Module 2: Receptor Theory (final version)
therapeutic index
the point of dosage that adverse reactions become too great to support its therapeutic usage: LD50/ED50
the higher the value, the safer the drug (LD50 and ED50 far from each other)
Population response curvves
ED50 = dose that produces the desired effect in 50% of treated population
Desensitization
physiological adaptation
altered drug metabolism
exhaustion of mediators
translocation of receptors
changes in receptors
uncoupling of associated signaling molecules
altered conformation
gradual diminishing response to drug
Synergy vs. additive
Additive
overaell effect is direct sum of individual drug effects
Synergy
overall effect is greater than sum of individual effects
spare receptor
cells/tissues express more receptors than required for max response
not very understood why this is, but large numbers of spare receptors = relatively modest amounts of ligands have a far greater chance of inducing max response
Receptor antagonism
non-competitive antagonism
chemical antagonism
physiological antagonism
signaling blockade
pharmacokinetic antoagonism
allosteric antagonism
inverse agonists
drug that binds to constitutively active receptor and reduces constitutive activity, "negatvie efficacy"
Partial agonists
drugs that may bind but may not cause optimal conformational changes in the receptor and thus will provoke some response but not maximum possible response (cannot achieve maximal efficacy)
irreversible antagonist
tend to be toxins
reduce potency of agonist drug
perma prevents receptor from ever binding an agonist
reversible competitive antagonist
most antagonists
decreases potency of agonist drug, decrease ED50
Hill-Langmuir applies
Dose response relationships
efficacy vs. potency
efficacy: measure of the maximal effect of drug @ saturating concentrations
potency: the amount of drug required to achieve specific level of response
ED50 = 50% effective dose (dose of drug required to illicit 50% maximal biological response
ED50 = measure of potency
(I can't do subscripts on here so some equations may look incorrect)
Quantitative aspects of drug-receptor interactions
law of mass action = k+1[A][R] = k-1[AR]
1st derivation: [A][R]/[AR] = k-1/k+1 = KD
2nd derivation (Hill-Langmuir): pA = [AR]/[Rtot} = [A]/KD+[A]
calculates fraction of drug occupied by receptors
ratio of occupied receptors to unbound receptor and drug equals the ratio of dissociation and association rate constants which = KD
association rate = dissociation rate
rate of rxn is proportional to the product of the [reactants]
Drug-receptor interactions
dissociation constant = KD
higher KD = lower affinity, vice versa (inverse relationship)
[drug] required to occupy 50% of receptors @ equilibrium
Drug-receptor binding
most therapeutic drugs = reversible rxn
association rate contant = k+1
dissociation rate constant = k-1
agonists
efficacy
antagonists
affinity
NO efficacy
