Drug-Receptor Interactions

Question 1

What is the importance of receptors?

Answer 1

• Pharmaceutical industry and drug development
• Physiology of endogenous transmitters
• chemical toxicity
• Viral toxicity

Question 2

How do agonists bind to their receptors?

Answer 2

Mostly reversibly, agonists bind to receptors and then dissociate

Question 3

What are the 2 major types of receptors involved in drug interactions?

Answer 3

1. Ligand Gated Ion Channels LIGC (ionotropic)

2. G-Protein Coupled Receptors GPCR (metabotropic)

Question 4

Name an irreversible antagonist

Answer 4

Aspirin - acetylates COX enzyme

Question 5

What is the role of the thalamus in the brain?

Answer 5

Thalamus modulates pain

Question 6

How does receptor transduction occur via LIGC?

Answer 6

An influx of ions causes hyper/depolarisation causing a cellular effect

• occurs in milliseconds
  e. g. nAChR

Question 7

What is drug efficacy determined by ?

Answer 7

• Threshold concentration
• EC₅₀
• maximal concentration

Question 8

What is irreversible antagonism?

Answer 8

When an antagonist binds irreversibly either to agonist/non-agonist binding sites on the receptor
via covalent bonds
Reduces the number of free receptors

Question 9

Why is the agonist-receptor binding weak?

Answer 9

Relatively weak and reversible binding due to Hydrogen and Ionic bonding
Van der waals forces allow dissociation

Question 10

How do receptors limit the need for a large [drug]?

Answer 10

Receptors amplify signals so only a small number of drug-receptor interactions can produce a biological response

Question 11

Where can partial agonists be found?

Answer 11

Present at receptors with high affinity but less efficacy

Question 12

Using the agonist-receptor mechanism explain why opioids are so addictive to humans?

Answer 12

Thalamus in the brain contains many opioid receptors

There is therefore high opioid binding

Question 13

Outline a drug receptor mechanism

Answer 13

Drug A (agonist) + Receptor  AR  AR+ --> response 
                             (Ka occupation)(EC₅₀ activation)

Ka occupation governed by affinity
EC₅₀ activation governed by efficacy
- an agonist has both efficacy and affinity

Question 14

What does a smaller Ka value mean?

Answer 14

Agonist has a greater affinity for receptors so binds more

Question 15

Give an example of non competitive antagonism

Answer 15

Ketamine blocks glutamine receptors by acting at a different (allosteric) site in the receptor to glutamate (agonist)

Question 16

How do G protein coupled receptors cause transduction?

Answer 16

An excitability change occurs, caused by ions or a secondary messengers causing cellular effects
via Ca2+ release or protein phosphorylation
- takes longer (seconds)
e.g. Muscarinic AcHR

Question 17

What is the relationship between EC₅₀ and Ka for a maximum biological response?

Answer 17

Affinity (Ka) and Efficacy (EC₅₀) are not equal

- full occupancy isn’t required for a maximum response

Question 18

What is an Agonist?

Answer 18

A drug that binds to a receptor causing a biological response

Question 19

What is non competitive antagonism?

Answer 19

When the antagonist binds to a differing site from the agonist

Question 20

What is the law of mass action?

Answer 20

A + Rfree AR

A = [agonist]
Rfree = [free receptors]
AR = [agonist-receptor complexes]

Question 21

How does a non surmountable graph look?

Answer 21

Curve slope is reduced and the maximum is depressed

Question 22

How is drug affinity regulated?

Answer 22

Reversible binding of an agonist to its receptor is governed by the law of mass action

Question 23

What is the effect of partial agonists?

Answer 23

Reduce withdrawal effects

Reduce additive ‘highs’

Question 24

What is Bmax value?

Answer 24

Maximum number of receptors which can be bound by the drug

Question 25

What does the term drug affinity mean?

Answer 25

The ability of a drug molecule to bind to a receptor site

Question 26

What is meant by the term surmountable antagonism?

Answer 26

When the same maximal response is obtained via increasing [A] as you can out-compete the antagonist

Question 27

What is the threshold?

Answer 27

Maximum amount of drug required for a biological response?

Question 28

What is the relationship between Ant. and concentration curve?

Answer 28

In the presence of Ant., the concentration curve shifts to right as its linearly related

Question 29

What is Drug Efficacy?

Answer 29

The ability of a drug to elicit a biological response from a drug-receptor interaction

Question 30

What is the consequence of competitive antagonism?

Answer 30

If Kant < Ka, then Ant has a greater affinity for receptors than A [A] must increase to overcome Ant binding to receptors

Question 31

What is EC₅₀?

Answer 31

The effective concentration giving a 50% biological response

Question 32

Explain what is meant by a partial agonist

Answer 32

An agonist drug producing a biological effect that is always less than the maximum capacity of the tissue

Question 33

Give an example of a partial agonist used for opioid addiction

Answer 33

Brupernorphine used for opioid addiction - heroin induced highs are reduced in the presence of partial agonists

Question 34

What is the law of mass action affected by?

Answer 34

Dependent on [reactants] (agonist and free receptor concentrations)

Question 35

Why is there a maximum no. of AR complexes that can form?

Answer 35

There is a maximal no. of AR interactions due to a finite number of receptors

Question 36

How does competitive antagonism arise?

Answer 36

A and Ant compete for the same receptor binding site | Reaction is then dependent on 2 equilibrium constants (Ka and Kant)

Question 37

What is Ka?

Answer 37

The amount of drug required to occupy 1/2 max no. of receptors the [A] at equilibrium e.g. Ka at 50nM means at this conc. 1/2 the max no. of receptors are bound by the drug

Question 38

What is the Ka value for drugs?

Answer 38

Each drug has its own individual Ka value

Question 39

Which drug molecules do receptors bind to?

Answer 39

Reversibly bind to both Agonists or antagonists only

Question 40

How is EC₅₀ used?

Answer 40

Used to compare drug potency (determined by drug efficacy and affinity)

Question 41

What is an Antagonist?

Answer 41

A drug blocking the effect of an agonist commonly by binding to its receptor antagonist binding to receptor inhibits biological responses

Question 42

What does the law of mass action predict?

Answer 42

Low [A] means lots of free receptors so few AR interactions If [A] increases, more AR complexes form, reaction driven to right, so more [A], few receptors left free => reaction reaches maximum