phamacodynamics

Question 1

mechanism of drug action

Answer 1

The effects on the body of most drugs are a result of interactions with functional macromolecular components (receptors) of the organism

Drugs do not create effects, they modify ongoing functions

Question 2

Receptors have dual functions

Answer 2

Ligand (L) + Receptor (R) LR complex -(transduction)-> effect

Question 3

not all drugs produce effects via interactions with receptors

Answer 3

Enzyme inhibitors
Transporter inhibitors
Inhibitors of ion channels

the first step of all drugs is usually the reversible binding to the protein

Drug + Protein Drug/protein complex

Question 4

Receptors are an excellent drug target because:

Answer 4

Provide Specificity: (only a subset of receptors will be affected by the drug)

Provide Selectivity: (receptors are coupled to specific signaling pathways)

Provide Sensitivity: Receptor binding events are amplified intracellularly

Question 5

Law of mass action

Answer 5

L + R –> LR complex (k1)

L + R

Question 6

equilibrium dissociation constant (Kd)

Answer 6

describes the goodness of fit between L and R
inversely related to affinity of L of the R
has units of M

(when Kd is high the affinity is really low and L wont bind to the R)

Question 7

how Kd is determined

Answer 7

Rt (total R)= [LR] + [R]

[LR] = (Rt * [L]) / (Kd + [L])

When [L] is really large, [LR]=Rt
When [L] = Kd; [LR]= 1/2 Rt

Question 8

binding occurs bc of

Answer 8

the formation of bonds between the ligand and the receptors

ionic bonds: R have charged AAs, with many ligands are weak acids/based and are charged at phys pH, MAJOR determinant of k1

H bonds (due to electronegativity of O or N and a bound positive H)

Van der Waals : act at only very close interactions, multiplicative, greatly strengthened, MAJOR determinant of k2

Question 9

occupancy theory

Answer 9

L + R LR –> effect

E is proportional to the fraction of LR/Rt
Emax occurs when all R are in LR

E = (Emax * C) / (Kact + C)

Kact and EC50 : the Ligand concentration (C) at 1/2 of the Emax

Question 10

intrinsic activity

Answer 10

A drug response is proportional to both the fraction of occupied receptors AND the intrinsic activity (alpha)

Alpha: is the ratio of the Emax of the drug of interest to the maximum E max

E/Emax = alpha LR/ Rt
Agonist alpha= 1
Antagonist alpha = 0
Partial agonist 0< alpha < 1

Ligand affinity and ligand intrinsic activity/efficacy are independent factors (not all Rs have to be occupied to get E max) therefore Kd ø EC50 mainly bc of spare receptors

spare receptors increase the sensitivity to the ligand