Lecture 2 - Drug receptor interaction

Question 1

Importance of understanding receptors (4)

Answer 1

Pharmaceutical industry and drug development.
Physiology of endogenous transmitters.
Chemical toxicity.
Viral toxicity.

Question 2

Receptor transduction (4)

Answer 2

Ion channel opens de/hyper(polarisation) occurs. Milliseconds. E.G. Nicotinic and ACh receptor.

GPCRs - Bind to drug receptors and stimulates secondary messenger, then physiological effect occurs.. Takes seconds. E.G. Muscarinic and ACh receptors.

Question 3

Nicotinic (1)

Answer 3

Receptor polypeptides, respond to ACh.

Question 4

Muscarinic (2)

Answer 4

Mediating the effects produced on organs and tissues by ACh.
Slowed heart rate.
Increased activity of smooth muscle.

Question 5

Agonist - Definition (1)

Answer 5

Drug that binds to receptor to produce a BR.

Question 6

Antagonist - Definition (1)

Answer 6

Blocks action of agonist by binding to receptor (does not elicit BR).

Question 7

Partial agonist - Definition (1)

Answer 7

Drug that binds to receptor to produce a BR, never maximal effect.
Contains properties of an antagonist.

Question 8

Inverse agonist - Definition (1)

Answer 8

Produces opposite BR of an agonist.

Binds to receptor.

Question 9

Affinity - Definition (1)

Answer 9

Ability for a drug to bind to receptor site.

Question 10

Efficacy - Definition (1)

Answer 10

Ability of drug to elicit a BR from a drug-receptor interaction.

Question 11

Agonist (6)

Answer 11

Both affinity and efficacy.
Bind reversibly.
Selectively bind e.g. adrenaline to B receptor.
Conformational change –> BE.
Hydrogen/Ionic/VdW bonds - Weak/Reversible binding dissociations.
Covalent bonding - Stable strong bonds/Irrversible binding/poor dissociations.

Question 12

MOPr autoradiographic binding mapping in the brain (6)

Answer 12

MOPr - receptor in mice.
Morphine bound to opiod receptors.
More yellow/red receptors in brain region.
Nucleus accumbens - reward centre of the brain/feel good receptors.
Heroin/Fentalin are addictive , give you feeling of being high.
High amount of receptors in thalamus. Thalamus helps modulate pain.
Morphine used to treat pain.

Question 13

What determines drug affinity? (4,5)

Answer 13

Law of Mass Action: Dependent on concentrations of the reactants involved.
A = [Agonist]
RFree = [Free receptors]
AR = [Receptors bound to agonist]
Ka= Equilibrium constant = when 50% of receptors are free and 50% bound to agonist.
Each drug has its own Ka.
Small Ka = Agonist has a greater affinity.

Saturation binding receptors
Increase conc of drug you want to measure.
Output = How much drug actually binds to the receptor, will increase but not continuously as there is a finite amount of receptors.
Bmax - Max amount of receptors that are bound by drug.
Kd = Bmax/2 = Amount of drug needed to occupy half the max amount of receptors.

Question 14

What determines efficacy? (5)

Answer 14

EC50 = effective concentration giving 50% biological response, used to compare drug potency.
Point where BR stops increasing due to a finite amount of receptors.
Required to work out dosages.
Ka (Affinity) and EC50 of a drug are not equal.
You do not need full occupancy to give a maximum response.
Receptors amplify signals, so only a small number of drug-receptor interactions can produce biological effects. This is why drugs can work at low concentrations.

Question 15

Partial agonists (6)

Answer 15

e.g. Buprenorphine for opiod addiction.
Present at receptors - high affinity, but less efficacy.
Reduces withdrawal effects.
Reduces addictive ‘highs’.
Heroin high reduced due to PA.
Full agonist = e.g. Morphine = full efficacy = euphoric feelings. Problem is coming off, this is where PA used. If heroin is used ontop of PA it is ineffective as receptor sites are already bound.
Antagonist e.g Naloxone.

Question 16

Competitive/Surmountable Antagonism (7)

Answer 16

Receptors only bind to Agonist (A) or Antagonist (Ant).
Compete for same binding site.
Bind reversibly.
Reaction now dependent on two equilibrium.
Ka and Kant.
Ka> Kant then Antagonist has greater affinity for receptors than agonist.
Look at reponse vs agonist conc curve, this will shift to the right in presence of antagonists.
e.g. B adrenoreceptor antagonist atenelol on adrenaline. Atenelol reduces heart rate, Reduces endogenous affect of adrenaline on heart.

Question 17

Non-Surmountable Antagonism (5)

Answer 17

Both reduce number of receptors the agonist cna bind to = reduce max response.

1) Non-competitive antagonism
Ant binds to diff site from A.
e.g. Ketamine blocks glutamine receptors, acts at diff site.

2) Irreversible antagonism
Ant binds irreversibly to agonist/non-agonist binding sites on recptor through covalent bonds.
e.g. Asprin (reduces pain/inflammation) acetylates COX enzyme.

Question 18

Drug clinics and heroin (3)

Answer 18

Give drug addicts an epi pen containing naloxone.
Competitive opiod receptor antagonist.
Reacts with same receptors as heroin.
If they overdose they should use this pen to displace heroin and save the persons life.