ICPP 9 Pharmacodynamics Flashcards
Types of targets for drugs
GPCRs
Ion channels
Kinases
Nuclear receptors
Enzymes, transporters, DNA
What are olfactory receptors?
Related to smell and taste
What are orphan receptors?
Potential drug targets
What a body does to the drug is defined as what?
Pharmacokinetics
What a drug does to the body is defined as what?
Pharmacodynamics
What factor is critical in determining drug action and therefore in what concentration drugs need to be considered in?
The concentration of drug molecules around receptors
Molarity
What is a ligand?
Examples
Something that binds to a receptor
e.g. drug, hormones, neurotransmitter
Molarity equation
M = g/L divided by MWt (molecular weight)
Ligand concentration at receptors usually in which range?
Micromolar > nanomolar > picomolar
How do drugs exert their effects?
Binding to a target (mainly proteins)
What are the prefixes for?
10^0
10^-3
10^-6
10^-9
10^-12
Molar M 10^0
Millimolar mM 10^-3
Micromolar uM 10^-6
Nanomolar nM 10^-9
Picomolar pM 10^-12
Why do most drugs bind reversibly to receptors?
Binding is governed by association and dissociation
What is avogadro’s number?
6x10^23
For a ligand to bind to a receptor what must it have?
Affinity
Define affinity
A measure of how tightly a ligand binds to its receptor
What are the two effects of most drugs?
Agonist - activate receptor
Antagonist - block the binding of activating ligands/agonist
Define efficacy
The ability of a ligand to evoke a response
Relationship between affinity and binding
Higher affinity = stronger binding
Lower affinity = weaker binding
What is receptor activation governed by?
Intrinsic efficacy
Compare and contrast efficacy and affinity in agonists and antagonists
Agonists - have affinity, intrinsic efficacy and efficacy
Antagonists - only have affinity (no efficacy)
Define intrinsic efficacy
How good a ligand is at causing a conformational change in its target to produce an active receptor
Agonist efficacy vs intrinsic efficacy
Efficacy - ability of an agonist to elicit a response
Intrinsic efficacy - how good a ligand is at causing a conformational change in its target to produce an active receptor
Why is affinity important for a ligand?
High affinity allows binding at low concentrations of ligands
What is Bmax?
Max binding capacity
What is Kd?
Dissociation constant
Conc. of drug required to occupy 50% of available receptor
What can you derive from a bound vs ligand conc. plot?
Bmax - mac binding capacity
Kd - conc. of drug needed to occupy 50% of available receptors
Relationship between Kd and affinity
Low Kd = higher affinity
Reciprocal relationship
Which drug has a higher affinity and why?
Drug A: Kd = 10^-9
Drug B: Kd = 10^-3
Drug A
lower Kd = higher affinity
Lower conc is needed to occupy 50% of receptors
What drug is used to treat morphine/heroin overdose?
How does this drug act?
naloxone
High affinity antagonist for u-opioid receptors
Out competes opioids
What is naloxone used for?
How does it work?
Treat morphine/heroin overdose
High affinity antagonist for u-opioid receptors
Out competes opioids
What is the common plot used for drug concentrations vs binding graphs?
Common shape
Semi-logarithmic
Drug on x-axis if logarithmic
Sigmoidal shape
How can we measure receptor response to agonist?
What can be derived from the plot?
Concentration-response curve
Emax - effect max
EC50 - effective concentration giving 50% of maximal response (drug potency)
Difference between concentration and dose
Concentration - known amount of drug at site of action
Dose - amount of drug at site of action is unknown due to excretion or metabolism
What is potency?
EC50
Effective conc. giving 50% of the maximal response
What does potency depend on?
Affinity
Intrinsic efficacy
Cell/tissue specific components
Relationship between EC50 and drug potency
Low EC50 = high drug potency
Less conc. needed to give 50% of maximal response
What do spare receptors indicate?
<100% occupancy = 100% response
Why do we have spare receptors?
Increase sensitivity/potency
Allows responses at low concentrations of agonist
What is a partial agonist?
Ligand that evoke responses lower than Emax
Lower intrinsic efficacy
Outline the relevance of altered receptor number
Receptor numbers are not fixed:
- tend to increase with low activity (up-regulation)
- tend to decrease with high activity (down-regulation)
In terms of EC50, compare and contrast partial and full antagonists
Full - EC50 < Kd
Partial EC50 = Kd
How can partial agonists provide antagonism?
Can inhibit the effect of another drug
Stops drug from binding
Describe the properties of a partial agonist
Lower intrinsic activity
Lower efficacy
Insufficient intrinsic efficacy for maximal response
No spare receptors
Clinical relevance of partial agonists
- Allow for more controlled response
- Works in the absence of endogenous ligand
- Acts as antagonist if high levels of full agonist
What are the 3 types of receptor antagonism?
- reversible competitive antagonism
- irreversible competitive antagonism
- non-competitive antagonism
Outline reversible competitive antagonism
- Same binding site as lignad
- can be overcome as antagonist dissociates
- conc-response curve moves right
- Emax achieved
How can a partial agonist become a full agonist?
Increasing receptor number to produce a full response
What is IC50?
Conc. of antagonist that gives 50% inhibition
Outline irreversible competitive antagonism
- bind to same site as ligand
- antagonists dissociate very slowly or not at all - cant be overcome e
- conc-response curve moves right and down
Concentration response curve in reversible competitive antagonism
Moves right
Concentration response curve in irreversible competitive antagonism
Moves right and down
Outline non-competitive antagonism
Binds to allosteric site + causes change in shape of active site/receptor
Apparent volume distribution equation
Vd = dose/plasma conc
