Module 8: Drug Receptor Interactions

Question 1

There are two receptor theories that we use to describe drug receptor interactions:

Answer 1

1) The simple occupancy theory

2) The modified occupancy theory

Question 2

Describe the simple occupancy theory:

- What does it imply?

Answer 2

The simple occupancy theory states:

1) The intensity of a drug’s response is proportional to the number of receptors occupied.
2) The maximal response occurs when all the receptors are occupied.

This implies that two drugs that act at the same receptor should produce the same effect.

• This is not true!
• We know this because there are many drugs that act at the same receptor yet have different efficacies.

Question 3

Describe the modified occupancy theory:

Answer 3

The modified occupancy theory identifies that some characteristics of drug receptor interactions cannot be accounted for by the simple occupancy theory - The modified occupancy theory states:

1) The intensity of a drug’s response is proportional to the number of receptors occupied.
2) Two drugs occupying the same receptor can have different binding strengths (i.e. affinity).
3) Two drugs occupying the same receptor can have different abilities to activate the receptor (i.e. intrinsic activity).

• In summary, in addition to accounting for the number of receptors occupied, the modified occupancy theory takes into account the affinity of the drug for the receptor and the ability of the drug to activate the receptor.

Question 4

What is affinity in relation to the Modified Occupancy Theory?
- High vs. low?

Answer 4

Affinity is the attraction that a drug has for its receptor.

Drugs with a high affinity are highly attracted to their receptor and therefore bind to the receptor effectively even at low concentration.

Drugs with low affinity are weakly attracted to their receptor and therefore bind ineffectively to the receptor even at high concentration.

Question 5

T/F

The affinity of a drug is the primary determinant of a drug’s potency.

Answer 5

True

Drugs with high affinity for their receptor have high potency whereas drugs with low affinity for their receptor have low potency.

Question 6

What is intrinsic activity in relation to the modified occupancy theory?
- High vs. low?

Answer 6

Intrinsic activity is the ability of a drug to activate the receptor.

Drugs that have high intrinsic activity cause intense receptor activation.
- drugs with high intrinsic activity have high maximal efficacy

Drugs with low intrinsic activity only minimally activate the receptor.
- drugs with low intrinsic activity have low maximal efficacy.

Question 7

Classification of drug receptor interactions

• What are (2) outcomes?
• Types of interactions (3)

Answer 7

After a drug binds to a receptor it can either:

1) activate the receptor; or
2) block other ligands from binding to the receptor.

Types:

1) Agonist –a molecule that binds to a receptor and activates it
- Agonists mimic the action of endogenous ligands
2) Antagonists – molecules that bind to a receptor but do not activate it.
3) Partial Agonists – molecules that bind to the receptor but have minimal ability to activate it.

Question 8

T/F
Since agonists are molecules that activate receptors, endogenous molecules that activate receptors are considered agonists.

Answer 8

True

- Some of these include neurotransmitters and hormones.

Question 9

What do agonist drugs mimic?

Answer 9

The action of the body’s endogenous molecules

Question 10

T/F
Agonists can be thought of as having both affinity AND intrinsic activity since they are able to bind and activate a receptor.

Answer 10

True

Question 11

Do agonists always increase physiological responses?

Answer 11

Not always

- Agonists may cause either increased or decreased physiological response depending on which receptor is activated.

Question 12

Can agonists cause different effects?

Answer 12

Some agonists can bind to different receptors (remember specificity) and therefore may cause different effects depending on the dose.
- A good example of this is dopamine, an endogenous neurotransmitter that we also give as a drug.

Question 13

What is an antagonist?

Answer 13

Antagonists bind to receptors but do not activate them.

Question 14

T/F

Antagonists can be thought of as having affinity and intrinsic activity.

Answer 14

False

- Antagonists can be thought of as having affinity BUT NO intrinsic activity.

Question 15

How do antagonists generate their effect?

Answer 15

Antagonists generate their effect by preventing the binding of endogenous molecules and other agonist drugs.

Question 16

• Would an antagonist do anything if there was no agonist present?

Answer 16

NO!

- The pharmacological effect of an antagonist is dependent on the presence of an agonist.

Question 17

T/F

The activity of antagonists can be used to treat drug overdose.

Answer 17

True

Question 18

What type of drug is a beta blocker?

- Action?

Answer 18

Antagonist

- Block the binding of endogenous epinephrine to beta-1 receptors in the heart, slows beating of heart

Question 19

What type of drug are antihistamines?

- Action?

Answer 19

Antagonist

- Block the binding of histamine to H1 histamine receptors in the nasal mucosa, prevents symptoms of allergies

Question 20

What type of drug are gastric acid reducers?

Answer 20

Antagonist

- Block the binding of histamine H2 histamine receptors in the gut, decreases gastric acid secretions

Question 21

What type of drug are opioid receptor blockers?

Answer 21

Antagonist

- Block the binding of opioids to opiate receptors, useful for treating opiate overdose

Question 22

What are 3 types of antagonists?

Answer 22

1) Competitive: Binding occurs at the same site as the agonist and is reversible.
2) Irreversible: Binding occurs at the same site as the agonist but is irreversible.
3) Allosteric: Binding occurs at a different site than the agonist.

Question 23

Competitive antagonists:

• What do they compete with?
• Reversible?
• Equal affinity… which occupies binding site?
• What can the effect be overcome by?

Answer 23

• Compete for binding with an agonist at the same binding site.
• Binding is reversible.
  •- f the antagonist and agonist have equal affinity, the one with the highest concentration will occupy the binding site.
• Because the binding is reversible, the effect of a competitive antagonist can be overcome by increasing the concentration of the agonist.

Question 24

Irreversible antagonists:

• Binds to?
• Reversible?
• Intensity depends on?
• Effects?
• Time?
• Use?

Answer 24

• Irreversible antagonists bind to the same receptor site as the agonist.
• Binding is irreversible and therefore non-competitive.
• Remember that the intensity of response depends on the agonist binding to the receptor. If the antagonist permanently blocks receptor sites, it effectively decreases the maximal response the agonist may have.
• The effects of irreversible antagonists cannot be overcome by increasing the dose of agonist.
• Does this mean the effects last forever? NO! Our body is constantly degrading old receptors and making new ones. The effect of irreversible antagonists lasts until the receptor is replaced.
• Because the agents are irreversible in nature they are very seldom used in therapeutics.

Question 25

Allosteric Antagonists:

• Where do they bind?
• What does it do?
• Reversible?
• Competitive?
• Effects?
• Result?

Answer 25

• Allosteric antagonists bind to a different site on the receptor than the agonist does.
• Binding of the allosteric antagonist changes the conformation of the receptor so the agonist is no longer able to bind.
• The binding of an allosteric antagonist is reversible but not competitive.
• The binding is non-competitive because the agonist and allosteric inhibitor bind to different sites on the receptor.
• Similar to irreversible antagonists, the effects of allosteric antagonists cannot be overcome by increasing the dose of agonist.
• Allosteric antagonists effectively decrease the maximal response that the agonist may elicit.

Question 26

What are partial agonists?

Answer 26

Partial agonists are agonists that have only minimal or moderate intrinsic activity

Question 27

The maximal efficacy that a partial agonist can produce is…

Answer 27

… less than that of a full agonist.

Question 28

Partial agonists are also able to act as antagonists. How is this possible?

Answer 28

Remember that a partial agonist has only minimal or moderate activity to activate a receptor.
- Therefore binding of a partial agonist will cause minimal or moderate activation of the receptor but will also block the binding of a full agonist.

Question 29

T/F

The number of receptors on the cell surface is constant and can change with exposure to drugs.

Answer 29

False

- The number of receptors on the cell surface is not constant and can change with exposure to drugs.

Question 30

T/F

- For most drugs, their action depends on the receptor being present on the cell surface

Answer 30

True

Exception: intracellular receptors/transcription factors which are normally found inside the cell

Question 31

What is drug tolerance?

Answer 31

When patients are continually exposed to agonists, the response to the agonist may decrease. - This is known as tolerance.

Question 32

Describe the 3 types of drug tolerance:

Answer 32

1) Desensitization – Continuous exposure to an agonist can cause receptor desensitization.
- In receptor desensitization, the receptor is internalized into the cell or destroyed.
- The net effect is a decrease in cell surface receptor expression and decreased drug effects.

2) Metabolic Tolerance – Continuous exposure to some drugs results in the induction of drug metabolizing enzymes.
- Induction of drug metabolizing enzymes may cause a decrease in the plasma concentration of the drug

3) Tachyphylaxis – A rapid decrease in the response to a drug.
- Some drugs require a drug free period between administrations to prevent rapidly developing tolerance.

Question 33

T/F

Continuous exposure to an antagonist has the opposite effect of tolerance.

Answer 33

True

In this case the cell is said to become hypersensitive or supersensitive.

• This occurs because the cell synthesizes more receptors.
• Therefore there are a greater number of receptors at the cell surface and the response increases.