Pharmacodynamics I - The concept of agonism Flashcards
What are the 2 functions of receptors?
Binding to and recognizing signalling molecules
Initiating signalling pathways
What kind of bonds are typical of receptor/ligand interactions?
Weak bonds such as hydrogen bonds, ionic bonds, and van der waals forces.
What influences affinity of a drug to bind to its target?
Complementary attractive forces of attraction
3d shape of drug and target
What key factors affect strength of chemical forces between receptor and ligand?
Type of bond
Distance between the receptor and ligand
Total number of bonds
What 2 factors affect how much of a drug is bound to receptors?
Affinity
Drug concentration
Is drug binding reversible?
Yes, reaction between drug binding and separation is in equilibrium
Fraction of target bound by drug=
[Drug]/([drug]+Ka) this is a rectangular hyperbolic function
Ka=[drug] where 50% of receptors ate bound
What phenomena cause the shape of the rectangular hypolic function seen in receptor binding vs [drug] graph?
Initially, no drugs bound to target.
At the plateau all receptors are bound by drug.
Until the point of saturation there is an increase in number of ligands bound to receptors but this increase slows down as the receptors are filling up.
What is Ka?
The [drug] at which 50% of receptors are bound
What information does Ka provide us with?
The affinity
What does a low Ka value indicate?
Low concentration for 50% of receptors to be bound by drug. This means the affinity is high. (relationship is inversely proportional)
What is drug selectivity?
A drug can have a higher affinity for certain molecules compared to others.
What are drugs that bind to and activate receptors that alter activity of downstream signalling pathways called?
Agonists
What is efficacy of an agonist?
The ability to activate a receptor after binding.
How does beta2 adrenoceptor get activated?
Adrenaline binds to it and movesone of the 7 transmembrane helices into a conformation that opens up for G protein to bind to it and to activate downstream signals.
What is the difference between full and partial agonists?
Full agonists have high efficacy and a high level of receptor activation with large effect.
Partial agonists have lower efficacy, less receptor activation and a smaller effect.
What do antagonists do?
Bind to receptors but have no efficacy so they don’t activate signals.
What drug-dependent factors affect agonist-induced changes?
Concentration
Affinity
Efficacy
What happens to drug effect if we decrease number of receptors in the cell?
We decrease overall effect
What can trigger a decrease in receptor density?
Disease (eg myasthenia gravis)
Drugs (irreversible antagonists)
Gene silencing techniques
What is the plot of [D] vs effect called?
Dose-response curve which is a measure of agonist potency
What is agonist potency?
Describes relationship between [agonist] and effect
What is EC50?
[agonist] that produced 50% of maximum possible effect
The lower the EC50 the more ____ the agonist.
Potent
Which common drug is an agonist?
Salbutamol
True or False?
Most widely-used drugs work as agonists.
False, most drugs work by binding to and inhibiting the function of the target.
