10 - Pharmacodynamics

Question 1

What determines a drugs action?

Answer 1

Question 2

How do you work out the molarity (concentration)?

Answer 2

Question 3

How do you get from M to mM to um to nm to pm?

Answer 3

Question 4

Why is it important to conside drug concentrations in molarity?

Answer 4

Two drugs of the same weight, e.g 100mg, will have a different concentration as they have different molecular weights

1 mole = 6 x 10²³ molecules

Question 5

How do drugs bind to receptor?

Answer 5

Reversibly

Question 6

What does a drug have to have in order to bind to a receptor and cause a response?

Answer 6

Affinity + efficacy

(efficacy is intrinsic efficacy and tissue-dependent factors)

Question 7

Define the following terms:

• Intrinsic efficacy
• Efficacy

Answer 7

1. Can cause a conformational change in the receptor to activate it
2. A measurable response

Question 8

What are the characteristics of an agonist and antagonist?

Answer 8

Question 9

Why might a drug have affinity and intrinsic efficacy but not cause a response?

Answer 9

NO EFFICACY, tissue dependent factors

Question 10

What is the difference between clinical efficacy and pharmacological efficacy?

Answer 10

• Clinical is how well a treatment succeeds in it’s aim.
• Pharmacology a drug could have no efficacy, as an antagonist, but could still have clinical efficacy because it treats a disease

Question 11

How do you measure the binding of ligands to receptors?

Answer 11

Incubate radioligands and receptors. Separate bound and free ligands by filtration

Question 12

Draw a concentration-binding curve with labels?

Answer 12

Remember on logs, -11 is smaller than -7

Question 13

Draw a concentration-response curve with labels.

Answer 13

Question 14

Define the following terms:

• Kd
• Emax
• Bmax
• EC₅₀

Answer 14

- Kd = the concentration of ligand that occupies 50% of receptors. reciprocal measure of affinity

- Emax = Maximum response

- Bmax = Maximum binding capacity

- EC₅₀ = Concentration of ligand that causes 50% of the maximal response. Reciprocal measure of potency,

Question 15

If a drug has a high potency what does this mean?

Answer 15

• Has high affinity, has low EC₅₀ therefore a high intrinsic efficacy, and cell/tissue-specific components
• Higher potency = lower dose

Question 16

What is the difference between concentration and dose of a drug?

Answer 16

Concentration = concentration of ligand/drug at receptor is known

Dose = concentration of ligand/drug at receptor is unknown

Question 17

What is asthma treatment an example of?

Answer 17

• Functional antagonism
• Selective not specific

Question 18

What are the two main drugs for asthma treatment and how do they work?

Answer 18

Question 19

What can be a tissue-dependent factor that affects efficacy?

Answer 19

Number of receptors on cell

Question 20

How do you measure affinity and potency?

Answer 20

Affinity = K_d

Potency = EC₅₀

Question 21

What does a response binding curve graph look like for a 100% binding and no spare receptors?

Answer 21

Question 22

Why might there be 100% response at less than 100% binding?

Answer 22

Spare receptors

Question 23

Why do spare receptors exist?

Answer 23

• Usually in catalytic receptors, e.g tyrosine kinase
• Increase sensitivity of cells
• Lower concentration of ligand needed for same response with more receptors

1. Amplification of signal so not all receptors have to be stimulated

2. Response limited by post-receptor event

Question 24

What is an example of receptors that dont have 100% binding occupancy but full response?

Answer 24

M3 receptors, 10% occupancy for maximum contraction

Question 25

What is the relationship between receptors and ligands?

Answer 25

When number of receptors increase, potency of drug increases

Question 26

Why do receptor numbers change?

Answer 26

**- Upregulation:** More receptors due to low activity **- Downregulation:** Less receptors due to overstimulation (taking drugs) Downregulation leads to tolerance and withdrawal symptoms

Question 27

What does the graph of a partial agonist look like?

Answer 27

Question 29

What is a measure of intrinsic activity?

Answer 29

- Maximal response, higher response higher intrinsic activity - Partial agonists have lower intrinsic activity therefore lower efficacy

Question 30

What is the relevance of partial agonists?

Answer 30

- More controlled responses - Act as antagonists when high levels of full agonist - Work in absence of ligand

Question 31

Why does heroin cause death?

Answer 31

Respiratory depression

Question 32

What is the advantage of using buprenorphine over morphine?

Answer 32

Question 33

Why is buprrenorphine used to wean heroin addicts?

Answer 33

- Mixed antagonist - Will bind to receptors over heroin, cause some euphoria but not give full effect as partial agonist so withdrawal symptoms

Question 34

What are the three types of antagonism in drugs?

Answer 34

- Reversible Competitive - Irreversible Competitive - Non-competitive antagonism

Question 35

What is potency?

Answer 35

Potency = Affinity + Efficacy

Question 36

Why can a partial agonist cause a full response\>

Answer 36

Spare receptors

Question 37

What do graphs look like for a reversible antagonist?

Answer 37

Reversible competitive can be overcome by increasing the concentration of agonist

Question 38

How is opioid-mediated respiratory depression reversed?

Answer 38

Naloxone High affinity, competitive antagonist, will compete with heroin and opiods for receptors

Question 39

What happens with an irreversible competitive antagonist?

Answer 39

Irreversible binding

Question 40

What is an example of irreversible competitive antagonism and why is it advantageous?

Answer 40

Lower concentration needed than reversible competitive antagonist

Question 41

What is a treatment for thrombosis?

Answer 41

Clopidogrel (Prodrug - irreversible competitive agonist)

Question 42

What is non-competitive antagonist and an example?

Answer 42

- Binds to allosteric site (not orthosteric where ligand binds) and causes a conformational change in the receptor, changing it's efficacy or affinity - Similar to irreversible competitive antagonist - Maraviroc (negative allosteric modulator of chemokine receptor 5 where HIV enters cells)

Question 43

What type of drug molecule are each of these and label them in order of their efficacy and potency

Answer 43

Question 44

How does irreversible competitive antagonism work?

Answer 44

Covalent bonding of the antagonist to the receptors orthosteric site

Question 45

Why might there be 100% maximum response but only 40% binding?

Answer 45

Signal amplification and Spare receptors