S9-10) Pharmacodynamics

Question 1

How do drugs exert their effects?

Answer 1

Drugs exert their effects by binding to a target (mainly proteins)

Question 2

The concentration of drug molecules around receptors is critical in determining drug action.

Account for the measure of concentration

Answer 2

Concentration is measured in terms of molarity

Question 3

What are the prefixes for the following:

10⁰

10^-3

10^-6

10^-9

10^-12

Answer 3

• Molar (M): 10⁰
• Millimolar (mM): 10^-3
• Micromolar (μM): 10^-6
• Nanomolar (nM): 10^-9
• Picomolar (pM): 10^-12

Question 4

Why do most drugs bind reversibly to receptors?

Answer 4

Binding is governed by association and dissociation

Question 5

What are the two effects of most drugs?

Answer 5

• Agonist: activate a receptor
• Antagonist: block the binding of an endogenous agonist

Question 6

How do drugs act on receptors?

Answer 6

• They must bind to the receptor
• They must have an affinity for the receptor in order to bind
• receptor must have a conformational change in order to evoke a response = intrinisc efficacy

Question 7

After the receptor is activated, things must occur to evoke a response.

What is the concept that governs this?

Answer 7

• Efficacy is the ability of a ligand to evoke a response
• Activation is governed by intrinsic efficacy (agonists only)

Question 8

Compare and contrast efficacy in agonists and antagonists

Answer 8

• Agonists have affinity, intrinsic efficacy and efficacy
• Antagonists have affinity only (no efficacy)

Question 9

Binding is how we quantify drug-receptor interaction.

In light of this, what is K_d?

Answer 9

• K_d = dissociation constant
• K_d is the concentration of ligand (drug) required to occupy 50% of available receptors
• measures the strenght between the ligand and target // affinity
• lower the Kd value the higher the affinity

Question 10

Which of the following drugs have a higher affinity?

• Drug A: K_d = 10^-9
• Drug B: K_d = 10^-3

Answer 10

• Drug A as a lower concentration is required to occupy 50% of receptors
• For K_d, the lower the value, the higher the affinity (reciprocal)

Question 11

Why is affinity important for ligands?

Answer 11

High affinity allows binding at low concentrations of hormones, neurotransmitters and drugs

Question 12

What form of regression does drug concentration follow?

Answer 12

Logarithmic

Question 13

The terms concentration and dose are often used interchangeably.

Distinguish between them

Answer 13

• Concentration is the known amount of drug at site of action
• Dose is the amount of drug at site of action is unknown

Question 14

What is potency?

Answer 14

• Potency (EC₅₀) is the effective concentration giving 50% of the maximal response
• It depends on both affinity and intrinsic efficacy plus cell/tissue specific components
• does the drug have bith affiity and efficacy

Question 15

How do cell/tissue dependent factors such as receptor number influence agonist potency?

Answer 15

• ‘The greater the receptors = the greater the response’ is not always true
• Response is often controlled/limited by other factors
• E.g. a muscle can only contract so much, a gland can only secrete so much*

This revolves around the concept of spare receptors

Question 16

What does the presence of spare receptors indicate?

Answer 16

Spare receptors means < 100% occupancy = 100% response

Question 17

Spare receptors allow for amplification is a signal transduction pathway.

In terms of GPCRs, illustrate this.

Answer 17

A few adrenaline molecules can cause a massive cellular response:

• The β-adrenoceptor → Gs protein → adenylyl cyclase part of the cascade causes relatively little amplification
• Nevertheless, activation of adenylyl cyclase generates many molecules of cyclic AMP which then activate the enzyme PKA

Question 18

Why are there spare receptors?

Answer 18

• Spare receptors increase sensitvity
• It allows responses at low concentrations of agonist
• more opportunity for for binding and inducing a theraputic effect
• not all the target protein binding sites need to be occupied to get a maximal response

Question 19

What is the effect of changing receptor number?

Answer 19

Changing receptor number changes agonist potency and can affect the maximal response

Question 20

Discuss the relevance of altered receptor number

Answer 20

Receptor numbers are not fixed:

• Tend to increase with low activity (up-regulation)
• Tend to decrease with high activity (down-regulation)

Question 21

What are full and partial agonists?

Answer 21

Partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist they exhibit a lesser potency

Question 22

In terms of EC₅₀, compare and contrast partial and full agonists

Answer 22

• Full agonist: EC₅₀ < K_d

- Partial agonist: EC₅₀ = K_d

Question 23

Describe the properties of a partial agonist

Answer 23

• Lower intrinsic activity
• Lower efficacy
• Insufficient intrinsic efficacy for maximal response

Question 24

What is the clinical relevance of partial agonists?

Answer 24

• Allows for a more controlled response e.g. adequate pain control
• Works in the absence/low levels of endogenous ligand
• Acts as antagonist if high levels of full agonist

Question 25

How can a partial agonist become a full agonist?

Answer 25

**Increasing receptor number** – there is still low intrinsic efficacy at each receptor, but enough receptors to produce a full response - it can also act as an **antagonist for the full receptor** as it does not activate the full response = **withdrawls** (sometimes they have a higher affinity for the receptor)

Question 26

Antagonists block the effects of agonists. What are the three types of antagonism?

Answer 26

- Reversible competitive antagonism - Irreversible competitive antagonism - Non-competitive antagonism

Question 27

Outline reversible competitive antagonism

Answer 27

**In reversible competitive antagonism,** antagonists compete with agonists for binding: - Inhibition is surmountable - Greater [antagonist] = greater inhibition

Question 28

What is IC₅₀?

Answer 28

**- IC₅₀** is the concentration of antagonist giving 50% inhibition - It is the index of antagonist potency and is determined by [agonist]

Question 29

Outline irreversible competitive antagonism

Answer 29

In **irreversible competitive antagonism,** the antagonist dissociates slowly or not at all: - Parallel shift to the right as spare receptors are filled by antagonist - Maximal response suppressed at [higher] due to insufficient receptors for full response - Non-surmountable - cause a depression in the Emax

Question 30

Outline non-competitive antagonism

Answer 30

**In non-competitive antagonism**, the antagonist binds to allosteric site: - No competition for binding site - Thus, negative allosteric modulation - decrease Emax with increasing concs

Question 31

definition of a ligand

Answer 31

molecule that binds specifically to a receptor to form a ligand - receptor complex

Question 32

agonist / antagonist

Answer 32

agonists - produce intended biological response = **affinity and efficacy** antagonists - bind to a receptor but dont produce an effect (they inhibit) = **affinity but no efficacy**

Question 33

affinity and efficacy

Answer 33

**binding** is goverened by **affinity** but the **receptor activation** depends of **efficiacy**

Question 34

cell/ tissue dependent response

Answer 34

sequential steps driven by og signal from the ligand binding with its target that leads to the finak steps of a measured therapeutic response

Question 35

clinical efficacy

Answer 35

measures how well a treatment succeeds in acheiving its theraputic aim

Question 36

drug - receptor interactions

Answer 36

- radioligand (radioactive version of thr ligand) - the more binding of the receptors the karger the measurable signal

Question 37

concentration - response curves dose - response curves

Answer 37

1) precise conc of of a drug / ligand can be manipulated and a specific aspect of the response can be measured 2) dise - response curves - measuring responses in a whole animal or human subject eg tumour reduction

Question 38

why may some organs express more target proteins that required to produce a max measured therapeutic response

Answer 38

- they have spare receptors // receptor reserve

Question 39

decribe the effects of different activity levels

Answer 39

high - reduce number of target proteins low - increase expression of target proteins