10 - Pharmacodynamics Flashcards
What determines a drugs action?
How do you work out the molarity (concentration)?
How do you get from M to mM to um to nm to pm?
Why is it important to conside drug concentrations in molarity?
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
How do drugs bind to receptor?
Reversibly
What does a drug have to have in order to bind to a receptor and cause a response?
Affinity + efficacy
(efficacy is intrinsic efficacy and tissue-dependent factors)
Define the following terms:
- Intrinsic efficacy
- Efficacy
- Can cause a conformational change in the receptor to activate it
- A measurable response
What are the characteristics of an agonist and antagonist?
Why might a drug have affinity and intrinsic efficacy but not cause a response?
NO EFFICACY, tissue dependent factors
What is the difference between clinical efficacy and pharmacological efficacy?
- 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
How do you measure the binding of ligands to receptors?
Incubate radioligands and receptors. Separate bound and free ligands by filtration
Draw a concentration-binding curve with labels?
Remember on logs, -11 is smaller than -7
Draw a concentration-response curve with labels.
Define the following terms:
- Kd
- Emax
- Bmax
- EC50
- 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,
If a drug has a high potency what does this mean?
- Has high affinity, has low EC50 therefore a high intrinsic efficacy, and cell/tissue-specific components
- Higher potency = lower dose
What is the difference between concentration and dose of a drug?
Concentration = concentration of ligand/drug at receptor is known
Dose = concentration of ligand/drug at receptor is unknown
What is asthma treatment an example of?
- Functional antagonism
- Selective not specific
What are the two main drugs for asthma treatment and how do they work?
What can be a tissue-dependent factor that affects efficacy?
Number of receptors on cell
How do you measure affinity and potency?
Affinity = Kd
Potency = EC50
What does a response binding curve graph look like for a 100% binding and no spare receptors?
Why might there be 100% response at less than 100% binding?
Spare receptors
Why do spare receptors exist?
- 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
What is an example of receptors that dont have 100% binding occupancy but full response?
M3 receptors, 10% occupancy for maximum contraction
What is the relationship between receptors and ligands?
When number of receptors increase, potency of drug increases
Why do receptor numbers change?
- Upregulation: More receptors due to low activity
- Downregulation: Less receptors due to overstimulation (taking drugs)
Downregulation leads to tolerance and withdrawal symptoms
What does the graph of a partial agonist look like?
What is a measure of intrinsic activity?
- Maximal response, higher response higher intrinsic activity
- Partial agonists have lower intrinsic activity therefore lower efficacy
What is the relevance of partial agonists?
- More controlled responses
- Act as antagonists when high levels of full agonist
- Work in absence of ligand
Why does heroin cause death?
Respiratory depression
What is the advantage of using buprenorphine over morphine?
Why is buprrenorphine used to wean heroin addicts?
- Mixed antagonist
- Will bind to receptors over heroin, cause some euphoria but not give full effect as partial agonist so withdrawal symptoms
What are the three types of antagonism in drugs?
- Reversible Competitive
- Irreversible Competitive
- Non-competitive antagonism
What is potency?
Potency = Affinity + Efficacy
Why can a partial agonist cause a full response>
Spare receptors
What do graphs look like for a reversible antagonist?
Reversible competitive can be overcome by increasing the concentration of agonist
How is opioid-mediated respiratory depression reversed?
Naloxone
High affinity, competitive antagonist, will compete with heroin and opiods for receptors
What happens with an irreversible competitive antagonist?
Irreversible binding
What is an example of irreversible competitive antagonism and why is it advantageous?
Lower concentration needed than reversible competitive antagonist
What is a treatment for thrombosis?
Clopidogrel
(Prodrug - irreversible competitive agonist)
What is non-competitive antagonist and an example?
- 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)
What type of drug molecule are each of these and label them in order of their efficacy and potency
How does irreversible competitive antagonism work?
Covalent bonding of the antagonist to the receptors orthosteric site
Why might there be 100% maximum response but only 40% binding?
Signal amplification and Spare receptors
