Antagonism and Dose response relationships and Principles of Therapeutics Flashcards
Part IIa and IIb
inhibit or block the effects of an agonist
Antagonists
Type of antagonist that combines with the agonist and thereby disallows interaction with its site of action
Chemical
Physiological agonists:
- Activates an opposing physiological input
2. Could be an agonist
eg. Acetylcholine and norepinephrine are _________ of each other with respect to regulation of heart rate.
physiological antagonists
Blocks the effects of the agonist at its site of action (i.e. receptor)
Pharmacological
Binds to exactly the same site as the agonist
Competitive pharmacological antagonist
EC50’ is
the EC50 for the agonist in the presence of a given concentration of antagonist;
K-sub-I is
the K-sub-D of the antagonist for the receptor
EC50’ =
EC50 (1+ ([antagonist]/ K1))
Binds to exactly the same site as the agonist
Competitive pharmacological antagonist
The ability of the agonist to produce a response in the presence of a competitive, equilibrium
antagonist is dependent upon
the affinity of the antagonist for the receptor and its concentration
R + D RD–> Effect
+
A –> AR No Effect
The ability of the antagonist to be effective is dependent upon both
its concentration and the concentration of agonist that is present
R + D RD–> Effect
+
A –> AR No Effect
All else being equal, the antagonist with highest affinity for the receptor will
produce the greatest inhibition
Binds to the agonist binding site in a covalent or very slowly reversing manner
Irreversible, competitive antagonist
Once the receptors are bound by this type of antagonist, they cannot be activated by agonist. This reduces the receptor pool
Irreversible, competitive antagonist
Irreversible, competitive antagonist :
When we look at the effect of the agonist in the presence of a non-equilibrium antagonist, the EC50 value _________ but the Emax is ________.
does not change
reduced
Therapeutic implications of using a non-equilibrium antagonist
(i) New receptor synthesis is ….
(ii) The degree of inhibition produced is not influenced very much by ….
- the only way to overcome the effects of the antagonist
- the concentration of agonist present
a) Blocks the activation of the receptor by an agonist at a site other than the agonist binding site;
Noncompetitive pharmacological antagonist
blocks the signal transduction step
Noncompetitive pharmacological antagonist
D + R DR –X–> Effect
Noncompetitive pharmacological antagonist
Noncompetitive pharmacological antagonist:
The agonist concentration curves look steeper/same as the effect of an irreversible, competitive antagonist
Same
Noncompetitive pharmacological antagonist:
Emax is _________ for non-competitive inhibitor
EC50 does/does not change
Is/is not influenced by presence of spare receptors
reduced
does not
is not
Noncompetitive pharmacological antagonist:
Antagonist effect is dependent or independent of agonist concentration at the receptor
independent
Noncompetitive pharmacological antagonist:
Can be used to inhibit the effects of multiple agonists that use
the same signal transduction cascade (eg. inhibition of voltage operated calcium channels)
Partial agonist/partial antagonist (PA)
1. Ligands that have affinity for the receptor and an intrinsic activity between
1 and 0
When a partial agonist is present alone, one sees an
agonist effect
when a partial agonist is present in combination with a full agonist, one sees an
antagonist-like effect
receptors are in equilibrium between
actively signaling (Ra) and inactive (Ri) forms
An agonist shifts the equilibrium of Ra and Ri relationship towards
more receptors in the Ra form
__________ has no effect, and therefore does not affect this equilibrium at all
A true antagonist
There is a class of ligand that has been identified that can shift the equilibrium toward the Ri form – called
“inverse agonists”
Inverse agonists ___________tonic activity of the receptor
decrease
A fundamental of therapeutics is that a relationship exists between the dose of a drug administered and its therapeutic effect
The dose response relationship
Idealized dose response curves mirror the concentration-effect curves one obtains in the laboratory
The dose response relationship
Factors that can intervene between the site of drug administration and its ultimate site of action; include:
(1) Absorption
(2) Distribution
(3) Metabolism and excretion
______ is the relationship between the amount of drug administered and its effect
Potency
ED50 value is inversely/directly related to potency
Inversely
Potency determines the position of the curve on the
x-axis
Determinants of potency
(1) affinity for the site of action
(2) ability to reach the site of action
(3) Both are important as is shown in the beta blocker example
_________is the maximal effect that is produced by a drug
Efficacy
On the graph, Efficacy is the maximum point on the _______ that is reached
y-axis
Determinants of efficacy include:
- Intrinsic activity
- characteristics of the effector
- limitations on the amount of drug that can be administered (often due to adverse effects)
Deviations from this shape (sigmoid)can occur because of:
(1) Additive effects of the drug
(2) Threshold effects
(3) Antagonist effects
Due to _____________ rarely is a physician able to determine a dose-response curve in an individual patient
Biological variability among patients
Most drug effects follow a _________
More often depicted as a ____________distribution
log-normal distribution
cumulative frequency
Reasons for variations in responses among individuals
Pharmacokinetic differences
Variations in the amount of endogenous agonist present
Changes in the number or functioning of the drug target
Differences in a component distal to the drug target
unexpected based upon the mechanism of action of the drug
idiosyncratic drug responses
at the tails of the frequency distribution
hyporeactive or hyperreactive
allergic or inflammatory response to the drug
hypersensitivity
slowly developing resistance to the drug
tolerance
rapidly developing resistance to the drug
tachyphylaxis
Cumulative frequency relationships between drug dose and population response are called
quantal dose response curves
Y or X-axis is a quantal measure of the response or effect
(1) i.e. it is an all or none measure
Y
the ratio of TD50/ED50
Therapeutic index
Shape of the curve reflects
the variability in response in the
population
These three things are all obtained depending upon the response measured
ED50, TD50, LD50
