Lecture 3: Pharmacodynamics Flashcards
(39 cards)
1
Q
Provide examples of enzyme inhibitors and their targets
A
- Aspirin: blocks cyclooxygenase 1 (COX1)
- Physostigmine: blocks cholinesterase.
2
Q
What is an example of an enzyme false substrate, and how does it work?
A
- Methyldopa
- It is converted to adrenaline and released from nerve terminals.
3
Q
Give examples of receptor activators (agonists) and receptor blockers (antagonists)
A
- Agonists: adrenaline and morphine
- Antagonist: tubocurarine
4
Q
Name a type of drugs that acts as ion channel blockers.
A
Local anesthetics
5
Q
Provide examples of drugs that act as ion channel modulators.
A
Diazepam and general anesthetics
6
Q
What is an example of a neurotransmitter uptake blocker?
A
Prozac
7
Q
What are receptors?
A
- 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
8
Q
What are the 4 types of receptors?
A
- Ionotropic: ligand gated ion channels
- GPCR: metabotropic
- Kinase-linked receptors
- Nuclear receptors: receptors linked to gene transcription
9
Q
Describe an agonist’s mechanism of action
A
- Drug binds to receptor
- Forms AR complex
- Causes conformational change in receptor protein
- Leading to response
- AR* = receptor in activated form
10
Q
How can agonist’s response be measured experimentally?
A
- 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
11
Q
Describe how a response is recorded in guinea pig ileum during an experiment.
A
- 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.
12
Q
What does EC50 represent in the context of concentration-response curves?
A
- 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.
13
Q
Why is a log concentration scale used in concentration-response curves?
A
- 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.
14
Q
Why is there a maximum response for the drug?
A
- 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
15
Q
Affinity
A
How well a drug binds to a receptor
16
Q
Efficacy
A
Measure of response once a drug is bound to a receptor
17
Q
Potency
A
Affinity + efficacy
18
Q
What does Kd tell us?
A
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.
19
Q
How does the Kd value relate to the affinity of binding?
A
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.
20
Q
What is the significance of the Kd value for a good agonist?
A
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.
21
Q
How can knowledge of the Kd value be useful in experimental design?
A
- 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.
22
Q
How do you calculate the proportion (P) of receptors occupied?
A
P = [Drug]/(Kd+[D])
23
Q
Why can’t ligand affinity be measured?
A
It involves a combination of affinity and efficacy
24
Q
What is the significance of removing nonspecific binding (NSB) in radioligand binding assays?
A
- 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.
25
Why is a large amount of cold (non-radioactive) ligand added to outcompete the radioactive ligand in binding assays?
- 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.
26
How can the concentration of bound ligand be calculated?
- [bound] = Bmax Xa / (Xa + Kd)
- Xa = concentration of ligand
- Bmax = total number of binding sites in prep (pmol/mg protein)
27
What is receptor desensitization?
- 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.
28
How does receptor desensitization occur?
- 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.
29
What is tachyphylaxis?
- 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.
30
How does tachyphylaxis differ from receptor desensitization?
- 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.
31
Describe some clinical use for agonists
- 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
32
Clinical use of partial agonists
- In theory
- Reduce over-activity but not block basal activity
- Buprenorphine (temgesic)
- Less abuse liability, dysphoria
33
What are partial β-antagonists?
- 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.
34
What is the significance of partial beta antagonists in hypertensive patients with bradycardia?
- 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.
35
Why are partial beta antagonists not used for stable angina or arrhythmias?
- Partial agonist effect
- They may not provide sufficient blockade of beta-adrenergic receptors to effectively manage these conditions
36
How do partial β-antagonists affect lipid and carbohydrate metabolism?
- 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
37
How are G-protein receptors typically active in the absence of a ligand?
- 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.
38
What is the role of inverse agonists in relation to constitutive activity of G-protein receptors?
- 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.
39
How do many antagonists function in the context of constitutive activity of G-protein receptors?
- 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.
