Antagonists Flashcards
What is the definition of an antagonist?
*Antagonists bind to receptors with affinity but do not activate them, meaning they have no efficacy.
*They block the receptor’s ability to respond to an agonist, resulting in a null response.
What are the key characteristics to antagonists?
*Affinity: The ability to bind to a receptor.
*No Efficacy: No activation of the receptor or signal transduction occurs after binding.
What are the mechanisms of action for antagonists?
*Antagonists compete with agonists for receptor binding sites.
*By occupying the receptors, antagonists prevent agonists from binding and initiating a biological response.
What are the clinical implications for antagonists?
*Used to inhibit overactive receptor activity or counteract the effects of endogenous agonists.
*Examples include beta-blockers, which antagonise beta-adrenergic receptors to manage hypertension.
What is antagonism?
An antagonist is a drug or ligand that reduces or blocks the response of an agonist.
What is an example of an antagonist?
Propranolol (Anti-hypertensive):
Blocks beta-1 adrenergic receptors, preventing adrenaline from binding.
Decreases heart rate and reduces the force of cardiac contractions
What is competetative antagonism?
*The antagonist competes directly with the agonist for the same receptor binding site.
*Effectiveness depends on the concentration of both agonist and antagonist.
What is non-competitive antagonism?
*The antagonist binds to a different site on the receptor or modifies the receptor irreversibly, preventing activation by the agonist.
What is reversible antagonism?
*The antagonist can dissociate from the receptor, allowing normal receptor activity to resume.
What is irreversible antagonism?
*The antagonist binds permanently or modifies the receptor, resulting in a long-lasting effect.
What are the four possible combinations for antagonism?
1:Competitive & Reversible
2:Competitive & Irreversible
3:Non-Competitive & Reversible
4:Non-Competitive & Irreversible
What is the definition of competitive antagonism?
*Competitive antagonism occurs when both the agonist and antagonist compete for the same receptor binding site.
*The receptor site in this scenario is referred to as the orthosteric site
What is an example of competitive antagonism?
Agonist (Adrenaline):
Binds to beta-1 adrenergic receptors in the heart.
Activates the receptor, increasing heart rate and enhancing cardiac muscle contraction.
Antagonist (Propranolol):
Competes with adrenaline for the same binding site on the beta-1 receptor.
Prevents adrenaline from binding, leading to decreased heart rate and reduced cardiac force
What is reversible antagonists in the absence of antagonist?
*The effect of a reversible competitive antagonist is dose-dependent.
Without any antagonist, there is no competition, and the agonist achieves its maximum potential effect.
*When no antagonist is present, the agonist binds freely to all available receptor sites.
*Agonist occupancy results in a 100% receptor activation, leading to the full biological response.
Explain the scenario of dissociation from receptors of reversible antagonists.
*If the concentration of the antagonist is higher than the agonist, the antagonist will occupy more of the receptor sites.
*As the antagonist dissociates, the agonist may bind to the receptor, restoring a portion of the biological response.
*33% in this example refers to the proportion of receptors that are occupied by the agonist after the antagonist dissociates
What is the mechanism of action of surmountable antagonism? + outcome
*Both agonist and antagonist compete for the same receptor binding sites.
*Increasing the agonist concentration enables it to outcompete the antagonist for receptor occupancy.
OUTCOME:
Despite the presence of the antagonist, the agonist’s maximal response (100%) can still be achieved if its concentration is sufficiently high.
What is the graph interpretation of surmountable antagonism?
*The presence of increasing concentrations of the antagonist (+1 nM, +10 nM, +100 nM) causes a rightward shift in the dose-response curve of the agonist.
*Potency (EC50) decreases with higher antagonist concentrations, as more agonist is required to achieve 50% of the maximal response.
*However, the maximal response (Rmax) remains unchanged
What are the key features of irreversible competitive antagonists ?
Irreversible antagonists bind permanently to receptors by forming covalent bonds.
Once bound, these antagonists inactivate the receptor and prevent agonist binding
What are the receptor reserves of irreversible competitive antagonists?
*Even with irreversible antagonists occupying a portion of receptors, spare receptors (receptor reserves) allow the agonist to achieve a maximal response.
*Example: Only 60% receptor occupancy by the agonist may be required to elicit the maximum response (Rmax).
What is the graph interpretation for irreversible competitive antagonists?
*The dose-response curve demonstrates that the maximal agonist response (100%) can still be achieved due to receptor reserves.
*However, if the receptor reserve is depleted by further antagonist binding, the maximal response will eventually decrease.
What is the receptor reserves like with irreversible competitive antagonists accompanied by agonist + +1nM antagonist?
*The presence of spare receptors allows the system to achieve a 100% maximal response (Rmax) even with some receptors occupied by irreversible antagonists.
*In this example, 75% receptor occupancy by the agonist is sufficient to reach the maximal response
What is the graph interpretation for irreversible competitive antagonists (w agonist +1nm)?
*With increasing concentrations of irreversible antagonists (+1 nM), the dose-response curve shifts slightly.
*As receptor reserves are depleted, higher agonist concentrations are required to maintain a response.
*Rmax remains unchanged initially but may decline if receptor reserves are completely depleted.
What happens with the receptor reserves in depletion?
Initially, receptor reserves compensate for the loss of active receptors, allowing the agonist to maintain 100% maximal response (Rmax).
As antagonist concentration increases (+1 nM, +10 nM), receptor reserves are exhausted, leading to the need for 100% receptor occupancy by the agonist to achieve the maximal response
What is the graph interpretation like with the depletion of receptors?
*With low antagonist concentrations, the curve shifts right due to increased EC50 (potency reduction).
*At higher antagonist concentrations, the maximal response remains unchanged only if sufficient receptor reserves exist.
*Once receptor reserves are depleted, the system cannot sustain the maximal response.
What is the graph interpretation of receptor reserve depletion?
*With increasing concentrations of the irreversible antagonist, the dose-response curve shifts rightward (indicating reduced potency).
*Eventually, the maximal response is reduced to ~60% due to the exhaustion of receptor reserves.
What is the response for non-surnmountable antagonism?
Initial Stage: Receptor reserves compensate for the loss, maintaining the maximal response (Rmax) despite increased antagonist concentrations.
Depletion of Receptor Reserves:
At higher antagonist concentrations (+100 nM, +1000 nM), receptor reserves are exhausted.
The agonist EC50 increases (potency declines) and the maximal response drops significantly.
With sufficient antagonist, the maximal response is reduced to ~20%, indicating non-surmountable antagonism
What is the graph interpretation for non surnmountable antagonism?
The dose-response curve shifts to the right and downward as receptor reserves are progressively depleted.
Higher agonist concentrations cannot restore the maximal response due to the irreversible loss of receptors.
What is an example of non-competitive antagonism?
Glutamate Binding:
Glutamate (agonist) binds to its specific site on the NMDA receptor, leading to the opening of the ion channel and the influx of sodium and calcium ions.
Non-Competitive Antagonist: Memantine:
Memantine binds to a different site within the NMDA receptor.
This binding blocks the receptor’s ion channel, inhibiting ion influx even if glutamate is bound.
What is the mechanism of action of non-competitive antagonism?
Non-competitive antagonists reduce the maximal response (Rmax) of the agonist because their binding prevents receptor function irrespective of agonist concentration.
Non-competitive antagonists do not require structural similarity to the agonist.
What is the clinical relevance of memantine?
Memantine is used in treating neurodegenerative diseases like Alzheimer’s by modulating excessive NMDA receptor activity, reducing calcium overload and neuronal damage.
What are some examples of antagonism drugs?
Antacids:
Calcium carbonate or other bases neutralise stomach acid to alleviate acidity, indigestion, or heartburn.
Heavy Metal Chelators:
Bind to toxic metals like lead or mercury, preventing their harmful effects and aiding their excretion.
Antibody Therapy (Bevacizumab):
Targets and neutralises vascular endothelial growth factor (VEGF) to inhibit tumour growth.
What is pharmacokinetics antagonism?
Pharmacokinetic antagonism occurs when one drug affects the absorption, distribution, metabolism, or excretion of another drug, reducing its effectiveness.
What do pharmocokinetic antagonists do?
Decreased absorption / altered distribution
-anti-diarrhoeal drugs inhibit gut absorption of other drugs
-vasoconstriction by adrenaline restricts distribution of local anaesthetics
Increased metabolism
-phenobarbital increases liver enzyme activity and stimulates metabolism of many drugs, including
warfarin
Increased renal excretion
What is physiological antagonism?
Physiological antagonism occurs when two drugs produce opposite effects on the same physiological process via different mechanisms
What do physiological antagonists do?
Different physiological mechanism
-blood pressure regulation by DIURETICS
- diuretics increases the urine output and by which it reduces the sympathetic control of blood pressure (by adrenaline)
