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51 Cards in this Set
- Front
- Back
What is the general definition of an Antagonist?
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A molecule that inhibits or blocks the effects of an agonist.
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3 general types of antagonists:
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-Chemical
-Physiological -Pharmacological |
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What is a chemical antagonist?
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One that actually combines with an agonist, preventing it from interacting with its target site of action.
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What is an example of a chemical antagonist?
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Protamine - binds/inactivates heparin.
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How do Physiological Antagonists work?
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By activating opposing physiological inputs
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What is an example of a physiological antagonist/agonist pair?
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Sympathetic NE and Parasympathetic ACh regulation of heartrate
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Is NE a pharmacological antagonist?
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No; it's actually an agonist of the adrenergic receptor.
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What is a Pharmacological antagonist?
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One that blocks the effects of an agonist at its site of action
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What makes Antagonists different from agonists?
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Antagonists have no intrinsic activity at all; binding to the receptor has no effect other than to prevent an agonist from binding.
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2 What 2 things is a response to a compound binding its receptor proportional?
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1. Fraction of occupied receptors
2. Intrinsic activity |
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What is Intrinsic activity?
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Emax of compound of interest
---------------------------- maximum Emax |
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2 General categories of Antagonists:
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-Competitive
-Noncompetitive |
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What is the difference between competitive and noncompetitive antagonists?
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-Competitive bind to the exactly same site on the receptor as the agonist
-Noncompetitive bind to a different site than the agonist |
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What are 2 types of Competitive antagonists?
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-Competitive Equilibrium antagonists
-Competitive Nonequilibrium antagonists |
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What makes Competitive equilibrium antagonists unique?
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They are reversible and can be surmounted by increasing the agonist concentration
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What makes Competitive nonequilibrium antagonists unique?
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They are nonreversible and cannot be surmounted by increasing the agonist.
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What is EC50?
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The concentration of a drug that produces 50% of max effect.
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How does a competitive equilibrium antagonist alter the concentration/effect curve?
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It increases the EC50 and shifts the curve to the right.
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What do we call an EC50 after it has been increased by a competitive equilibrium antagonist?
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EC50'
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What is the Kd of an antagonist called?
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Ki
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What is Ki?
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The dissociation constant of an antagonist.
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What is the equation for calculating the new EC50' after adding a competitive equilibrium antagonist?
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[Antagonist]
EC50' = EC50 (1 + (------------) Ki |
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What happens to the change in EC50 of an agonist as the Ki of the antagonist increases?
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The EC50 changes less, because the antagonist has a tendency to dissociate and is hence weak.
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What happens to the change in EC50 of an agonist as the concentration of antagonist increases?
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The EC50 increases more
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So the ability of an agonist to produce a response in the presence of a competitive equilibrium antagonist is dependent upon what 2 things?
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-Concentration of antagonist
-Affinity of the antagonist for the receptor (1/Ki) |
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What is the amount of inhibition caused by a competitive equilibrium antagonist dependent upon?
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-Concentration of agonist
-Concentration of antagonist |
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When comparing two competitive equilibrium antagonists, what will make one able to produce greater inhibition, all else being equal?
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Lower Ki (higher affinity)
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What is the 2nd type of competitive antagonist?
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Nonequilibrium, nonsurmountable, irreversible.
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What makes a nonequilibrium competitive antagonist irreversible?
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It binds the receptor covalently
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What effect do nonreversible competitive antagonists have on the system?
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They reduce the receptor pool
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How does a nonreversible competitive antagonist alter the effect vs: concentration curve when spare receptors are present?
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It increases the EC50 and shifts the curve to the right, just the same as for an equilibrium reversible antagonist.
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How does a nonreversible competitive antagonist alter the effect vs: concentration curve when spare receptors are NOT present?
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It does not shift the curve to the right, but simply decreases the Emax that can be produced by the agonist.
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How does a nonreversible competitive antagonist alter the EC50 when spare receptors are not present?
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It does not alter the EC50
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What is the only way to overcome the effects of a nonreversible competitive antagonist?
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Synthesize new receptors
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If you were to compare Conc vs Effect curves for a competitive reversible and irreversible antagonist in the presence of spare receptors, how could you tell them apart?
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By adding the antagonist, washing it off, and then re-analyzing the curve.
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What happens to each type of competitive antagonist when you wash the system?
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-Reversible gets washed off so you don't see any antagonism
-Irreversible won't wash off, so you continue to see the antagonistic effect |
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What is a clinical condition in which an irreversible antagonist is a good drug?
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Pheochromocytoma - by irreversibly inhibiting the alpha-adrenergic receptor with Phenoxybenzamine
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Why is the irreversible inhibition of alpha-adrenergic receptors with Phenoxybenzamine a good way to treat Pheochromocytoma?
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Because even if you get sudden spikes in the agonists NE/Epi, you won't see sudden spikes in blood pressure.
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What is the predominant difference in a noncompetitive antagonist compared to competitive?
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It blocks the effects of agonist activation of a receptor at a site OTHER than the binding site.
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If a noncompetitive antagonist does not prevent L+R from forming LR complexes, how does it act as an antagonist?
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It prevents transduction of the LR complex into an effect.
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What does the agonist concentration curve for a noncompetitive antagonist look like?
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Same as for an irreversible competitive antagonist
-No change in EC50 -Decreased Emax |
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What are the 2 main therapeutic implications of noncompetitive antagonists?
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1. Antagonist effect is essently independent of the [agonist]
2. Can use it to inhibit multiple agonists that use the same signal transduction cascade |
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Does the presence of spare receptors change how a noncompetitive antagonist will alter the agonist concentration curve?
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No; it will always just lower the Emax and leave the EC50 unchanged.
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What are 2 ways that you could differentiate a noncompetitive antagonist from an equilibrium reversible antagonist?
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1. Noncompetitive has NO Ki
2. Wash experiment - both would wash off |
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What is a partial agonist?
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A ligand with affinity for a receptor, and intrinsic activity between 0 and 1
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What effect is seen when a partial agonist is present alone?
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Agonist-like
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What effect is seen when a partial agonist is present with a full agonist?
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An antagonist effect
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What are receptors like normally?
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Tonically, constitutively active
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What is the theory for how agonists actually work?
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Bind the active form of a receptor and stabilize it
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What is a molecule that binds the inactive form of a receptor and stabilizes it?
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An inverse agonist
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What is the difference between an inverse agonist and an antagonist?
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Inverse agonists cause a change in the receptor - stabilizing it in the inactive form; Antagonists cause NO change in the receptor at all.
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