Mechanisms of Drug Action

Question 1

Name 5 ways drugs initiate signaling.

Answer 1

1) Transactivation in steroid receptors=> hormone diffuses in, binds to intracellular receptor, activates to transcription factor
2) Ligand activates intracellular domain, which acts as an enzyme => converts a substrate
3) Ligand activates coupled intracellular partner which acts as a kinase to phosphorylate a specific target protein
4) Ligand activated ion channel activation (i.e. nicotinic Ach receptor) allows Na ions to flow into cell
5) G protein coupled receptors => coupled to Adenylate cyclase via a G protein, leading to ATP to cAMP production

Question 2

Which type of bonds terminate drug action?

Answer 2

All non-covalent complexes dissociate and terminate drug action

Question 3

What is ED50?

Answer 3

An effective dose (ED) is the dose or amount of drug that produces a therapeutic response/desired effect in some fraction of the subjects taking it.

ED50 or “median effective dose” is the dose that produces a quantal dose response (all or nothing) in 50% of the population that takes it

Question 4

What is LD50?

Answer 4

Lethal doses are usually expressed as median lethal dose (LD50), the point where 50% of test subjects exposed would die, in the units of mg/kg body weight

Question 5

Describe the graded/continual dose response.

Answer 5

A graded/continual dose response describes the change in effect on an organism caused by differing levels of exposure (or doses) to a stressor (usually a chemical) after a certain exposure time.

This type of graphical analyses is more common than a quantal dose response.

Question 6

What is TD50?

Answer 6

The median toxic dose (TD50) of a drug or toxin is the dose at which toxicity occurs in 50% of cases.

The median toxic dose encompasses the category of toxicity that is greater than half maximum effective concentration (ED50) but less than the median lethal dose (LD50)

Question 7

What does the degree of safety depend on?

Answer 7

Degree of safety depends on adequate separation between desirable effective dose (ED) undesirable effective dose (LD) => ED and LD should not overlap at any point (ED100 should not touch LD100)

Question 8

What is the therapeutic index?

Answer 8

The therapeutic index (TI) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.

TI=LD50/ED50 should be >1 (ideally >10)

Question 9

What is the margin of safety index?

Answer 9

The margin of safety index (MI) is more conservative than the therapeutic index.

MI= LD1/ED99 should be >1

Question 10

What is the protective index?

Answer 10

The protective index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.

PI = ED50 undesirable/99 dose ED 50 desirable
or
PI = TD50/ED50 should be >1 (the larger the better)

Question 11

What is the chronicity index?

Answer 11

The chronicity index measures the clearance of a drug and is important in considering the cumulative toxicity of a drug, since drugs are rarely given once.

CI = one dose LD50/99 dose ED50
CI = 1   translates to total clearance (best)

Question 12

What is the threshold dose?

Answer 12

The threshold dose is the apparent “all or none” phenomenon that occurs at a particular dose.

Question 13

Define potency.

Answer 13

Potency refers to the relative dose required to produce a given effect.

Question 14

Define intrinsic activity/efficacy.

Answer 14

Intrinsic activity (efficacy) refers to the magnitude of the maximal response (highest dose).

Question 15

Name 5 ways drugs can antagonize receptor action.

Answer 15

1) Chemical antagonism
2) Functional antagonism
3) Competitive antagonism
4) Non-competitive antagonism
5) Partial agonism/antagonism

Question 16

Define chemical antagonism.

Answer 16

Direct interaction of the agonist and antagonist

Question 17

Define functional antagonism.

Answer 17

Two agonists act independently but lead to opposite biological effects (i.e. opposite actions of Ach and Epi)

Question 18

Define competitive antagonism.

Answer 18

The antagonist binds the receptor but elicits no response, effectively competing with the agonist for binding. and blocking against action.

Two types:

1) Reversible/equilibrium competitive antagonism => non-covalent (largest class)
2) Irreversible /non-equilibrium competitive antagonism => covalent

Question 19

Describe the characteristics of reversible/equilibrium competitive antagonism.

Answer 19

In reversible/equilibrium competitive antagonism:

• An increase in agonist dose will restore efficacy (apparent potency)
• Dose response curve shifts right (increased required dose per response)

Question 20

Describe the characteristics of irreversible/non-equilibrium competitive antagonism.

Answer 20

In irreversible/non-equilibrium competitive antagonism:

• An increase in agonist dose does NOT restore efficacy
• Depressed dose response curve is observed

Question 21

Describe non-competitive antagonism

Answer 21

The antagonist acts at a site other than the site of agonist binding but affects the same process

Question 22

Describe partial agonism/antagonism.

Answer 22

Partial agonists can have full agonist and antagonist characteristics

Question 23

What is additivity?

Answer 23

The effect of two drugs given in combination is additive

Question 24

Define synergy.

Answer 24

Simple synergy => the effect of two drugs is greater than additive.

Potentiation => one (or both) drugs has no apparent effect alone, but dramatically alters the effect of the other drug in combination (can be dangerous)

Question 25

Which statistics would be used to evaluate the usefulness of a drug?

Answer 25

Compare LD50 to ED50