pharmacodynamics and receptors

pharmacodynamics

drug concentration at site of action to pharmacologic effect to clincal response that goes into toxicity and effectiveness

2 fundamental characteristics of a receptor

recognition capacity (binding) and amplification (initiation of response)

epinephrine

receptor binding resuolts in increase serum glucose

drug-receptor interation: binding

driving force for drug-receptor interaction-low energy state of drug receptor complex (binding energy)

Kd

measure of affinity to receptor (a dissociation constant)

what forces hold a drug-receptor complex together?

drug and receptor must have close complementary surfaces, small changes in gibbs free energy can greatly increase in binding. binding forces are weak, reversible, and noncovalent

which interactions contribute more strongly to drug-receptor binding

ionic, ion-dipole, dipole-dipole, and hydrogen bonding

which forces are weaker but together or multiple of them can impact binding

hydrophobic interaction, van der waals forces, and charge-transfer interactions

charge-transfer complexes (molecular dipole-dipole)

typically pi stacking in drugs and recptors involve pi systems that are electron rich (donors) like phenol that allow electron density to be raised and pi systems that are relatively electron poor (acceptor) which are aromatic rings with EWG that can be important in stabilizing drug interactions

hydrophobic interactions

increase in entropy of H20 molecules decreases free energy and therefore the complex is stabilzied. think like dissolves like

van der waals forces

as molecules approach, temporary dipoles in one molecule induce opposite dipoles in another therefore producing an intermolecular attraction

drug receptor interactions affinity

often expressed as the dissociation constant (Kd) which is the inverse of the association constant (Ka). treats binding and the effect of binding as separate phenomena

efficacy

alpha after drug binds

agonist

ligand that binds to a receptor and induces the same response as the reference molecule.can have both affinity for the receptor and efficacy with respect to a response

full agonist

if the ligand can bind to receptor site but induces less than the maximum response (alpha= 1)

partial agonist

if the ligant can induce less than the maximum response ( alpha < 1)

dose-response curve (find Kd)

use any measure of response (y) and means of measuring drug-receptor interactions (x) and at half of sigmoidal

full agonist vs partial agonist on a dose response curve

full agonist will reach 100%(1) while partical would be below

two stages of drug- receptor interactions

complexation with receptor (affinity) and initiation of response (efficacy intrinsic activity). full agonist does not equal full affinity

antagonist

ligand that binds to a receptor and blocks the response of the reference molecule. have affinity for the receptor but no efficacy with respect to a response (alpha=0)

competitive antagonist

binds to same site as drug. maximal drug response can be achieved if enough drug is added. apparent kD changes

noncompetitive anatagonist

binds to a different site on the receptor but still blocks activity. “non-surmountable”- the maximum response cannot be achieved in the presence of a noncompetitive antagonist. apparent Kd does not change

invert agonsist

binds receptor and causes opposite effect

to effect a certain response of a receptor

design an agonist

to block a particular response of a natural ligand of a receptor

design an antagonist

to produce the oppsite effect of the natural ligand

design an inverse agonist

a full or partial agonist displays what

a positive efficacy

an antagonist displays what

zero efficacy

a full or partial inverse agonist displays what

a negative efficacy

agonist vs antagonist structure

often structural similarity vs little structural similarity

drug receptor chirality

receptors are chiral (all L-amino acids) and racemic mixture forms two diasteromeric complex which have different energies stabilities

topographical and sterochemical considerations

Kd for enantiomers are different where eutomer is more potnent and distomer is less potent

ratio of potencies of enantiomers

eudismic ratio usually a high ratio is when antagonist has sterogenic center in pharmacophore because receptor complementarity would not be retained for the distomer

pfeiffer’s rule

an increase in eutomer potency will be accompained by an increase in eudismic ratio

distomer are what

an impurity that may contribute to side effects and/or toxicity

receptor interaction

enantiomers cannot be distinguished with only two binding site

three-point attachment concept

receptor needs at least three points of interaction to distinguish enantiomers

occupancy theory

intensity of pharmacological effect is directly proportional to number of receptors occupried. does not rationalize how two drugs can occupy the same receptor and act differently

rate theory

activation of receptors is proportional to the total number of encounters of a drug with its receptor per unit time. does not rationalize why different types of compounds exhibit the characteristics they do

induced fit theory

agonist induces conformation change-response, antagonist does not induce conformational change-no response, partial agonist induces partial conformational change-partial response

activation-aggregation theory

receptor is always in a state of dynamic equilibrium between activated form (Ro) and inactive form (To) where agonists shift equilibrium to Ro (biological response), antagonist shift equilibrium to To (no biological response), partial agonists bind to both Ro and To