Pharmacodynamics Flashcards
What does is pharmacodynamics the study of?
Drug-receptor interactions and their biological response
What are the general properties of receptors?
Low concentration, high affinity, selective, reversible reaction, complementary binding site
How is the affinity of a drug for its receptor quantified?
Equilibrium dissociation constant Kd
What unit is Kd measured in?
M
Which out of antagonists and agonists cause a conformational change in the receptor?
Agonists
What is the law of mass action?
D + R <–> DR
How is the rate of forward reaction mesured?
k1 [D][R]
1 as subscript
ow is the rate of backward reaction measured?
K-1 [DR]
-1 as subscript
What is Kd at equilibrium?
[D][R] / [DR]
What is the Langmuir equation?
r = [D] / [D]+Kd
What is represented by r in the Langmuir equation?
Fractional occupancy of receptors
What shape will the curve of r against [D] be?
Rectangular hyperbola
What shape will the curve of r against log [D] be?
Sigmoidal, approximately linear between 20-80% fractional occupancy
In what situation is [D] equal to Kd?
When r (fractional occupancy) = 1/2
For what interactions can the Langmuir equation / r-log[D] plots be used?
Simple bimolecular interactions
How can the Langmuir equation be modified to account for complex interactions?
r = [D]n / [D]n + Kd
How can the Hill coefficient n be found?
Gradient of log r/1-r against log[D]
What does a Hill coefficient of > 1 represent?
Positive cooperativity
What does a Hill coefficient of < 1 represent?
Negative cooperativity
What does a Hill coefficient of 1 represent?
Simple interaction
What is the occupancy theory?
Response [E] is directly proportional to number of receptors occupied
What is the rate theory?
Response [E] is directly proportional to rate of receptor occupation
What does R equal in occupancy theory?
E / Emax and D / D + Kd
What is R in occupancy theory?
Fractional response
What is pD2?
-log of [D] that gives 1/2 maximal response, always positive
At half maximal response, what can be said about [D]?
It is equal to Kd
What is quantified by pD2?
Affinity of agonist for its receptor
What does a high pD2 indicate?
Drug acts at low concentrations
What is competitive antagonism?
Agonist and antagonist bind to the same site
How can competitive antagonists be overcome?
Increasing drug concentration
What is non-competitive antagonism?
Antagonist binds to different site to agonist, or acts irreversibly
What is a common example of competitive antagonism?
Acetylcholine (agonist) against atropine (antagonist)
What happens to an E/Emax against log[D] curve when more competitive antagonist is added?
Shifts in parallel to the right
What happens to an E/Emax against log[D] curve when more non-competitive antagonist is added?
Flattens downwards
Which type of antagonism decreases Emax?
Non-competitive
What is Ka[D] / (KdKa + Kd[A] + Ka[D])?
[DR] / Rt (total receptors)
What is the dose ratio?
Ratio of agonist concentration that elicits the same response in absence or presence of antagonist
What is the simplified Gaddum-Schild equation?
[A] / Ka = [Da]/[D0] - 1
How is dose ratio calculated?
[Da] / [D0]
What is pA2?
-log of antagonist concentration that gives dose ratio of 2
How can pA2 be calculated?
-log[Ka]
What is pAx?
-log of antagonist concentration that gives dose ratio of x
What is specificity assumption of the occupancy theory (assumption 1)?
There are specific receptors for specific agonists
What is the response assumption of the occupancy theory (assumption 2)?
All agonists for a given receptor can produce the same maximal response
What is the reversibility assumption of the occupancy theory (assumption 3)?
The drug-receptor interaction is rapidly reversible
What is the accessibility assumption of the occupancy theory (assumption 4)?
All receptors are equally accessible to the drug
What is the interaction assumption of the occupancy theory (assumption 5)?
The receptors do not interact with each other
What is the occupation assumption of the occupancy theory (assumption 6)?
The maximum response occurs when all receptors are occupied
What is the phenomenon of partial agonists?
Some agonists produce only a weak response
How can a partial agonists interact with a full agonist?
Acting as a competitive antagonist
What is intrinsic activity (alpha) a measure of?
Ability for a drug to produce an effect
What is the intrinsic activity of a full agonist?
1
What is the intrinsic activity of a partial agonist?
< 1
What is the intrinsic activity of an antagonist?
0
What is the phenomenon of spare receptors?
Maximum response can be reached without every receptor being occupied
At low concentrations, what does a high efficacy antagonist appear to be?
Competitive
At high concentrations, what does a high efficacy antagonist appear to be?
Non-competitive
What modifications are made to the occupancy theory to account for partial agonists and spare receptors?
The effect will depend on the affinity of the drug for receptor, and the ability of the drug to induce a conformational change
What is stabilised by a high efficacy agonists?
Active receptor conformation
What is meant by a receptor’s constitutive activity?
Basal activity in resting state
What do inverse agonists do?
Decrease constitutive activity of a receptor
