Mechanisms Of Drug Action, Dose-Effect Relationships, & Drug Selectivity - All Of The Cottone Lectures

Front 1

Most drugs that target enzymes have what effect?

Back 1

inhibitors

Front 2

Most drugs that target transporters (i.e. reuptake of serotonin) have what effect?

Back 2

inhibitors

Front 3

Most drugs that target ion channels have what effect?

Back 3

inhibitory

Front 4

Dose intensity curves aka? What do they show?

Back 4

aka non-quantal curves:

show how big the effect of a drug is

Front 5

Dose frequency curves aka? What do they show?

Back 5

aka quantal curves

show how many in a population are effected

Front 6

KD50?

Back 6

drug concentration at which 50% of receptors are occupied

Front 7

EC50?

EMax?

Back 7

EC50 = Drug concentration producing an effect that is 50% of the maximum effect

EMax = maximum effect of a drug

Front 8

Potency?

Back 8

Potency = EC50 = [ ] of a drug able to give the 50% of its maximal effect

Front 9

Efficacy?

Back 9

Efficacy = Emax = maximum effect of a drug achievable at high dose

Front 10

How are potency and efficacy related

Back 10

They aren't related sukkaaaaa

Front 11

When comparing two drugs, a lower EC50 = ?

Back 11

lower EC50 = higher potency

Front 12

When looking at a graph of two drugs, the drug with the higher Emax is _________ and the drug with the lower EC50 is _________

Back 12

When looking at a graph of two drugs, the drug with the higher Emax is more efficacious and the drug with the lower EC50 is more potent

Front 13

Potency ≈ how well the drug ?

Efficacy ≈ how well the drug ?

Back 13

Potency ≈ how well the drug binds the receptor

Efficacy ≈ how well the drug produces the effect

Front 14

BoundReceptor/TotalReceptor = ?

Back 14

BoundReceptor/TotalReceptor =

[Drug]/KD + [Drug] =

1/1+ KD/[Drug]

Front 15

Drug A binding receptor R equation?

Back 15

1 + KA/[A]

Front 16

Selectivity?

What is a highly selective drug?

Back 16

ability of a drug to affect one tissue or receptor in preference to another

A highly selective drug is a drug which affects only a receptor or tissue without affecting others

Front 17

Full agonist = ?

Partial agonist = ?

Back 17

Full agonist: a drug that binds to a receptor and produces a maximal biologic response

Partial agonist: a drug that has efficacy greater than zero but less than that of a full agonist

Front 18

Neutral antagonist = ?

Inverse agonist = ?

Back 18

Neutral antagonist: a drug that does not induce a biological response and reduces/blocks the response induced by the agonist

Inverse agonist: a drug that induces a pharmacological response opposite to that of the agonist.

Front 19

Antagonism?

Back 19

the process by which a drug decreases or opposes the action of another drug or endogenous ligand

Front 20

Chemical antagonism

Back 20

antagonist interacts with the agonist to render the agonist inactive.

Front 21

pharmacokinetic antagonism?

Back 21

antagonist accelerates the metabolism or the elimination of the agonist.

Front 22

physiological antagonism

Back 22

antagonist activates a different mechanisms that opposes the effects of the agonist

Front 23

3 types of pharmacological antagonism?

Back 23

1. Reversible competitive
2. Noncompetitive
3. Irreversible competitive

Front 24

Reversible competitive antagonism:

mechanism?

changes in curve on graph?

effect on EMax?

effect on potency?

Back 24

mechanism = 2 drugs compete for same site

curve = shifts right

effect on EMax = unchanged

effect on potency = higher ED50 = lower potency

Front 25

Equation for competitive inhibition?

Back 25

a'/a = 1 + [B]/Kb

a' = the new EC50 in presence of inhibitor

Front 26

Non-competitive:

mechanism?

effect on EMax?

effect on potency?

Back 26

mechanism = binds receptor at a different site (agonist can still bind) = insurmountable

effect on EMax = lowered

effect on potency = unchanged

curve looks like it is getting squashed

Front 27

irreversible competitive:

mechanism?

effect on EMax?

effect on potency?

Back 27

mechanism = usually covalent binding to receptor = insurmountable

effect on EMax = lower

effect on potency = unchanged

resembles non-competitive

Front 28

(From slide 54):

If there is a full agonist in the pts system at a concentration lower than the Emax of a partial agonist, what happens to the appartent efficacy if you add the partial agonist?

Back 28

Adding a partial agonist will increase the effect

Front 29

(From slide 54):

If there is a full agonist in the pts system at a concentration higher than the Emax of a partial agonist, what happens to the appartent efficacy if you add the partial agonist?

Back 29

Adding a partial agonist will decrease the effect

Front 30

(From slide 54):

If there is a full agonist in the pts system at a concentration equal to the Emax of a partial agonist, what happens to the appartent efficacy if you add the partial agonist?

Back 30

There is no real change in effect

Front 31

(From slide 54):

If there is a partial agonist in the pts system at a concentration lower than the Emax of a full agonist, what happens to the appartent efficacy if you add the full agonist?

Back 31

The full agonist will increase the effect. Always.

Front 32

Effect of agonist when spare receptors are present?

Back 32

When spare receptors are present, an agonist may produce a maximum response even though the agonist concentration is not high enough to fully occupy all of the available receptors

Front 33

How do spare receptors change the efficacy with respect to %bound? Spare receptors effect on potency?

Back 33

In the case of no spare receptors %bound = %effective.

Spare receptors: %bound <<< %effective

Potency of agonists appears higher

Front 34

Spare receptors effect on partial agonists?

Back 34

a partial agonist may produce the same apparent maximum response as a full agonist

Front 35

Spare receptors effect on non-competitive and irreversible inhibitors?

Back 35

the decrease in maximum response expected from a noncompetitive or irreversible inhibitor may be partially hidden:

Emax doesn't decrease by as much

Potency does! change: it decreases

Front 36

Spare receptors effect on competitive inhibitors?

Back 36

%effect and %bound change by the same magnitude.

%bound is still less than %effect and the curve is still shifted to the right and you can use the same a'/a = 1 + B/Kb

Front 37

compare the Kinactive and the Kactive using the two state model for:

agonists =

competitive antagonists =

inverse agonists =

Back 37

agonists = Kinactive > Kactive

competitive antagonists = Kinactive = Kactive

inverse agonists = Kinactive < Kactive

Front 38

Summation

Back 38

Joint effect of the two drugs is the algebraic sum of their individual effects

Front 39

Synnergism

Back 39

two drugs add to give an effect greater than the sum of their individual effects

Front 40

Potentiation

Back 40

inert drug potentiates the effect of another drug

can effect potency and efficacy

Front 41

Allosteric modulators

Back 41

bind receptor at site other than that of endogenous ligand and potentiate or inhibit the effect of the ligand

Front 42

population dose effect curve?

Back 42

Sigmoidal shape = adds all pts who responded to a drug at a certain dose + all pts who responded at a lower dose.

Front 43

quantal curve slope changes?

Back 43

shallower = more variability between pts in their response.

narrow curve = less variability

Front 44

LD50?

Therapeutic index?

Back 44

LD50 = dose producing death in 50% of patients

Therapeutic index = TI = ratio of LD50 to ED50: LD50/ED50 --> the higher the better

Front 45

Pitfall of TI?

Back 45

Only compares LD50 points. Doesn't compare the tails of the curves that could overlap and mean more toxicity/variability

Front 46

Standardized safety margin?

Back 46

[(LD1% - ED99%)/ED99%] X 100

The higher the better