F7 Quantifying drug action - affinity

Question 1

what does an agonist do?

Answer 1

• reproduces the effects of endogenous messenger
• binds and activates receptor to produce response

Question 2

what does an antagonist do?

Answer 2

• blocks the effects of endogenous messenger
• prevents agonists binding so they have no effect

Question 3

what is pharmacokinetic antagonism?

Answer 3

• drug reduces the agonist drug concentration at the site of action
• drug-drug interactions

Question 4

what is physiological antagonism?

Answer 4

• physiological actions of the 2 drugs oppose each other through acting by separate molecular mechanisms
• eg. acetylcholine and noradrenaline on heart rate

Question 5

how can a stimulating messenger act as an antagonist?

Answer 5

• drug combines with the stimulating messenger to inactivate it
• drug doesn’t bind to receptor but binds to messenger to activate the messenger molecule

Question 6

how can blood vessels in tumours be targeted for cancer treatment?

Answer 6

• tumours need a blood supply to grow and survive
• blocking blood vessel formation is an anti-cancer therapy

Question 7

describe the antibody therapy example of Avastin

Answer 7

• 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)

Question 8

what is the affinity of a drug?

Answer 8

• its ability to bind to its receptor

Question 9

what is the efficacy of a drug?

Answer 9

• its ability (once bound to its receptor) to activate the receptor by a conformational change

Question 10

does a receptor AGONIST have affinity or efficacy?

Answer 10

• both
• it binds to its receptor (affinity) and triggers a response (efficacy)

Question 11

does a receptor ANTAGONIST have affinity or efficacy?

Answer 11

• only affinity
• it binds (affinity) but doesn’t trigger a response, it just blocks

Question 12

what does it mean to say that drug binding obeys the law of mass action?

Answer 12

• 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

Question 13

what is kON?

Answer 13

• association rate constant (constant for the forward rate equation)

Question 14

what is kOFF?

Answer 14

• dissociation rate constant

Question 15

what are the rate equations for forward and backward reactions of receptor-drug binding?

Answer 15

forward rate = kON[D][R]

backward rate = kOFF[DR]

Question 16

how can the forward and backward rate equations be rearranged when the reaction is at equilibrium? (drug-receptor interactions)

Answer 16

kON [D][R] = kOFF [DR]

Question 17

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?

Answer 17

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

Question 18

what symbol is used to display ‘proportional receptor occupancy’?

Answer 18

• α (alpha)
• when α is 1, all receptors are occupied by drug
• when α is 0, no receptors are occupied by the drug

Question 19

what can KD be defined as?

Answer 19

• the drug conc needed to occupy 50% of receptors at equilibrium
• i.e. a measure of its binding affinity

Question 20

how can high and low KD values be explained?

Answer 20

• 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

Question 21

how can we measure KD (equilibrium dissociation constant)?

Answer 21

• radioligand binding
• saturation analysis
• competition analysis

Question 22

how does radioligand binding allow for measuring KD?

Answer 22

• radiolabelled drug probe binds to target
• you can then count the radioactivity bound to the assay sample

Question 23

what is KA?

Answer 23

• affinity constant
• 1 / KD (inverse of KD)

Question 24

if a drug has a 100 fold higher affinity for receptors than another drug, how can this drug be described?

Answer 24

• more selective than the other for the receptors