Pharmacodynamics
Simulated Computer Exercise
Most of the drugs that interact with either physiological or pharmacological
receptors behave according to the following relationship:
Eff=Effmax*C/(C+EC50)
Eff=Effmax*D/(D+ED50)
While receptor binding follows similar relationship:
B=Bmax*C/(C+Kd)
Exercise 1
Using Excel (or similar software) construct a dose-response curve describing
the response of blood pressure (BP, mean value at rest 90 mmHg) to
Norepinephrine (EC50=0.1 M; BPmax=190 mmHg). Change the plot to semilogarithmic, double inverse (Lineweaver-Burk); Eadie-Hoffstee type). On the
same plots, add a curve for phenylephrine (EC50=3 M, BPmax=190 mmHg).
Describe the binding of norepinephrine (Kd 0.1 M) to a preparation of
membranes from rat aorta (Bmax=2 pmol/mg prot). Use the different plotting
methods. Construct plot of effect vs. binding. How informative is this plot?
Construct another plot that describes fractional activity vs. fractional
occupancy. What are the advantages of this type of description? What will
happen to all the plots if the density of -adrenergic receptors is increased
two-fold (Bmax=4 pmol/mg prot)?
Which of the graphs that you have
constructed is more clearly indicative of receptor reserve (spare receptors)?
Exercise 2
Repeat Exercise 1 in the presence of two concentrations (0.1 and 10 nM) of
the competitive -adrenergic antagonist, prazosin (Kd=1 nM).
What is the
effect of prazosin on norepinephrine’s potency and efficacy?
Exercise 3
Repeat Exercise 1 in the presence of two concentrations (0.1 and 10 nM) of
the non-competitive -adrenergic antagonist, phenoxybenzamine (Kd=10 nM).
What is the effect of phenoxybenzamine on norepinephrine’s potency and
efficacy?
Exercise 4
Describe qualitatively (using hand-drawn plots, if necessary) what is the effect
of receptor reserve on potency and efficacy of agonists, competitive
antagonists, non-competitive antagonists, partial agonists. How would you
overcome the difficulties in identifying these drugs in the presence of a large
receptor reserve?