Schild plot Flashcards
competitive antagonists
Very important drugs e.g. pancuronium, cetirizine, propranolol
Used to inhibit the effects of a neurotransmitter or hormone
Their effects can be overcome by increasing the concentration
of the AGONIST i.e. the blockade is surmountable
a measure of RCA affinity?
The extent to which the agonist curve is shifted by the antagonist (i.e.
the amount of agonist you must add to overcome the blocking action
of the antagonist) is related to the affinity of the ANTAGONIST for the
receptor
The shift in the curves can be measured using the “dose-ratio” i.e.
the ratio of the concentration of agonist producing the same sized
response in the presence and absence of the antagonist
For a reversible competitive antagonist, the dose-ratio should
increase linearly with the concentration of the antagonist (another
way of saying you get a parallel shift in the curves)
how to obtain pA2?
Start by constructing
(log)concentration-response curves for
the agonist in the presence of several
concentrations of antagonist
This allows the pA2 to be calculated by
“Schild analysis”
It also tells us whether the antagonism is
reversible and competitive
If you don’t see a parallel.
i
the schild equation?
The Schild equation
log (dose ratio -1) = 1 x log (antagonist concentration) – log
KB
KB is the equilibrium dissociation constant (equivalent to KD) for
an antagonist measured using this technique
For a reversible competitive antagonist a plot of log (dose
ratio-1) versus log antagonist concentration (a Schild plot)
should have a gradient of 1.0 and intercept the X-axis at
(-log10KB)
For a reversible competitive antagonist:
-log10KB = pKB = pA2
steps to produce a schild plot?
Construct (log)concentration-response
curves to the agonist in the presence
of several concentrations of antagonist
From the curves read the logEC50
values for the agonist in the absence
and presence of the different
concentrations of antagonist
Calculate the EC50 values for the
agonist in the absence and presence
of the different concentrations of
antagonist
Calculate the dose ratio for each
concentration of antagonist
you should be able to complete the table:
conc of antagonist
log (antagonist)
log EC50
EC50 (M)
Dose ratio
Dose ratio-1
Log (dose ratio-1)
interpreting a schild plot key points:
A couple of important points
If the slope (gradient) of the Schild plot does not equal 1.0, (or at
least fall in the range 0.8 to 1.2) then this tells us that the antagonist
is not a reversible competitive antagonist (something else is going
on…)
Note that the pA2 obtained for the antagonist is independent of the
agonist used; it is a measure of antagonist affinity for the receptor
which is a property independent of the agonist
Often receptors are characterised by the pA2 values calculated for
different antagonists acting on them
