Pharmacodynamics Module 2 - Receptor Theory

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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