Module 2: Receptor Theory (final version)

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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