Agonists -1 Flashcards
What are the three receptor states? + describe what they are
Receptor States:
1:Inactive (Free): The receptor is in its baseline state, unbound by a drug or ligand, and does not initiate any response.
2:Bound, Inactive: The drug binds to the receptor but does not activate it (e.g., an antagonist).
3:Bound, Active: The receptor is bound by an agonist, triggering a conformational change that activates downstream signalling pathways.
What is affinity?
*Drugs with high affinity are more effective at binding their target receptors, potentially leading to stronger or more prolonged responses.
*Affinity also influences the potency of a drug, which determines its required dosage for efficacy.
What is the clinical relevance of affinity?
: Understanding receptor affinity helps in drug development, ensuring the drug’s selective binding to target receptors to minimize side effects.
What is efficacy?
Defined as the ability of a drug to produce a biological response (stimulatory or inhibitory) after binding to its target receptor.
It measures the drug’s ability to induce conformational changes in the receptor, leading to an active state.
What is the pharmacological significance of efficacy?
Drugs with high efficacy can fully activate receptors and elicit a maximal response (full agonists).
Drugs with partial efficacy (partial agonists) activate receptors but cannot produce the same maximal effect as full agonists.
Antagonists have zero efficacy because they bind receptors but do not activate them.
What are the clinical significance of efficacy?
Efficacy is crucial in determining the therapeutic potential of drugs.
High-efficacy drugs are often preferred for conditions requiring a strong physiological response, while partial agonists may be used when a moderate effect is desired
What is adrenaline + what does it do?
1:A naturally occurring agonist.
2:Acts on β-2 adrenergic receptors to relax airway smooth muscles and dilate airways.
Its widespread physiological effects make it less selective, affecting multiple adrenergic receptors.
What is salbutamol and what does it do?
1:A β-2 adrenergic receptor-selective agonist.
2:Designed specifically to target β-2 receptors, primarily in the lungs.
3:Used clinically as an anti-asthma drug to relieve bronchospasm and promote airway dilation.
What is the mechanism of action between adrenaline and salbutamol?
1:Both adrenaline and salbutamol activate β-2 receptors.
2:This activation triggers intracellular signalling pathways leading to smooth muscle relaxation and airway dilation
Why are chemical structures useful but limited?
Similar chemical structures (e.g., adrenaline and dopamine) can lead to different receptor affinities and biological effects.
A small change in the functional group can drastically alter the drug’s target, selectivity, and physiological response.
This underscores the importance of understanding both the chemical and biological contexts in drug-receptor interactions.
What must agonists be able to do?
Takeaway: Agonists must possess both affinity (ability to bind) and efficacy (ability to activate) to elicit a physiological response. Understanding this dual property is essential for drug design, as it helps target specific receptors while maximising therapeutic effects and minimising side effects
Describe the binding dynamics?
1:A drug interacts with a receptor to form a drug-receptor complex.
2:This process is governed by two opposing rates:
Forward Rate (Association): The rate at which the drug binds to the receptor.
Reverse Rate
(Dissociation): The rate at which the drug-receptor complex dissociates back into its components.
What is the law of mass action?
Describes the relationship between reactants and products in a reversible reaction at equilibrium.
What is the equilibrium condition?
At equilibrium, the rate of association equals the rate of dissociation
What is the equilibrium dissociation constant?
Represents the concentration of drug required to occupy 50% of available receptors at equilibrium. A lower KD indicates higher affinity, as less drug is needed to achieve binding.
What are the practical complications to binding?
KD provides a quantitative measure of drug affinity for its receptor.
Drugs with a lower KD are often more potent because they bind more tightly to their targets.
What is graph A showing? (check folder)
(linear dose-parabolic curve, difficult to identify)
What is graph B showing?
1: (log dose, ideally preferred in quantitative pharmacology)
A log dose-response curve, represented as a sigmoid shape.
2:kD (Dissociation Constant):
1:Defined as the drug concentration required to occupy 50% of receptors.
2:Represents the measure of drug affinity.
Key Insight:
1:Lower kD values indicate higher drug affinity, as a lower drug concentration is sufficient to achieve 50% receptor occupancy
What is RMAX + what it describes?
Represents the highest level of therapeutic effect that a drug can produce.
It is an intrinsic property of the drug, determined by its interaction dynamics with the target receptor.
Different drugs may exhibit different maximal efficacies even when interacting with the same receptor type.
What is the classification of drugs based on efficacy?
1:Full Agonist: Produces the maximum possible response when it binds to its receptor.
2:Partial Agonist: Produces a submaximal response even when all available receptors are occupied.
3:Antagonist: Blocks the action of agonists and has no intrinsic efficacy as it does not produce a therapeutic effect
What is potency (EC50) + describe details?
Refers to the amount or concentration of a drug required to produce a specific effect (drug’s effectiveness).
A more potent drug requires a lower dose to achieve the desired effect compared to a less potent drug.
Potency is quantified as the dose or concentration at which half of the maximal effect (EC50) is achieved.
Often associated with the strength or power of a drug in producing its pharmacological effect.
What are the clinical implications to potency?
Drugs with high potency require lower doses, which may minimise side effects and improve patient adherence.
Understanding the interplay of potency, efficacy, and affinity is crucial for optimising therapeutic interventions.
What does the cascade that triggers signals entail?
Signalling molecules: Amplify the initial signal.
Ion flow: Through channels contributing to cellular responses.
Second messengers: Such as cAMP and calcium ions, further amplify the signal.
mRNA and proteins: Induce long-term changes in the cell.
implications of signal amplification and spare receptors
Potency reflects the effective drug concentration required to elicit a significant biological response.
Affinity (kD) is a measure of how tightly the drug binds to the receptor, but it does not account for post-receptor signalling amplification.
what is going on with spare receptors/ receptor reserves?
Not all receptors need to be occupied to produce a maximal response.
The presence of spare receptors allows the system to achieve a full response even when the drug concentration is below that required to occupy all receptors (EC50 < kD).
This increases the efficiency and sensitivity of the system.
