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QUANTITATIVE ASPECTS OF DRUG ACTION ilo s By the end of this lecture you will be able to :  Recognize different dose response curves  Classify different.

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Presentation on theme: "QUANTITATIVE ASPECTS OF DRUG ACTION ilo s By the end of this lecture you will be able to :  Recognize different dose response curves  Classify different."— Presentation transcript:

1 QUANTITATIVE ASPECTS OF DRUG ACTION ilo s 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

2 QUANTIFY ASPECTS OF DRUG ACTION RD Bind Occupy Initiate Activate 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

3 k1k1 k2k2 association rate constant dissociation rate constant RD Bind Occupy Initiate Activate RD RESPONSE[R] + DR* Concentration-Binding Curve B = B max xC C+ KD 50 The relationship between drug binding & drug concentration is expressed mathematically by the following equation

4 Concentration-Binding Curve KDKD KDKD ( B max ): T otal density of receptors in the tissue Concentration-Binding curves are used to determine: 1.The binding capacity ( B max ) → 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 K D i.e. inverse relation (k D ) = [C] of D required to occupy 50% of receptors at equilibrium

5 DOSE RESPONSE CURVE A continuous response  BP, HR, FBG, Cholesterol,… GRADED DOSE RESPONSE CURVE An 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 the therapeutic window of a drug is defined ? How does response vary with C?

6 DOSE RESPONSE CURVE QUANTAL DOSE RESPONSE CURVE GRADED DOSE RESPONSE CURVE

7 A continuous response  BP, HR, FBG, Cholesterol,… GRADED DOSE RESPONSE CURVE

8 % of Maximal Effect [C] GRADED DOSE RESPONSE CURVE Max effect = E max Effect when all the receptors are occupied by D C that gives the half-maximal effect E= E max xC C+ EC 50 As C ↑  response increment ↓ % of Maximal Effect [C] EC 50 Graded dose-response curves are used to determine: 1.The max efficacy ( E max ) → 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 EC 50, 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. EC 50

9 GRADED DOSE RESPONSE CURVE A > efficacy than B B Partial Agonist EFFICACY POTENCY A > potent B

10 X > potent than Y & Z X & Z > efficacy than YX & Z are equal efficacy Y> potent than Z GRADED DOSE RESPONSE CURVE Y > potent but < efficacious than Z

11 DOSE RESPONSE CURVE QUANTAL DOSE RESPONSE CURVE GRADED DOSE RESPONSE CURVE

12 QANTAL DOSE RESPONSE CURVE All-non responses * specified therap. response * adverse response * lethal outcome % subjects responding Dose-frequency relationship

13 [Dose] ED 50 % subjects responding QANTAL DOSE RESPONSE CURVE: used to determine TD 50 LD 50 50% of individuals exhibit the specified therapeutic response Median toxic doseMedian 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. TD 50 ED 50 When low → the drug has a narrow margin of safety digoxin When high → the drug has a safe profile diazepam Therapeutic Effect Toxic Effect Lethal Effect

14 Physiological Chemical PharmacokineticNon- 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 action Phenobarbitone induces an accelerated hepatic metabolism warfarine Omeprozole & histamine ANTAGONISM Dimercaprol reduces heavy metal toxicity [ lead, ….]

15 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

16 Antagonist 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 Surmountable Antagonism can be overcome by increasing concentration of agonist = Surmountable Phenoxybenzamine & Noradrenaline Atropine vs Ach Irreversible COMPETATIVE ANTAGONISM

17 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

18 Agonist Agonist + irreversible competitive antagonist Agonist + non-competitive antagonist % of Maximal Effect [C] NON-SURMOUNTABLE Antagonism cannot be overcome 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 ) SURMOUNTABLE Antagonism can be overcomed by increasing concentration of agonist = SURMOUNTABLE Verapamil vs noradrenaline

19 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 DDistinguish the therapeutic utility of each of these curves


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