QUANTITATIVE ASPECTS OF DRUG ACTION

ilos By the end of this lecture you will be able to :

Recognize different dose response curves

Classify different types of antagonism

Determine quantitative aspects of drug receptor binding

Distinguish the therapeutic utility of each of these curves

The tendency of a drug to bind to the receptors is governed by its affinity.

The ability for it, once bound, to activate the receptor is denoted by its efficacy.

AFFINITY

EFFICACY

QUANTIFY ASPECTS OF DRUG ACTION

RD

BindOccupy

InitiateActivate

RD RESPONSE[R]

+ DR*

Relate concentration [C] of D used (x- axis) to the R produced (y-axis)

Relate concentration [C] of D used (x- axis) to the binding capacity at receptors (y-axis)

AFFINITY

Concentration-Binding Curve Dose Response Curve

EFFICACY

POTENCY

k1

k2

association rate constant

dissociation rate constant

RD

BindOccupy

InitiateActivate

RD RESPONSE[R]

+ DR*

Concentration-Binding Curve

B = -----------Bmax xC

C+ KD50

The relationship between drug binding & drug concentration is expressed mathematically by the following equation

Concentration-Binding Curve

KD KD

(Bmax): Total density of receptors in the tissue

Concentration-Binding curves are used to determine:

1. The binding capacity (Bmax) → total density of receptors in the tissues. 2. The affinity of D for receptor The higher the affinity of D for receptor the lower is the KD i.e. inverse relation

(kD ) = [C] of D required to occupy 50% of receptors at equilibrium

???

DOSE RESPONSE CURVE

QUANTAL DOSE RESPONSE CURVE

GRADED DOSE RESPONSE CURVE

A continuous responseBP, HR, FBG, Cholesterol,…

GRADED DOSE RESPONSE CURVE

% of Maximal

Effect

[C]

0

20

40

60

80

100

0 200 400 600 800

GRADED DOSE RESPONSE CURVE

Max effect = Emax Effect when all the receptors are occupied by D

C that gives the half-maximal effect

E= -----------Emax xC

C+ EC50

As C ↑ response increment ↓

0

20

40

60

80

100

1 10 100 1000

% of Maximal

Effect

[C]EC50Graded dose-response curves are used to determine:

1. The max efficacy (Emax) → highest limit of dose-response relationship on response axis. 2. The potency = The concentration of drug required to produce a specified response The smaller the EC50 , the greater the potency of the agonist, i.e the lower C needed to elicit the maximum biological response.3. Compare the relative potency and efficacy of drugs that produce the same effect.

EC50

GRADED DOSE RESPONSE CURVE

A >

effic

acy

than

B

B P

artia

l Ago

nist

EFFIC

ACY

POTENCYA > potent B

X > potent than Y & Z

X &

Z >

effi

cacy

than

Y

X &

Z a

re e

qual

effi

cacy

Y> potent than Z

GRADED DOSE RESPONSE CURVE

Y > potent but

< efficacious than Z

DOSE RESPONSE CURVE

QUANTAL DOSE RESPONSE CURVE

GRADED DOSE RESPONSE CURVE

QANTAL DOSE RESPONSE CURVE All-non responses* specified therap. response * adverse response * lethal outcome

% s

ubje

cts

resp

ondi

ng

Dose-frequency relationship

0

20

40

60

80

100

1 10 100 1000

[Dose]

ED50

% s

ubje

cts

resp

ondi

ngQANTAL DOSE RESPONSE CURVE: used to determine

TD50 LD5050% of individuals exhibit the specified therapeutic responseMedian toxic dose Median lethal doseMedian Effective Dose

Predict the safety profile

Therapeutic Index

The relation between dose to induce a desired effect versus that producing the unwanted effect.

TD50

ED50

When low → the drug has a narrow margin of safety digoxinWhen high → the drug has a safe profile diazepam

Therapeutic Effect

Toxic Effect

Lethal Effect

Types

Physiological

Chemical Pharmacokinetic Non-Competitive

It is the diminution or the complete abolishment of the effect of one drug in the presence of another.

Receptor Blockade

Competitive

Two drugs react chemically resulting in loss of activity of active drug

Two drugs possess opposing actions in the body, so tend to cancel each other’s effect

The antagonist effectively reduces the concentration of the active drug at the site of actionPhenobarbitone induces an accelerated hepatic metabolism warfarine

Omeprozole & histamine

ANTAGONISM

Dimercaprol reduces heavy metal toxicity [ lead, ….]

Receptor Blockade

Competitive

Non-Competitive

Antagonist prevents binding of agonist to the receptor at the same binding site ( = competes with it at same occupancy site )

Antagonist block at some point the chain of events that ignite the response of agonist

Agonist and Antagonist can be bound simultaneously

Agonist and Antagonist compete( only one is bound)

ANTAGONISM

Irreversible

Reversible

ReversibleAntagonist readily dissociate from binding site of agonist to the receptor

Antagonist form stable, permanent / near permanent chemical bond with receptor.

Inactivation lasts for duration of receptor turnover or its de- novo synthesis → explains its longevity of action

Antagonism can be overcomed by increasing concentration of agonist = Surmountable

Phenoxybenzamine & Noradrenaline

Atropine vs Ach

Irreversible

COMPETATIVE ANTAGONISM

Parellel shift to the right, without any change in slope or maximum

No parellel shift but both a decrease in slope and a reduced maximum are obtained.

Competitive Antagonism

Irreversible

Reversible

Agonist

Agonist + irreversible competitive antagonist

Agonist + non-competitive antagonist

0

20

40

60

80

100

1 10 100 1000

% of Maximal Effect

[C]

Antagonism cannot be overcomed by increasing concentration of agonist = NON-SURMOUNTABLE

Agonist + reversible competitive antagonist

Competitive vs Noncompetative Antagonism

Depression of maximal response +/- rightward shifts ( if some R are spare )

Antagonism can be overcomed by increasing concentration of agonist = SURMOUNTABLE

Verapamil vs noradrenaline

QUANTITATIVE ASPECTS OF DRUG ACTION

By the end of this lecture you ARE able to :

Recognize different dose response curves

Classify different types of antagonism

Determine quantitative aspects of drug receptor binding

Distinguish the therapeutic utility of each of these curves

G O O D

L U C K