F7 Quantifying drug action - affinity Flashcards
what does an agonist do?
- reproduces the effects of endogenous messenger
- binds and activates receptor to produce response
what does an antagonist do?
- blocks the effects of endogenous messenger
- prevents agonists binding so they have no effect
what is pharmacokinetic antagonism?
- drug reduces the agonist drug concentration at the site of action
- drug-drug interactions
what is physiological antagonism?
- physiological actions of the 2 drugs oppose each other through acting by separate molecular mechanisms
- eg. acetylcholine and noradrenaline on heart rate
how can a stimulating messenger act as an antagonist?
- drug combines with the stimulating messenger to inactivate it
- drug doesn’t bind to receptor but binds to messenger to activate the messenger molecule
how can blood vessels in tumours be targeted for cancer treatment?
- tumours need a blood supply to grow and survive
- blocking blood vessel formation is an anti-cancer therapy
describe the antibody therapy example of Avastin
- Avastin inactivates the stimulus (VEGF) by binding to it rather than blocking its receptor by binding to that
- therefore, no tumour angiogenesis (new blood vessels)
what is the affinity of a drug?
- its ability to bind to its receptor
what is the efficacy of a drug?
- its ability (once bound to its receptor) to activate the receptor by a conformational change
does a receptor AGONIST have affinity or efficacy?
- both
- it binds to its receptor (affinity) and triggers a response (efficacy)
does a receptor ANTAGONIST have affinity or efficacy?
- only affinity
- it binds (affinity) but doesn’t trigger a response, it just blocks
what does it mean to say that drug binding obeys the law of mass action?
- rates of binding are proportional to conc of the participants in your binding mixture
- as conc of drug in the blood / at the site of action rises, binding increases
what is kON?
- association rate constant (constant for the forward rate equation)
what is kOFF?
- dissociation rate constant
what are the rate equations for forward and backward reactions of receptor-drug binding?
forward rate = kON[D][R]
backward rate = kOFF[DR]
how can the forward and backward rate equations be rearranged when the reaction is at equilibrium? (drug-receptor interactions)
kON [D][R] = kOFF [DR]
what is the equilibrium dissociation constant in regards to drug-receptor interactions? (KD)
what does a smaller KD indicate? what can KD also be defined as?
kOFF / kON
- a smaller KD indicates the drug has a higher affinity and higher [DR]
- can also be defined as drug conc needed to occupy half of the molecular target proteins at equilibrium
what symbol is used to display ‘proportional receptor occupancy’?
- α (alpha)
- when α is 1, all receptors are occupied by drug
- when α is 0, no receptors are occupied by the drug
what can KD be defined as?
- the drug conc needed to occupy 50% of receptors at equilibrium
- i.e. a measure of its binding affinity
how can high and low KD values be explained?
- if a drug has a lower affinity, you need more drug to occupy the same amount of receptors
- low affinity drugs have high KD values
- higher affinity drugs have lower KD values
how can we measure KD (equilibrium dissociation constant)?
- radioligand binding
- saturation analysis
- competition analysis
how does radioligand binding allow for measuring KD?
- radiolabelled drug probe binds to target
- you can then count the radioactivity bound to the assay sample
what is KA?
- affinity constant
- 1 / KD (inverse of KD)
if a drug has a 100 fold higher affinity for receptors than another drug, how can this drug be described?
- more selective than the other for the receptors
