Module 8 - Drug Receptor Interactions

Question 1

what are the 2 receptor theories that we use to describe drug-receptor interactions

Answer 1

1. simple occupancy theory
2. modified occupancy theory

Question 2

simple occupancy theory states what?

Answer 2

1. 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

Modified occupancy theory states?

Answer 3

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).

• 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

Modified Occupancy Theory – Affinity

Answer 4

• affinity is the attraction that a drug has for it’s receptor

Question 5

Drugs with High affinity

Answer 5

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

Drugs with high affinity for their receptor have high potency

Question 6

Drugs with Low affinity

Answer 6

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

drugs with low affinity for their receptor have low potency.

Question 7

Modified Occupancy Theory – Intrinsic Activity

Answer 7

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

Question 8

Drugs with high intrinsic activity

Answer 8

Cause intense receptor activation
- drugs with high intrinsic activity have high maximal efficacy

Question 9

Drugs with low intrinsic activity

Answer 9

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

Question 10

Agonist definition

Answer 10

a molecule that binds to a receptor and activates it. Agonists mimic the action of endogenous ligands

Question 11

Antagonist definition

Answer 11

Molecules that bind to a receptor but do not activate it.

Question 12

Partial Agonists definition

Answer 12

Molecules that bind to the receptor but have minimal ability to activate it.

Question 13

What do agonists do?

Answer 13

Drugs that we design as agonists are often targeted to mimic the action of the body’s endogenous molecules.
- both affinity AND intrinsic activity since they are able to bind and activate a receptor
- 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 14

Physiological response of an agonist

Answer 14

does not always increase a physiological response (i.e. heart rate). Agonists may cause either increased or decreased physiological response depending on which receptor is activated

Question 15

what do antagonists do

Answer 15

• bind to receptors but do NOT activate them
• have affinity BUT NO intrinsic activity
• profound pharmacological effects
• 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 agonist

Question 17

Examples of Antagonist drugs

Answer 17

Beta blockers - block binding of endogenous epinephrine to beta 1 receptors in the heart = slows heart

Antihistamines - block binding of histamine to H1 receptors in nasal mucosa = prevents allergy symptoms

Gastric Acid Reducers - block binding of histamine H2 receptors in the gut = decreased gastric acid secretion

Opioid Receptor Blockers - block binding of opioids to opiate receptors - treats overdose

Question 18

What treats overdose?

Answer 18

antagonist

Question 19

types of antagonists

Answer 19

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

Question 20

competitive antagonist

Answer 20

• compete for binding with agonist at the same binding site
• is reversible
• If 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 21

irreversible antagonist

Answer 21

• bind to the same receptor site as the agonist
• binding is irreversible (non-competitive)
• The effects of irreversible antagonists cannot be overcome by increasing the dose of agonist.
• Because the agents are irreversible in nature they are very seldom used in therapeutics

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.

Question 22

Do the effects of irreversible antagonists last forever?

Answer 22

NO! Our body is constantly degrading old receptors and making new ones. The effect of irreversible antagonists lasts until the receptor is replaced.

Question 23

Allosteric Antagonists

Answer 23

• 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 24

Partial Agonist

Answer 24

• are agonists that have only minimal or moderate intrinsic activity.
• The maximal efficacy that a partial agonist can produce is less than that of a full agonist.
• Partial agonists are also able to act as antagonists

Question 25

How can partial agonists also act as antagonists

Answer 25

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 26

Regulation of cell surface receptor expression

Answer 26

• The number of receptors on the cell surface is not constant and can change with exposure to drugs.
• For most drugs, their action depends on the receptor being present on the cell surface (exception: intracellular receptors/transcription factors, which are normally found inside the cell).

Question 27

drug tolerance

Answer 27

when patients are continually exposed to agonists, the response to the agonist may decrease. this is known as tolerance

Question 28

3 types of drug tolerance

Answer 28

1. desensitization
2. metabolic tolerance
3. tachyphylaxis

Question 29

Desensitization

Answer 29

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.

Question 30

Metabolic tolerance

Answer 30

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.

Question 31

Tachyphylaxis

Answer 31

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

Question 32

what is receptor upregulation

Answer 32

• continuous exposure to an antagonist has the opposite effect of tolerance.
• In this case, the cell is said to become hypersensitive or super sensitive.
• This occurs because the cell synthesizes more receptors.
• Therefore, there are a greater number of receptors at the cell surface and the response increases