Module 2: Receptor Theory (final version)

antagonists

NO efficacy

affinity

agonists

affinity

efficacy

most therapeutic drugs = reversible rxn

dissociation rate constant = k-1

association rate contant = k+1

dissociation constant = KD

[drug] required to occupy 50% of receptors @ equilibrium

higher KD = lower affinity, vice versa (inverse relationship)

law of mass action = k+1[A][R] = k-1[AR]

rate of rxn is proportional to the product of the [reactants]

association rate = dissociation rate

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

ratio of occupied receptors to unbound receptor and drug equals the ratio of dissociation and association rate constants which = KD

2nd derivation (Hill-Langmuir): pA = [AR]/[Rtot} = [A]/KD+[A]

calculates fraction of drug occupied by receptors

ED50 = 50% effective dose (dose of drug required to illicit 50% maximal biological response

ED50 = measure of potency

efficacy vs. potency

potency: the amount of drug required to achieve specific level of response

efficacy: measure of the maximal effect of drug @ saturating concentrations

reversible competitive antagonist

Hill-Langmuir applies

decreases potency of agonist drug, decrease ED50

most antagonists

irreversible antagonist

perma prevents receptor from ever binding an agonist

reduce potency of agonist drug

tend to be toxins

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)

inverse agonists

drug that binds to constitutively active receptor and reduces constitutive activity, "negatvie efficacy"

non-competitive antagonism

allosteric antagonism

pharmacokinetic antoagonism

signaling blockade

physiological antagonism

chemical antagonism

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

Synergy

overall effect is greater than sum of individual effects

Additive

overaell effect is direct sum of individual drug effects

gradual diminishing response to drug

changes in receptors

altered conformation

uncoupling of associated signaling molecules

translocation of receptors

exhaustion of mediators

altered drug metabolism

physiological adaptation

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

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)