Module 2 - Receptor Theory

membrane receptors

ion channels

carriers/transporter molecules

enzymes

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

affinity for receptor

efficacy when bound

agonists: have affinity and efficacy

antagonists: have affinity but no efficacy (no effect)

blocks agonist ligands from binding same receptor

reversible reaction

association rate constant: k+1

dissociation rate constant: k-1

Full agonists

may have different potency but can achieve maximal efficacy, maximal response

Partial agonists

drugs that bind but may not cause optimal conformational changes in receptor = some response but not maximum response

lower efficacy

Inverse agonists

binds to constitutively active receptor = reduction in that constitutive activity

some receptors have low level of constitutive activity regardless of agonist being bound

causes change in receptor signal (a reduction though, hence inverse)

negative efficacy

gradual diminishing of response to drug - tolerance

changes in receptors

altered conformation

uncoupling of associated signaling molecules

translocation of receptors

which are destroyed

exhaustion of mediators

altered drug metabolism

physiological adaptation

systems in body try and compensate for imbalance

dose at which patient responds; all or nothing

ED50 is dose that produces desired effect in 50% of treated population

population response curve uses quantal data as a frequency distribution curve to allow for evaluation of drug efficacy in total population

Equilibrium dissociation constant (KD): concentration of drug required to occupy 50% of receptors

KD units of concentration: mol/L (M)

can be graphed linear or logarithmic

KD = k-1/k+1 [A][R]/[AR]

shoes ratio of occupied receptors to unbound receptor and drug

drug w/ high affinity for receptor

lower dose required to achieve 50% receptor binding

lower KD

drug w/ low affinity for receptor

higher dose required to achieve 50% receptor binding

higher KD

Law of mass action

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

rate of rxn proportional to the product of concentration of reactants

PA = [AR]/[Rtot] = [A]/KD+[A]

Subtopic

concentration of receptors occupied/total receptor concentration

can't determine number of receptors, but we do know KD for drugs

calculates effects of antagonist or agonist receptor binding

%age drug bound o receptor may not be equivalent to %age of real tissue response

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

Dose Response Curve

time dose is administered and the response achieved

log scale used because effects usually occur w/in narrow concentration range

ED50 is measure of potency (power of drug)

ED25 (amount of drug to get 25% response)

ED90 (amount of drug to get 90% response)

potency indicates amount of drug required to achieve specific LEVEL of response

Efficacy: maximal effect of drug at saturating concentrations

agonist can stimulate a signal response from a receptor (intrinsic activity)

reversible antagonist: decrease potency of agonist drug

competes for binding sites and dilutes agonist

if you add more agonist you can recover same receptor occupation

administering reversible competitive antagonist in presence of agonist drug shifts binding curve right (more agonist needed to achieve same receptor occupancy)

agonist drug in presence of antagonist shifts dose response curve right = increase in effective ED50 of agonist drug)

most common antagonists

irreversible antagonist: binds to receptor and remains there (covalent binding)

reduces potency of agonist drug

reduces total number of receptors available for agonist - reduces maximal response that agonist drug can provoke (efficacy)

seen in case of toxins

Non-competitive antagonism

allosteric antagonism

pharmacokinetic antagonism

signaling blockade

physiological antagonism

chemical antagonism

zero efficacy

additive effect: overall effect is greater than sum of individual drug effects (drug combinations)

one drug preventing metabolism/breakdown of second drug

increases efficacy of drug

two drugs targeting diff. molecules on same signaling path = enhanced downstream effect

limiting dose for drug is point that adverse rxns (toxicity) become too great to support its therapeutic usage

TI: LD50/ED50

Drug is considered safe if therapeutic index is high

Drug is unsafe is therapeutic index is low

LD = lethal dose; ED = effective dose

we don't want overlap between therapeutic and toxic doses of drug; greater separation = safer

Certain Safety Factor (CSF) = LD1/ED99

CSF>1 = dose effective in 99% of population is lower than dose that is toxic in 1% of population

CSF<1 = therapeutic dose may be toxic in more than 1% of population