Presentation on theme: "QUANTITATIVE ASPECTS OF DRUG ACTION"— Presentation transcript:
1 QUANTITATIVE ASPECTS OF DRUG ACTION ilosBy the end of this lecture you will be able to :Determine quantitative aspects of drug receptor bindingRecognize different dose response curvesDistinguish the therapeutic utility of each of these curvesClassify different types of antagonismQUANTITATIVE ASPECTS OF DRUG ACTION
2 QUANTIFY ASPECTS OF DRUG ACTION BindOccupyInitiateActivateRESPONSE[R]+DR*Relate concentration [C] of D used (x- axis) to the binding capacity at receptors (y-axis)Relate concentration [C] of D used (x- axis) to the R produced (y-axis)Concentration-Binding CurveDose Response CurveAFFINITYEFFICACYPOTENCY
3 Concentration-Binding Curve OccupyInitiateActivateassociation rate constantk1D+RDRDR*RESPONSE[R]k2dissociation rate constantThe relationship between drug binding & drug concentration is expressed mathematically by the following equationB =Bmax xCC+ KD50
4 ? ? ? Concentration-Binding Curve (Bmax): Total density of receptors in the tissueKDKD(kD ) = [C] of D required to occupy 50% of receptors at equilibrium?Concentration-Binding curves are used to determine:The binding capacity (Bmax) → total density of receptors in the tissues.The affinity of D for receptorThe higher the affinity of D for receptor the lower is the KD i.e. inverse relation??
5 How does response vary with C? BP, HR, FBG, Cholesterol,… DOSE RESPONSE CURVEHow does response vary with C?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 outcomeQUANTAL DOSE RESPONSE CURVEHow the therapeutic window of a drug is defined ?
8 GRADED DOSE RESPONSE CURVE Max effect = EmaxEffect when all the receptors are occupied by D% of Maximal Effect[C]20406080100200400600800204060801001101000% of Maximal Effect[C]EC50As C ↑ response increment ↓E=Emax xCC+ EC50EC50Graded dose-response curves are used to determine:The max efficacy (Emax) → highest limit of dose-response relationship on response axis.The potency = The concentration of drug required to produce a specified responseThe 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.C that gives the half-maximal effect
9 GRADED DOSE RESPONSE CURVE EFFICACYA > efficacy than BB Partial AgonistPOTENCYA > potent B
10 X & Z > efficacy than Y < efficacious than Z GRADED DOSE RESPONSE CURVEX & Z are equal efficacyX & Z > efficacy than YY > potent but< efficacious than ZX > potent than Y & ZY> potent than Z
13 Predict the safety profile QANTAL DOSE RESPONSE CURVE: used to determine100Lethal Effect80Toxic EffectTherapeutic Effect60% subjects responding4020[Dose]1101001000ED50TD50LD50Median Effective Dose50% of individuals exhibit the specified therapeutic responseMedian toxic doseMedian lethal doseTherapeutic IndexTD50ED50The 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
14 ANTAGONISMIt is the diminution or the complete abolishment of the effect of one drug in the presence of another.TypesChemicalPhysiologicalPharmacokineticReceptor BlockadeCompetitiveNon-CompetitiveThe antagonist effectively reduces the concentration of the active drug at the site of actionTwo drugs react chemically resulting in loss of activity of active drugDimercaprol reduces heavy metal toxicity [ lead, ….]Phenobarbitone induces an accelerated hepatic metabolism warfarineTwo drugs possess opposing actions in the body, so tend to cancel each other’s effectOmeprozole & histamine
15 ANTAGONISM Non-Competitive Receptor Blockade Reversible Competitive Antagonist block at some point the chain of events that ignite the response of agonistAgonist and Antagonist can be bound simultaneouslyReceptor BlockadeCompetitiveReversibleAntagonist prevents binding of agonist to the receptor at the same binding site ( = competes with it at same occupancy site )Agonist and Antagonist compete( only one is bound)Irreversible
16 COMPETATIVE ANTAGONISM IrreversibleReversibleAntagonist readily dissociate from binding site of agonist to the receptorAntagonism can be overcome by increasing concentration of agonist = SurmountableAtropine vs AchAntagonist 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 actionPhenoxybenzamine & Noradrenaline
17 Competitive Antagonism ReversibleParellel shift to the right, without any change in slope or maximumIrreversibleNo parellel shift but both a decrease in slope and a reduced maximum are obtained.
18 Competitive vs Noncompetative Antagonism Antagonism can be overcomed by increasing concentration of agonist = SURMOUNTABLE% of Maximal EffectAgonist + reversible competitive antagonist20406080100AgonistAgonist + irreversible competitive antagonistAgonist + non-competitive antagonistDepression of maximal response +/- rightward shifts ( if some R are spare )Verapamil vs noradrenaline[C]1101001000Antagonism cannot be overcome by increasing concentration of agonist = NON-SURMOUNTABLE
19 QUANTITATIVE ASPECTS OF DRUG ACTION LUCKBy the end of this lecture you ARE able to :Determine quantitative aspects of drug receptor bindingRecognize different dose response curvesDistinguish the therapeutic utility of each of these curvesClassify different types of antagonism