

Question 33

Give an example of a reversible competitive antagonist

Answer 33

• naloxone
• high affinity for u-opioid receptors

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Question 34

Irreversible competitive antagonists

Answer 34

• with increased antagonist or increased time more receptors are blocked by antagonist
• this is non-surmountable
• this would cause a parallel shift to the right of the graph and at higher concentrations suppress the maximal response ( EMAX decreases)

Question 35

Define orthosteric site

Answer 35

• the binding site where a ligand usually binds aka the active site

Question 36

Non competitive antagonist

Answer 36

• binds to sllosteric site which results in a conformational change
• this reduces orthosteric ligand affinity / and or efficacy
• causes a parallel shift to the right - decreases maximal response at higher concentrations of non comp antagonist

Question 37

What is an example of a non competitive antagonist drug

Answer 37

Maraviroc