Pharmacodynamics

Question 1

Define a partial agonist

Answer 1

Binds to receptor and causes a sub maximal response

Question 2

Define antagonist

Answer 2

Prevents binding of agonist or interferes with response outcome

Question 3

What is the law of mass action

Answer 3

The velocity of a chemical reaction is proportional to the molecular concentrations of the reacting components

Question 4

What is the relationship between the equilbrium constant for a drug/receptor complex and the concentrations of drug and receptor

Answer 4

KD = [D][R]/[DR]

Question 5

What does 1/KD represent

Answer 5

The reciprocal of KD represents drug affinity for the receptor

Question 6

Equation relating receptor occupancy to drug concentration

Answer 6

r = [D]/KD+[D]

Question 7

Implications of r = [D]/KD+[D] for proportion of receptor occupancy at given drug concentrations

Answer 7

When drug concentration is zero occupancy will be zero
When drug concentration equal to KD then occupancy will be 1/2
When drug concentration rises KD becomes relatively small so occupancy reaches close to but never exactly 100%

Question 8

What is the efficacy of a pure agonist

Answer 8

1

Question 9

Formulae for response from a drug on a receptor

Answer 9

R=Er
Response = efficacy x occupancy

R = E[D]/KD+[D]

Question 10

What is the shape of a curve plotting occupancy (r) against drug concentration [D]
Why

Answer 10

Rectangular hyperbola
Rapid increase then levelling out

As more receptors occupied fewer opportunities for binding

Question 11

How would a graph of drug concentration and response appear for a pure agonist with efficacy of 1

Answer 11

Same as concentration occupancy graph - a rectangular hyperbola

Question 12

How does log drug concentration vs receptor occupancy appear

Answer 12

Sigmoidal shape

Question 13

How would altering the KA (KD, dissociation constant) change a drug concentration occupancy graph. What stays the same

Answer 13

Curve shifts right or left but end points the same (0 at 0, maximal occupancy at same concentration

Question 14

What is the effect of doubling affinity of dissociation constant

Answer 14

KD = 1/affinity
Thus double affinity half KD

Question 15

Example of a common receptor with multiple binding sites

Answer 15

Nicotinic ach - both alpha subunits must bind ach to elicit a response

Question 16

What is a partial agonist
What is the efficacy of a partial agonist

Answer 16

Reversible binds to a receptor mediating a less than maximal response.
Between 0 and 1

Question 17

What are the features of a log [drug] vs response curve for a partial agonist

Answer 17

Sigmoid shaped curve
Shifted downwards vs full agonist- maximal response does not reach 1
If affinity is the same for full agonist then KA would be the same, but classically affinity will also be lower resulting in a right shift

Question 18

What are the features of a log [drug] vs occupancy curve for a partial agonist vs full agonist with same KA

Answer 18

Same!

Question 19

What is the effect on response of adding increasing amounts of partial agonist to a pure agonist

Answer 19

After a certain amount then observed effect will approach that of partial agonist alone.

Question 20

What is a reversible competitive antagonist

Answer 20

Agent that reversibly binds with receptor site but has an efficacy of 0
The prevent binding of agonist thus preventing subsequent response

Question 21

What is the drug : occupancy graph for a reversible competitive antagonist
What about drug : response graph

Answer 21

Occupancy - same as for an agonist with same dissociation constant
Response - zero, irrespective of drug concentration.

Question 22

What is the effect of adding a reversible competitive antagonist on an agonist log [drug] response graph

Answer 22

Parallel shift to right
No change in maximal response
Antagonist overcome by increasing agonist concentration

Question 23

What is the dose ratio with respect to reversible competitive antagonists

Answer 23

The ratio of the concentration of agonist in the presence of antagonist at a response of 0.5 vs concentration of full unopposed agonist at same response level.
Ie the factor by which the agonist must be increased by in order to overcome the antagonist

Question 24

What does the dose ratio depend on

Answer 24

Antagonist concentration and affinity

Question 25

What is an irreversible competitive antagonist How does it attach to receptors

Answer 25

Competes with agonist for receptor site but once attached dissociates very slowly or not at all. Usually forms covalent bonds.

Question 26

How does an irreversible competitive antagonist effect a log [drug] vs response curve

Answer 26

No effect on dissociation constant, KD will remain the same Max response is suppressed (downward shift) Not overcome by increasing agonist concentrations

Question 27

What is a lineweaver burk plot? What does it show?

Answer 27

Double reciprocal plot x = 1/[D] y = 1/R Intercept of y axis gives 1/E (efficacy) Intercept of x axis gives -1/KD

Question 28

Effect of an non competitive irreversible antagonist on lineweaver burk? Effect of competetive antagonist

Answer 28

Non competitive irreversible - line moves up, y intercept raised (increased 1/E, thus decreased efficacy) x intercept -1/KD remains the same Competitive - y intercept remains the same (same efficacy), x intercept less negative (-1/KD less negative thus increased KD

Question 29

What are silent receptors

Answer 29

Theoretically response = efficacy x occupancy thus for a pure agonist response = occupancy, however, the silent receptor theory notes that a proportion of the total pool of receptors must be activated before any response is noted - it’s not just a simple linear relationship

Question 30

What is the relevance of hysteresis to pharmacodynamics

Answer 30

Hysteresis is where response to stimuli in one direction does not follow the same path in the opposite, eg binding of a drug confirs stability thus requiring energy to break it away, it associates more readily than it dissociates. Increasing drug concentrations cause faster effect than when drug concentrations decrease and the energy needs to be provided to break the bonds before less receptors are occupied.

Question 31

Broad Sources of variability within drug pharmacodynamics

Answer 31

Between individuals Temporal variation in one individual

Question 32

What are the ED50 and LD50

Answer 32

Ed - dose causing specified effect in 50% popn Ld - dose causing lethal effect in 50% popn

Question 33

What is the therapeutic index

Answer 33

Ratio of ed50:ld50

Question 34

If two drugs with similar effects are administered together what are the potential outcomes

Answer 34

Subadditive (reduced response in one or both) Additive - both produce their normal response for the dose Superadditive - synergistic response with higher response for one or both

Question 35

Examples of coenzymes

Answer 35

Vitamins Ions

Question 36

What do enzymes do

Answer 36

Bind a substrate to specific binding site forming low energy bonds providing a low energy pathway that facilitates reaching of equilibrium They speed reactions up - they do not change the final balance of products

Question 37

What is the enzyme equilibrium constant

Answer 37

Keq = product/reactants