S9-10) Pharmacodynamics Flashcards
How do drugs exert their effects?
Drugs exert their effects by binding to a target (mainly proteins)
The concentration of drug molecules around receptors is critical in determining drug action.
Account for the measure of concentration
Concentration is measured in terms of molarity
What are the prefixes for the following:
100
10-3
10-6
10-9
10-12
- Molar (M): 100
- Millimolar (mM): 10-3
- Micromolar (μM): 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 are the two effects of most drugs?
- Agonist: activate a receptor
- Antagonist: block the binding of an endogenous agonist
How do drugs act on receptors?
- 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
After the receptor is activated, things must occur to evoke a response.
What is the concept that governs this?
- Efficacy is the ability of a ligand to evoke a response
- Activation is governed by intrinsic efficacy (agonists only)
Compare and contrast efficacy in agonists and antagonists
- Agonists have affinity, intrinsic efficacy and efficacy
- Antagonists have affinity only (no efficacy)
Binding is how we quantify drug-receptor interaction.
In light of this, what is Kd?
- Kd = dissociation constant
- Kd 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
Which of the following drugs have a higher affinity?
- Drug A: Kd = 10-9
- Drug B: Kd = 10-3
- Drug A as a lower concentration is required to occupy 50% of receptors
- For Kd, the lower the value, the higher the affinity (reciprocal)
Why is affinity important for ligands?
High affinity allows binding at low concentrations of hormones, neurotransmitters and drugs
What form of regression does drug concentration follow?
Logarithmic
The terms concentration and dose are often used interchangeably.
Distinguish between them
- Concentration is the known amount of drug at site of action
- Dose is the amount of drug at site of action is unknown
What is potency?
- 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
How do cell/tissue dependent factors such as receptor number influence agonist potency?
- ‘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
What does the presence of spare receptors indicate?
Spare receptors means < 100% occupancy = 100% response
Spare receptors allow for amplification is a signal transduction pathway.
In terms of GPCRs, illustrate this.
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
What is the effect of changing receptor number?
Changing receptor number changes agonist potency and can affect the maximal response
What are full and partial agonists?
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
In terms of EC50, compare and contrast partial and full agonists
- Full agonist: EC50 < Kd
- Partial agonist: EC50 = Kd
Describe the properties of a partial agonist
- Lower intrinsic activity
- Lower efficacy
- Insufficient intrinsic efficacy for maximal response
What is the clinical relevance of partial agonists?
- 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
How can a partial agonist become a full agonist?
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)
Outline reversible competitive antagonism
In reversible competitive antagonism, antagonists compete with agonists for binding:
- Inhibition is surmountable
- Greater [antagonist] = greater inhibition
What is IC50?
- IC50 is the concentration of antagonist giving 50% inhibition
- It is the index of antagonist potency and is determined by [agonist]
Outline irreversible competitive antagonism
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
Outline non-competitive antagonism
In non-competitive antagonism, the antagonist binds to allosteric site:
- No competition for binding site
- Thus, negative allosteric modulation
- decrease Emax with increasing concs
affinity and efficacy
binding is goverened by affinity but the receptor activation depends of efficiacy
why may some organs express more target proteins that required to produce a max measured therapeutic response
- they have spare receptors // receptor reserve
