17. Pharmacodynamics: Receptor Theory Flashcards
What is the equation for molarity?
Molarity = g/L / molecular weight
What range are ligand concentrations at receptors usually in?
Micromolar to picomolar
What are the 2 way drugs can act in?
Block the binding of an endogenous agonist - antagonist
Activate a receptor - agonist
What is affinity?
How well a ligand binds to the receptor
i.e. higher affinity = stronger binding
What is intrinsic efficacy?
Activation of a receptor caused as a response to agonist binding
Why is there no response when an antagonist binds?
No intrinsic efficacy
Only has affinity
Why can agonists stimulate a response?
Have affinity
Have intrinsic efficacy - can activate the receptors
Have efficacy - cause a measurable response
What is clinical efficacy?
An indication of how well a treatment succeeds in achieving its aim
E.g. lowers blood pressure, cure headache
How do you measure binding of ligands?
By binding of a radioactively labelled ligand (radioligand) to cells or membranes prepared from cells
Measure number of ligands bound
What is Bmax?
Maximum binding capacity
What is Kd?
Dissociation constant
Inverses proportional to affinity
Lower the Kd, higher the affinity
Concentration of ligand required to occupy 50% of the available receptors
Why is high affinity good?
It allows binding at low concentrations of hormones, neurotransmitters, drugs etc.
What is EC50?
Effective concentration giving 50% of the maximal response
Measure of agonist potency
Depends on both affinity and intrinsic efficacy
What is the difference between concentration and dose?
Concentration: known concentration of drug at site of action e.g. in cells and tissues
Dose: concentration at site of action generally unkown e.g. dose to a patient in mg or mg/kg
Spare receptors
In some cases <100% occupancy but still with 100% response, this means there are spare receptors
Why do spare receptors exist?
Amplification in the signal transduction pathway
Response limited by a post-receptor event
They increase sensitivity/potency and allow responses at low concentrations of agonists
What can affect receptor numbers?
Vary with cell type
Tend to increase with low activity - up-regulation
Tend to decrease with high activity - down-regulation
How are partial agonists different to full agonists?
Partial have lower intrinsic activity as lower efficacy than full agonists
Partial agonists EC50 =~ Kd
Partial have no spare receptors and have insufficient intrinsic efficacy for maximal response
What are the advantages of partial agonists?
Can allow a more controlled response
Work in absence of low levels of endogenous ligand
What is the disadvantage of partial agonists?
Can act as antagonist if high levels of full agonist
What is an example of a partial agonist?
Opioids - pain relief, recreational use (heroin)
What happens to sustained-drug taking people?
They have tolerance
Reduced receptor numbers
Reduced post-receptor signalling
Reversible competitive antagonism
Relies on a dynamic equilibrium between ligands and receptors
Greater concentration of antagonist means greater inhibition
What is IC50?
Gives an indication of antagonist affinity but influenced by concentration of antagonist and strength of stimulus (agonist)
What is the effect of reversible competitive antagonists on the graph?
Causes a parallel shift to the right of the agonist concentration-response curve
What is an example of competitive antagonism clinically?
Naoxone - high affinity, competitive antagonist at mu-opioid receptors
What is irreversible competitive antagonism?
Occurs when antagonist dissociates slowly or not at all
With increased concentration of antagonist or increased time, more receptors are blocked by antagonist
What affect do irreversible competitive antagonist have on the graph?
Cause a parallel shift to the right of agonist concentration-response curve
At higher concentrations suppress the maximal response as there are insufficient receptors for full response
What is non-competitive antagonism?
Endogenous ligand binds to orthosteric site
Agonists and antagonists bind to allosteric sites - reuse orthosteric ligand affinity and/or efficacy
