Module 2 - Receptor Theory
Therapeutic Index
Certain Safety Factor (CSF) = LD1/ED99
CSF<1 = therapeutic dose may be toxic in more than 1% of population
CSF>1 = dose effective in 99% of population is lower than dose that is toxic in 1% of population
TI: LD50/ED50
LD = lethal dose; ED = effective dose
we don't want overlap between therapeutic and toxic doses of drug; greater separation = safer
Drug is unsafe is therapeutic index is low
Drug is considered safe if therapeutic index is high
limiting dose for drug is point that adverse rxns (toxicity) become too great to support its therapeutic usage
Synergy
two drugs targeting diff. molecules on same signaling path = enhanced downstream effect
one drug preventing metabolism/breakdown of second drug
increases efficacy of drug
additive effect: overall effect is greater than sum of individual drug effects (drug combinations)
Receptor Antagonism
zero efficacy
Non-competitive antagonism
chemical antagonism
physiological antagonism
signaling blockade
pharmacokinetic antagonism
allosteric antagonism
irreversible antagonist: binds to receptor and remains there (covalent binding)
seen in case of toxins
reduces total number of receptors available for agonist - reduces maximal response that agonist drug can provoke (efficacy)
reduces potency of agonist drug
reversible antagonist: decrease potency of agonist drug
most common antagonists
agonist drug in presence of antagonist shifts dose response curve right = increase in effective ED50 of agonist drug)
administering reversible competitive antagonist in presence of agonist drug shifts binding curve right (more agonist needed to achieve same receptor occupancy)
if you add more agonist you can recover same receptor occupation
competes for binding sites and dilutes agonist
Dose Response Relationships
Dose Response Curve
Efficacy: maximal effect of drug at saturating concentrations
agonist can stimulate a signal response from a receptor (intrinsic activity)
ED50 is measure of potency (power of drug)
potency indicates amount of drug required to achieve specific LEVEL of response
ED90 (amount of drug to get 90% response)
ED25 (amount of drug to get 25% response)
log scale used because effects usually occur w/in narrow concentration range
time dose is administered and the response achieved
KD replaced by ED50 (50% effective dose - dose required to illicit 50% maximal biological response) or EC50 (50% effective concentration)
ED50 & EC50 describe potency of drug
%age drug bound o receptor may not be equivalent to %age of real tissue response
Percentage of drug-bound receptors
calculates effects of antagonist or agonist receptor binding
PA = [AR]/[Rtot] = [A]/KD+[A]
can't determine number of receptors, but we do know KD for drugs
concentration of receptors occupied/total receptor concentration
Subtopic
Main topic
Drug-receptor interaction
Law of mass action
rate of rxn proportional to the product of concentration of reactants
k+1[A][R] = k-1[AR]
no more drug added and rxn eventually reaches equilibrium where association rate = dissociation rate and conc. of reactants and products doesn't change
drug w/ low affinity for receptor
higher dose required to achieve 50% receptor binding
higher KD
drug w/ high affinity for receptor
lower dose required to achieve 50% receptor binding
lower KD
Equilibrium dissociation constant (KD): concentration of drug required to occupy 50% of receptors
KD = k-1/k+1 [A][R]/[AR]
shoes ratio of occupied receptors to unbound receptor and drug
can be graphed linear or logarithmic
KD units of concentration: mol/L (M)
Quantal response
population response curve uses quantal data as a frequency distribution curve to allow for evaluation of drug efficacy in total population
dose at which patient responds; all or nothing
ED50 is dose that produces desired effect in 50% of treated population
Desensitization/Tachyphylaxis
physiological adaptation
systems in body try and compensate for imbalance
altered drug metabolism
exhaustion of mediators
translocation of receptors
which are destroyed
changes in receptors
uncoupling of associated signaling molecules
altered conformation
gradual diminishing of response to drug - tolerance
Agonists
Inverse agonists
causes change in receptor signal (a reduction though, hence inverse)
negative efficacy
binds to constitutively active receptor = reduction in that constitutive activity
some receptors have low level of constitutive activity regardless of agonist being bound
Partial agonists
lower efficacy
drugs that bind but may not cause optimal conformational changes in receptor = some response but not maximum response
Full agonists
may have different potency but can achieve maximal efficacy, maximal response
Drug-receptor binding
dissociation rate constant: k-1
association rate constant: k+1
reversible reaction
antagonists: have affinity but no efficacy (no effect)
blocks agonist ligands from binding same receptor
agonists: have affinity and efficacy
efficacy when bound
affinity for receptor
Spare Receptors
unbound receptors/receptor reserve
large number spare receptors = modest amounts of ligands have greater change of inducing maximal response; easier for ligand to find receptor
"Drug won't work unless it is bound"
drug targets
enzymes
carriers/transporter molecules
ion channels
membrane receptors
drug target = receptor
