QUANTITATIVE ASPECTS OF DRUG ACTION
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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
Distinguish the therapeutic utility of each of these curves
ByProf. Omnia NayelAssoc. Prof. Osama Yousif
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DOSE RESPONSE CURVE
A continuous responseBP, HR, FBG, Cholesterol,…
GRADED DOSE RESPONSE CURVEAn all-or-non response
prevention of convulsion, arrhythmias or death…..
Relate C to % of patients eliciting the : * specified therapeutic response * adverse response * lethal outcome
QUANTAL DOSE RESPONSE CURVE
How does response vary with C?
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A continuous responseBP, HR, FBG, Cholesterol,…
GRADED DOSE RESPONSE CURVE
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% of Maximal
Effect
0
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0 200 400 600 800
Max effect = Emax Effect when all the receptors are occupied by D
C that gives the half-maximal effect
As C ↑ response increment ↓
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% of Maximal
Effect
EC50
Graded 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
[C]
[C]
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GRADED DOSE RESPONSE CURVE
A >
effic
acy
than
B
B Pa
rtial
Ago
nist
EFFICACY
POTENCYA > potent B
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X > potent than Y & Z
X &
Z >
effic
acy
than
Y
X &
Z ar
e eq
ual e
ffica
cy
Y> potent than Z
GRADED DOSE RESPONSE CURVE
Y > potent but
< efficacious than Z
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QANTAL DOSE RESPONSE CURVEAll-non responses
% s
ubje
cts
resp
ondi
ng
Dose-frequency relationship
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0
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[Dose]ED50
% s
ubje
cts
resp
ondi
ngQANTAL DOSE RESPONSE CURVE: used to determine
TD50LD50
1. 50% of individuals exhibit the specified therapeutic response2.Median toxic dose 3. Median lethal dose1. Median Effective Dose
Predict the safety profileTherapeutic Effect
Toxic EffectLethal Effect
2. “ “ “ toxic effects 3. “ “ “ death
Therapeutic Index
TD50
ED50
The relation between dose to induce a desired effect versus that producing the unwanted effect.
When low → the drug has a narrow margin of safety →digoxinWhen high → the drug has a safe profile → diazepam
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Types
2.Physiological
1. Chemical
3. Pharmacokinetic
5. Non-Competitive
It is the diminution or the complete abolishment of the effect of one drug in the presence of another.
4. Receptor Blockade (Competitive )
Two drugs react chemically resulting in loss of activity of active drug.Dimercaprol reduces heavy metal toxicity [ lead]
Two drugs possess opposing actions in body, so tend to cancel each other’s effect.
The antagonist effectively reduces the concentration of the active drug at the site of actionPhenobarbitone accelerates hepatic metabolism warfarin
Omeprozole & histamine
ANTAGONISM
Irreversible
Reversible
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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
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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
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Parallel shift to the right, without any change in slope or maximum
No parallel shift But both a decrease in slope and a reduced maximum are obtained.
Competitive Antagonism
Irreversible
Reversible
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Agonist
Agonist + irreversible competitive antagonist
Agonist + non-competitive antagonist
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% 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
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Quiz?• Concentration-binding-curves are used
to detect: A) highest limit of dose-response
relationship B) concentration of drug required to produce a specified response C) affinity of a drug for its receptor D) therapeutic index of a drug
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Quiz?• Drug A has a smaller EC50 than drug B.
This means that drug B is:
• A) more potent than AB) less potent than AC) more efficacious than AD) less efficacious than A
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Quiz?• An example of a reversible competitive
antagonist is:
• A) phenoxybenzamine to noradrenaline.B) omeprazole to histamineC) dimercaprol to leadD) atropine to acetylcholine
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Quiz?• Antagonism can be overcomed by
increasing concentration of agonist in:
• A) irreversible competitive antagonism.B) non-competitive antagonism C) reversible competitive antagonism D) pharmacokinetic antagonism