L2: Pharmacodynamics Flashcards
What is the Law of Mass Action
The rate of a chemical reaction is proportional to the product of the concentrations of reactants
- Each mass raised to a power equal to the coefficient that occurs in the chemical equation
- The drug-receptor interaction follows simple mass-action relationships
Define fractional occupancy in terms of D and Kd
The fraction of receptors occupied by ligand at a particular concentration
What is the “definition of Kd” ?
Dissociation Constant
Kd= [(D)(R)]/(DR)
Show that Kd = D when 50% of receptors are occupied
(DR)/Rt = D/(Kd+D)
When 50% of receptors are occupied:½ = D/(Kd+D)
Multiply both sides by 2: 1= 2 D/(Kd+D)
Multiply both sides by (Kd+D): Kd + D= 2D
Subtract D on both sides: Kd = D
On a log (drug) scale, find (10^-8M) and (3 x 10^-6M).
[UNDERSTAND THE LOG SCALE]
Log (10^-8M)= -8
Log (3*10^-6M)= -5.5 M
What is the difference between competitive vs. noncompetitive inhibition?
Competitive inhibition blocks the active site and can be overcome by increasing the quantity of substrate near the enzyme,
while non-competitive inhibition changes the conformation of active site and remains attached regardless of the presence of substrate or elapsed time.
What is the Cheng-Prusoff Correction?
Equation used to calculate Ki
(binding affinity of the inhibitor/antagonist)
What is the major assumption of the Cheng-Prusoff correction?
ASSUMPTION = COMPETITIVE
Assumes that the inhibitor binds at the orthosteric site, i.e. that the inhibitor is a competitive inhibitor.
- Produces good estimates of Ki at high agonist (i.e. Drug agonist, or natural ligand) concentrations, because at those concentrations of agonists, the (D + R = DR) equilibrium tends towards the right, thus there are not many receptor orthosteric sites available for the inhibitor to bind to, and changes are easier to measure; at low agonists concentrations, that equilibrium tends towards the left.
Concept and consequences of receptor desensitization
Loss of sensitivity to stimulation.
Concept and consequences of receptor supersensitivity
Increase in the responsiveness of the tissue to the drug.
*What is the approximately the percent of receptor occupation when the drug concentration is 10nM and the Kd value is 1nM?
a. 1%
b. 10%
c. 50%
e. 90%
f. 99%
e. 90%
*A competitive antagonist will:
a. Cause a decrease in Emax of an agonist
b. Cause a leftward shift in the dose response curve of an agonist
c. Be insurmountable
d. Cause only a partial effect
e. None of the above
E. NONE OF THE ABOVE!!!
(A was also an acceptable answer but E is the CORRECT answer)
**The easiest way to distinguish an inverse agonist from a neutral antagonist is
a. To show that the inverse agonist is less efficacious than the endogenous agonist
b. To have a system with high constitutive activity
c. To show competition between the drugs and a radioligand
d. To show that the drug blocks the effect of an agonist
e. None of the above
b. To have a system with high constitutive activity
*On a -log(drug) scale, where is 10 micromolar?
a. 8
b. 7
c. 6
e. 5
f. 4
d. 5
What is the approximate fractional occupancy of receptors when the concentration of the drug is 100 nM and its Kd is 10 nM?
A. 0.1
B. 0.3
C. 0.5
D. 0.9
E. 10
D. 0.9
On a -log(drug) scale, where is 30 mM?
A. 1.5
B. 2.5
C. 3.5
D. 4.5
E. 5.5
D. 4.5
Which of the following is NOT an assumption of the drug-receptor interaction?
a. ) Binding of the drug to the receptor causes some event which leads to a response
b. ) The response to the drug is graded and dose-dependent
c. ) The drug-receptor interaction follows simple mass-action relationships
d. ) The number of drug molecules is less than the number of receptor sites
e. ) For a given drug, the magnitude of the response is directly proportional to the fraction of total receptor sites occupied by drug molecules
d.) The number of drug molecules is less than the number of receptor sites
This is a defining characteristic of a partial agonist drug.
a. ) This type of drug cannot fully occupy the available receptors
b. ) This type of drug has a reduced affinity for the receptor compared to full agonists.
c. ) This type of drug produces a reduced response compared to a full agonist because of a limit on the ability to give enough partial agonist drug
d. ) This type of drug, even at doses that fully saturate the receptor, does not elicit a response as great as that seen with a full agonist.
d.) This type of drug, even at doses that fully saturate the receptor, does not elicit a response as great as that seen with a full agonist.
- *What is the fractional occupancy of the receptors when the drug concentration is 1.25 μM and it’s Kd = 5 μM?**
- (a reminder: 1 μM =10 -6 M)*
a. ) 0.3
b. ) 0.5
c. ) 0.2
d. ) 0.25
e. ) 0.75
c.) 0.2
Selectivity is the
a. ) Capacity of a drug to affect multiple sites of action
b. ) Capacity of a drug to produce multiple types of actions
c. ) Capacity of a drug to one type of action
d. ) Capacity of a drug to affect one site of action in preference to others
e. ) Capacity of a drug to cause a response
d.) Capacity of a drug to affect one site of action in preference to others
Which drug is more POTENT: B or C?
B is more Potent
*Potent: How MUCH drug it takes to cause an effect
Which drug is more efficacious: B or C?
Drug B is more Efficacious
*Efficacy: how HIGH occupancy or response curve goes
For a simple system, what is the relationship between:
e, DR, RT, D, Kd, Emax
What are the formulas for the Cheng & Prusoff equations?
(And what assumption must be made?)
