Lecture 3: Pharmacodynamics

Question 1

Provide examples of enzyme inhibitors and their targets

Answer 1

• Aspirin: blocks cyclooxygenase 1 (COX1)
• Physostigmine: blocks cholinesterase.

Question 2

What is an example of an enzyme false substrate, and how does it work?

Answer 2

• Methyldopa
  
  • It is converted to adrenaline and released from nerve terminals.

Question 3

Give examples of receptor activators (agonists) and receptor blockers (antagonists)

Answer 3

• Agonists: adrenaline and morphine
• Antagonist: tubocurarine

Question 4

Name a type of drugs that acts as ion channel blockers.

Answer 4

Local anesthetics

Question 5

Provide examples of drugs that act as ion channel modulators.

Answer 5

Diazepam and general anesthetics

Question 6

What is an example of a neurotransmitter uptake blocker?

Answer 6

Prozac

Question 7

What are receptors?

Answer 7

• Proteins in the membrane
• Allow EC signal to be transducent to IC signal to produce cellular response
• Proteins bind to neurotransmitters, hormones
• Can be used as drug targets

Question 8

What are the 4 types of receptors?

Answer 8

• Ionotropic: ligand gated ion channels
• GPCR: metabotropic
• Kinase-linked receptors
• Nuclear receptors: receptors linked to gene transcription

Question 9

Describe an agonist’s mechanism of action

Answer 9

• Drug binds to receptor
  
  • Forms AR complex
  • Causes conformational change in receptor protein
  • Leading to response
  • AR* = receptor in activated form

Question 10

How can agonist’s response be measured experimentally?

Answer 10

• Muscle contraction
• Membrane potential
• Electrical current/change in RMP via electrophysiology
• Second messenger (cAMP, IP3)
  
  • 4sklin increases Camp production
• Transmitter release thru electrophysiology
• Change in heart rate, BP in humans via ECG

Question 11

Describe how a response is recorded in guinea pig ileum during an experiment.

Answer 11

• Acetylcholine is typically used as an agonist.
• Acetylcholine binds to receptors in the guinea pig ileum → contracts
• Contraction is measured using a transducer, which converts the mechanical movement into an electrical signal.
• The electrical signal is then fed into a computer for analysis.
• Concentration-response curve generated from the experiment typically shows a sigmoidal shape, with individual data points representing different concentrations of the agonist.
  
  • The curve provides information about the maximum response elicited by the agonist and is a standard method for assessing agonist activity.

Question 12

What does EC50 represent in the context of concentration-response curves?

Answer 12

• EC50 (effective concentration that gives 50% of the maximum response) is a measure of potency for an agonist
• It represents the concentration of the agonist required to produce a response halfway between the baseline and maximum response.

Question 13

Why is a log concentration scale used in concentration-response curves?

Answer 13

• Allows for a wide range of concentrations to be plotted on a manageable scale
• If a linear scale were used, data points would be clustered at lower concentrations and spread too far apart at higher concentrations, making the curve difficult to interpret.
• Using a log scale ensures that data points are evenly distributed across the curve, providing a clearer representation of the relationship between concentration and response.

Question 14

Why is there a maximum response for the drug?

Answer 14

• Finite number of receptors: all occupied
  
  • Response is directly proportional to the AR complex
• Property of tissue/cell
  
  • Can only contract to a certain degree
  • Can’t keep contracting, can’t keep getting any smaller

Question 15

Affinity

Answer 15

How well a drug binds to a receptor

Question 16

Efficacy

Answer 16

Measure of response once a drug is bound to a receptor

Question 17

Potency

Answer 17

Affinity + efficacy

Question 18

What does Kd tell us?

Answer 18

Kd, or dissociation constant, is a measure of the concentration of a ligand (such as an agonist) required to occupy 50% of the available binding sites (receptors) on a target molecule.

Question 19

How does the Kd value relate to the affinity of binding?

Answer 19

The lower the Kd value, the higher the affinity of the ligand for its target receptor. A lower Kd indicates tighter binding between the ligand and the receptor.

Question 20

What is the significance of the Kd value for a good agonist?

Answer 20

For a good agonist, the Kd value should be low, preferably in the nanomolar range. This indicates strong affinity and efficient binding of the agonist to its receptor.

Question 21

How can knowledge of the Kd value be useful in experimental design?

Answer 21

• Allows researchers to determine the optimal concentration of the agonist to use in experiments
• Ensures that the agonist concentration is sufficient to produce the desired pharmacological effects without exceeding saturation of the receptor binding sites.

Question 22

How do you calculate the proportion (P) of receptors occupied?

Answer 22

P = [Drug]/(Kd+[D])

Question 23

Why can’t ligand affinity be measured?

Answer 23

It involves a combination of affinity and efficacy

Question 24

What is the significance of removing nonspecific binding (NSB) in radioligand binding assays?

Answer 24

• NSB: binding that is not specific to the receptor of interest and may occur in other areas or components of the assay system.
• To accurately assess the specific binding of the radioligand to its target receptors
• Subtracting the NSB from the total binding allows researchers to isolate and quantify the specific binding → more accurate representation of the ligand-receptor interaction.

Question 25

Why is a large amount of cold (non-radioactive) ligand added to outcompete the radioactive ligand in binding assays?

Answer 25

• To saturate and compete for all available binding sites, including nonspecific binding sites.
• Ensures that the radiolabeled ligand is specifically binding to the target receptors, and any remaining binding is considered nonspecific.
• Subtracting the nonspecific binding allows for a more precise determination of specific binding and a more reliable estimation of the ligand’s affinity for the receptors.

Question 26

How can the concentration of bound ligand be calculated?

Answer 26

• [bound] = Bmax Xa / (Xa + Kd)
• Xa = concentration of ligand
• Bmax = total number of binding sites in prep (pmol/mg protein)

Question 27

What is receptor desensitization?

Answer 27

• Decrease in cell or tissue responsiveness to a specific ligand that normally binds to and activates a receptor
• Typically occurs as a result of prolonged or repeated exposure to the ligand, leading to changes in the receptor itself that make it less responsive to the ligand.

Question 28

How does receptor desensitization occur?

Answer 28

• Changes in the receptor (e.g. phosphorylation, internalization, or alterations) in downstream signaling pathways, that reduce its sensitivity to the ligand.
• This process can lead to a decrease in the cellular response to the ligand despite its continued presence.

Question 29

What is tachyphylaxis?

Answer 29

• A rapid tolerance that occurs when a drug’s effectiveness diminishes quickly with repeated administrations within a short time frame.
• It involves a sharp decrease in the drug’s efficacy after just a few doses, even if the doses are separated by a relatively short interval.

Question 30

How does tachyphylaxis differ from receptor desensitization?

Answer 30

• Both involve a decrease in responsiveness to a ligand,
• Tachyphylaxis: rapid and pronounced tolerance to a drug’s effects, often occurring within a short time frame and not necessarily involving changes in the receptor itself.
• Receptor desensitization: occurs over a longer period of exposure to the ligand and involves specific alterations in the receptor that reduce its responsiveness.

Question 31

Describe some clinical use for agonists

Answer 31

• Adrenaline: increase rate n force of heart contraction, anaphylactic shock
• Salbutamol: asthma
• Oxymetazoline: nasal congestion
• Dopamine: increase in heart rate n force of contraction
• Morphine: analgesic for severe pain, opiate receptor agonist

Question 32

Clinical use of partial agonists

Answer 32

• In theory
  
  • Reduce over-activity but not block basal activity
• Buprenorphine (temgesic)
  
  • Less abuse liability, dysphoria

Question 33

What are partial β-antagonists?

Answer 33

• AKA β-blockers with intrinsic sympathomimetic activity (ISA)
• Class of medications that block beta-adrenergic receptors but also have partial agonist activity at these receptors.

Question 34

What is the significance of partial beta antagonists in hypertensive patients with bradycardia?

Answer 34

• Effective in hypertensive patients with moderate bradycardia [cause less pronounced decreases in heart rate compared to other beta-blockers]
• This property helps avoid further lowering of heart rate in patients with bradycardia.

Question 35

Why are partial beta antagonists not used for stable angina or arrhythmias?

Answer 35

• Partial agonist effect
• They may not provide sufficient blockade of beta-adrenergic receptors to effectively manage these conditions

Question 36

How do partial β-antagonists affect lipid and carbohydrate metabolism?

Answer 36

• Minimize disturbances in lipid n carbohydrate metabolism, which are commonly seen w other β-blockers
• E.g. decrease plasma HDL (high density lipoprotein) lvl → preferred option for patients w lipid metabolism concerns

Question 37

How are G-protein receptors typically active in the absence of a ligand?

Answer 37

• G-protein receptors often exhibit constitutive activity, meaning they are active even in the absence of a ligand.
• However, this activity may be too low to have significant physiological effects under normal conditions.

Question 38

What is the role of inverse agonists in relation to constitutive activity of G-protein receptors?

Answer 38

• Inverse agonists are compounds that reduce the constitutive activity of G-protein receptors.
• They essentially inhibit the basal activity of the receptor when no ligand is bound, leading to a decrease in the receptor’s signaling activity.

Question 39

How do many antagonists function in the context of constitutive activity of G-protein receptors?

Answer 39

• It’s important to note that many antagonists of G-protein receptors are actually inverse agonists.
• Traditional antagonists block the effects of agonists without affecting basal receptor activity
• Inverse agonists further reduce the constitutive activity of the receptor, potentially exerting additional therapeutic effects beyond simple blockade.