Pharmacodynamics Flashcards
Define a partial agonist
Binds to receptor and causes a sub maximal response
Define antagonist
Prevents binding of agonist or interferes with response outcome
What is the law of mass action
The velocity of a chemical reaction is proportional to the molecular concentrations of the reacting components
What is the relationship between the equilbrium constant for a drug/receptor complex and the concentrations of drug and receptor
KD = [D][R]/[DR]
What does 1/KD represent
The reciprocal of KD represents drug affinity for the receptor
Equation relating receptor occupancy to drug concentration
r = [D]/KD+[D]
Implications of r = [D]/KD+[D] for proportion of receptor occupancy at given drug concentrations
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%
What is the efficacy of a pure agonist
1
Formulae for response from a drug on a receptor
R=Er
Response = efficacy x occupancy
R = E[D]/KD+[D]
What is the shape of a curve plotting occupancy (r) against drug concentration [D]
Why
Rectangular hyperbola
Rapid increase then levelling out
As more receptors occupied fewer opportunities for binding
How would a graph of drug concentration and response appear for a pure agonist with efficacy of 1
Same as concentration occupancy graph - a rectangular hyperbola
How does log drug concentration vs receptor occupancy appear
Sigmoidal shape
How would altering the KA (KD, dissociation constant) change a drug concentration occupancy graph. What stays the same
Curve shifts right or left but end points the same (0 at 0, maximal occupancy at same concentration
What is the effect of doubling affinity of dissociation constant
KD = 1/affinity
Thus double affinity half KD
Example of a common receptor with multiple binding sites
Nicotinic ach - both alpha subunits must bind ach to elicit a response
What is a partial agonist
What is the efficacy of a partial agonist
Reversible binds to a receptor mediating a less than maximal response.
Between 0 and 1
What are the features of a log [drug] vs response curve for a partial agonist
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
What are the features of a log [drug] vs occupancy curve for a partial agonist vs full agonist with same KA
Same!
What is the effect on response of adding increasing amounts of partial agonist to a pure agonist
After a certain amount then observed effect will approach that of partial agonist alone.
What is a reversible competitive antagonist
Agent that reversibly binds with receptor site but has an efficacy of 0
The prevent binding of agonist thus preventing subsequent response
What is the drug : occupancy graph for a reversible competitive antagonist
What about drug : response graph
Occupancy - same as for an agonist with same dissociation constant
Response - zero, irrespective of drug concentration.
What is the effect of adding a reversible competitive antagonist on an agonist log [drug] response graph
Parallel shift to right
No change in maximal response
Antagonist overcome by increasing agonist concentration
What is the dose ratio with respect to reversible competitive antagonists
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
What does the dose ratio depend on
Antagonist concentration and affinity
What is an irreversible competitive antagonist
How does it attach to receptors
Competes with agonist for receptor site but once attached dissociates very slowly or not at all.
Usually forms covalent bonds.
How does an irreversible competitive antagonist effect a log [drug] vs response curve
No effect on dissociation constant, KD will remain the same
Max response is suppressed (downward shift)
Not overcome by increasing agonist concentrations
What is a lineweaver burk plot? What does it show?
Double reciprocal plot x = 1/[D] y = 1/R
Intercept of y axis gives 1/E (efficacy)
Intercept of x axis gives -1/KD
Effect of an non competitive irreversible antagonist on lineweaver burk?
Effect of competetive antagonist
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
What are silent receptors
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
What is the relevance of hysteresis to pharmacodynamics
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.
Broad Sources of variability within drug pharmacodynamics
Between individuals
Temporal variation in one individual
What are the ED50 and LD50
Ed - dose causing specified effect in 50% popn
Ld - dose causing lethal effect in 50% popn
What is the therapeutic index
Ratio of ed50:ld50
If two drugs with similar effects are administered together what are the potential outcomes
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
Examples of coenzymes
Vitamins
Ions
What do enzymes do
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
What is the enzyme equilibrium constant
Keq = product/reactants
