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41 Cards in this Set
- Front
- Back
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What allows for drug ligands to bind to their receptors?
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Formation of bonds
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What are 3 types of bonds involved in ligand-receptor binding?
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1. Ionic
2. Hydrogen 3. Van der waal |
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What is involved in Ionic bond formation?
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Charged amino acids on weak acids or bases
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What is the ionization state of many weak acids or bases that are drugs, at physiological pH?
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Charged
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What is Ionic bonding the major determinant of in pharmacodynamics?
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k1 - the association rate constant
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What allows for Hydrogen bonds to form?
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Hydrogens that are bound to electronegative atoms like FON, resulting in the H have a partial positive charge.
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How do Hydrogen bonds compare to ionic bonds in general?
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-H bonds are weaker
-Require ionic bonds to be formed first |
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What are the weakest bonds involved in ligands binding their receptors?
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Van der waals
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What type of bonds are Van der Waals?
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Hydrophobic interactions that require very close distances
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How do Van der Waals forces compare to ionic and hydrogen bonds?
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They are the weakest; only strong when added together.
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What effect do Van der Waals forces have on ligand-receptor binding?
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They STRENGHTEN the binding interaction generated by ionic/hydrogen bonding
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What are Van der Waals forces the major determinant of?
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K2 - the dissociation rate constant
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What does the Occupancy theory refer to?
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The transduction of ligand binding into a cellular effect.
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Who proposed the occupancy theory?
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AJ Clark
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What are the 2 implications of the occupancy theory?
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1. The Effect of a drug binding its receptor is proportional to the fraction of occupied receptors
2. Maximal effect occurs when all receptors are occupied |
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What is the ratio of Observed effect / Max effect equal to?
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[LR]/Rt
(the effect observed is proportional to the fraction of occupied receptors) |
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What is Kact?
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The activation constant
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What is another name for Kact?
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EC50
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What is the EC50?
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The concentration of ligand that results in 1/2max effect
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What is EC50 comparable to?
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Kd
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So how do you calculate E?
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E = Emax x C / Kact + C
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What does the Occupancy theory fail to remember?
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That there are drugs that bind to receptors and cause NO effect, or reduced effects
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Who modified the Occupancy theory to account for varying degrees of how much a drug can cause an effect?
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Ariens
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How did Ariens modify the occupancy theory?
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By saying that an Effect is proportional to the fraction of occupied receptors AND the intrinsic activity of the ligand
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What is the symbol for Intrinsic Activity?
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alpha
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How do we calculate the fraction of Observed Effect:Max Effect based on Arien's modification?
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E/Emax = alpha x (Lr/Rt)
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What is Intrinsic Activity mathematically?
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The ratio of Emax of the compound of interest acting on a certain receptor, to the maximum Emax for a full agonist of that receptor
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So Alpha =
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Alpha = Emax/Emax max
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What is the intrinsic activity of
-An agonist -A Partial agonist -An antagonist |
Agonist = 1
Partial Agonist = between 0-1 Antagonist = 0 |
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What is another name sometimes used for Intrinsic Activity?
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Efficacy
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What is a drug (ligand) that has Intrinsic Activity of 0, but High affinity for its receptor?
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Curare - the ACh receptor antagonist
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What happens to the rectangular hyperbolic shape of the concentration-effect curve if you instead plot logC?
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It becomes sigmoidal
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Who made the final modification to the occupancy theory?
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Stephenson
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What was Stephenson's modification of the occupancy theory?
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That not all receptors have to be occupied in order for maximal effect to be occurring
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How can the maximum effect be exerted by a drug if not all receptors are bound?
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Tissues have spare receptors
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What is the mathematical implication of the Stephenson modification?
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The Kd (conc of L at which 1/2 of all receptors are bound) is not necessarily equal to the EC50 (conc of L at which 1/2 the max effect is observed)
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How does the EC50 compare to Kd for most drugs in fact?
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It is often lower than the Kd
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How does the Stephenson modification change the calculation for E/Emax?
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E/Emax = f(a x LR/Rt)
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What is the function of spare receptors?
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To increase the sensitivity of a cell to a low concentration of ligand
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How do spare receptors increase the sensitivity of a cell to low drug concentrations?
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At the same concentration of D, a larger proportion of Rt will be occupied, and since 1 effect results from every Receptor bound, the effect is larger for a tissue with spare receptors.
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So the presence of spare receptors together with the normally low affinity of endogenous agonists allows for:
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High sensitivity without long activation time
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