Flashcards in Lecture 2: Pharmacodynamics Part 2 Deck (66)
We decide whether something is a full or partial agonist solely based on:
Efficacy. Potency doesn't have any part in determining if something is an agonist.
An agonist makes it more likely that a receptor will exist in the (more/less) active state
More active state. An agonist shifts the equilibrium toward the active receptor state.
T/F: Receptors can spontaneously convert to the active state without the agonist
True, there can be spontaneous conversion and the biological effect will be the same.
Drive equilibrium of the receptor from the active to the inactive state. It may destabilize the active state or stabilize the inactive state to do this.
Spontaneous dissociation of the agonist is caused by :
Random kinetic fluctuations
What would you expect to happen if you added an antagonist alone to an experimental setup?
No change in the experiment subject (e.g. blood vessel diameter would stay the same). Antagonists bind to receptors, but the receptor activity is only impacted in the presence of an agonist.
What would happen if you added an inverse agonist to an experimental setup?
The inverse agonist would cause the opposite effect of the agonist. For example, if the agonist causes a blood vessel to dilate the inverse agonist causes it to constrict.
______ have an independent impact upon receptor activity
Agonists and inverse agonists
______ have no functional impact on a receptor when they act alone
Types of Antagonism
Direct interaction of two substances in solution such that the effect of one or both is lost.
E.g. protamine (acidic anticoagulant) and heparin (basic anticoagulant); these drugs will associate with each other due to their opposite pH and the activity of both drugs is lost.
Indirect interaction of two substances with opposing physiological actions
E.g. Histamine lowers BP through vasodilation by binding histamine H1 receptor. Epinephrine raises blood pressure through vasoconstriction by binding alpha1-adrenergic receptors. These substances act on two different receptors to have two opposing effects.
Blockage of interaction of one substance with its receptor by another substance.
E.g. Cimetidine blocks binding of histamine to H2 receptors resulting in lower gastric acid secretion. It is a good drug for treating ulcers.
Pharmacological Antagonists bind receptors but do not __________. Their biological effects are derived from ______.
1. activate signal transduction mechanisms. There is no functional impact on the receptor.
2. blocking the ability of an agonist to bind and/or activate a receptor.
Two major subgroups of pharmacological antagonists
Competitive antagonists and non-competitive antagonists
-Bind reversibly to the receptor
-Inhibition can be overcome by increasing agonist concentration
-Primarily affect agonist potency
-Bind irreversibly to the receptor or allosterically (bind in a spot different than where the agonist binds)
-Inhibition cannot be overcome by increasing agonist concentration
-Primarily affect efficacy
What happens if the amount of agonist is increased in the presence of a competitive antagonist?
The competitive antagonist will be replaced by the agonist and restore the maximum biological effect.
Compare the potency and efficacy of an agonist in the absence and presence of a competitive antagonist
-Absence: maximum potency and maximum efficacy
-Presence: Potency is reduced, but maximum efficacy is retained. The full effect can still happen, but more of the agonist is needed to reach it.
*The same number of drug-receptor complexes can be formed, we just need more drug present because it must outcompete the antagonist.
T/F: Competitive antagonists reduce the number of receptors available for activation by the agonist
False. The same number of receptors are available because the antagonist binds reversibly to the receptor and a higher concentration of agonist can compete with the antagonist, causing it to unbind the receptor.
In the presence of a competitive antagonist, the dose-response curve for an agonist will shift:
Right. This is because the potency of the agonist is reduced.
Non-competitive antagonists bind ___ to receptors.
What happens when you add more agonist in the presence of a non-competitive antagonist?
Nothing happens because the non-competitive antagonist is bound covalently to the receptor, so the higher concentration of agonist cannot compete with it. The full magnitude of biological effect cannot be retained.
Compare the potency and efficacy of an agonist in the absence and presence of a non-competitive antagonist
Absence: maximum potency and efficacy
Presence: There is no change in potency, but efficacy is reduced. This is because a non-competitive antagonist reduces the number of receptors available to be activated so less drug-receptor complexes can be formed the magnitude of the biological effect is lowered.
T/F: Non competitive antagonists reduce the number of receptors available for activation by the agonist
True. Because the antagonist binds covalently/irreversibly, the number of available receptors decreases.
Antagonist of heart B1-adrenergic receptors. It blocks the interaction of epinephrine and B1-adrenergic receptors.
When you give increasing doses of propanolol, you would expect ____.
Decreasing heart rate.
ID50= inhibitory dose
IC50= inhibitory concentration
The antagonist dose at which 50% of Emax is achieved. This is also a reflection of potency.
Emax of an antagonist
Reflects the maximum biological effect achieved by an antagonist. This is NOT a measure of efficacy, because only agonists have efficacy.
-Efficacy refers to the functional impact a ligand has on a receptor. An antagonist does not have an impact on receptor function; it will bind, but it doesn't change receptor function. It just blocks the agonist from binding.