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Flashcards in Mechanisms of Drug Action Deck (25):

Name 5 ways drugs initiate signaling.

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


Which type of bonds terminate drug action?

All non-covalent complexes dissociate and terminate drug action


What is ED50?

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


What is LD50?

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


Describe the graded/continual dose response.

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.


What is TD50?

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)


What does the degree of safety depend on?

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)


What is the therapeutic index?

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)


What is the margin of safety index?

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

MI= LD1/ED99 should be >1


What is the protective index?

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
PI = TD50/ED50 should be >1 (the larger the better)


What is the chronicity index?

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)


What is the threshold dose?

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


Define potency.

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


Define intrinsic activity/efficacy.

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


Name 5 ways drugs can antagonize receptor action.

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


Define chemical antagonism.

Direct interaction of the agonist and antagonist


Define functional antagonism.

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


Define competitive antagonism.

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


Describe the characteristics of reversible/equilibrium competitive antagonism.

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)


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

In irreversible/non-equilibrium competitive antagonism:
- An increase in agonist dose does NOT restore efficacy
- Depressed dose response curve is observed


Describe non-competitive antagonism

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


Describe partial agonism/antagonism.

Partial agonists can have full agonist and antagonist characteristics


What is additivity?

The effect of two drugs given in combination is additive


Define synergy.

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)


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

Compare LD50 to ED50