Dose Response Curve & SAR.ppt for students

dose response curve and structure activity relation ship ppt

1. SUDHAKAR LAKAVATH
Non Medical Assistant
Department Of Pharmacology
Kakatiya Medical College
WARANGAL.

2. DOSE RESPONSE CURVE
What is DRC.
Types
Advantages

3. STRUCTURE ACTIVITY RELATIONSHIP
1.What is a chemical structure.
2.What is activity.
3.What is SAR.
4.why SAR exists.
5.What are the structural factors that influence the
physicochemical properties.
6.How the physicochemical properties influence the
activity of a molecule.
7.What are SAR studies and why are they done for a
chemical structure.
8.When SAR studies are done.
9.How SAR studies are done.

4. Relation between drug concentration & Response
It may be:
•Complex as observed clinically in patients.
•Simple in carefully controlled in vitrosystems.
•It can be described mathematically & represented
graphically.

5. Dose Response Curves/ Concentration Effect Curve
Definition: A graph between doses of a drug & responses produced , using an
in vitro /in vivobiological system.
Doses are plotted along X-axis/ abscissa.
Responses are plotted along Y-axis/ordinate.
Types:i. Graded DRC ii. Quantal DRC

6. Graded dose response curve:
Definition: It is a quantitative curve between increasing
doses/concentration of drug and varying responses .
Thresh hold dose: The minimum dose which produces an observable
response
Maximum/ ceiling dose: The dose which produces maximum response
& even with further increase in dose , there is no increase in response.

8. The relation between conc. & effect can be described mathematically.
E =E
maxx C
C + EC50
E = Effect observed
C = Concentration of the drug.
E
max= The maximum response produced by the drug
EC50 = The conc. of drug that produces 50% of max effect.
It can be represented graphically -----Hyperbola curve.

9. Ifthepercentageofreceptorsthatbinddrugis
plottedagainstdrugconc.asimilarcurveisobtained
(becausetheresponseisduetobindingtoreceptors)
B=B
maxxC
C + K
d
K
d=Conc.Thatbinds50%ofthereceptorinthe
system.
B
Max=Max.noofboundreceptor.

11. Semi Log dose response curve:
If dose is taken in logarithm & response in
arithmetic/linear scale, the curve is sigmoid shape.
Important characters:
•Potency
•Slope : Steep / Flat
•Maximum effect (E
max)
•Variability

14. Advantages of Semi Log dose response curve:
1.It sigmoid in shape with a linear mid portion, so:
•It occupies less space & many observations can be recorded on same
graph paper.
•This shapes expands the scale of dose axis at low conc. where the effect
is changing rapidly & compresses is at high conc. where the effect is
changing slowly.
•Comparison of two curves becomes easier.
2.Useful for:
–Determination of the potency.
–Determination of efficacy (EC
50/ E
max ).
–Determination of selectivity of effect.
–Receptor study , Drug Antagonism.
–Determination of biological variation.

20. Quantal dose response curve(dose Percent curve)
Definition:Quantal DRC is a curve/graph plotted between the percentage or
fraction of a populationthat shows a specified all or none response & dosesof
a drug.
QDRCis a cumulative graph of the frequency distribution of responders versus
the log dose .
On Y-axis is recorded % of responders & on X-axis log. doses are plotted.
Parameter: Pre-determined criterion
i.e production of convulsions , foot withdrawal
Quantal response:An all or none response.
•Either drug can produce convulsions/ no convulsions.
•Either drug can produce foot withdrawal/ no foot withdrawal.
•Either at specific dose a drug can produce death / no animal dies

23. Medianeffectivedose(ED50):Itisthedosethatis
requiredtoproducethespecifiedresponsein50%of
populationunderstudy.
MedianToxicdose(TD50):Itisthedosethatisrequired
toproducethespecifiedtoxiceffectin50%of
populationunderstudy.
Medianlethaldose(LD50):Itisthedoseofthedrug
requiredtokill50%ofanimalsunderstudy.

24. Uses of QDRC:
•Indicates the potential variability of responsiveness
among the population.
•Calculation of therapeutic index
•Comparing the potencies of drugs in experimental &
clinical settings.
•It can provide a valuable index of the selectivity of
drug’s action by comparing its ED
50for two different
quantal responses in a population.

25. Therapeuticindex:Itistheratioofmediantoxicdoseormedian
lethaldosetomedianeffectivedose.
Therapeutic Index (T.I) = LD50 [ Median letaldose]
ED50 [Median effective dose]
TI indicates that safely the dose can be increased without fear of
toxicity.
Drugs with LOW TI---less safe ,require monitoring of plasma
concentration. Digoxin, Lithium phenytoin, digitalis.
They havenarrowTherapeutic window .
Drugs with HIGH TI:Safer , They havewide Therapeutic window
Eg: Penicillin have high TI.
•

26. Margin of safety:LD 0.1
ED 99.9
LD 0.1is the minimum lethal dose for 0.1% of the population
ED 99.9is the minimum effective dose for 99.9% of population

28. Therapeutic window:

31. STRUCTURE
ACTIVITY
RELATIONSHIP

32. STRUCTURE ACTIVITY RELATIONSHIP
1.What is a chemical structure.?
2.What is activity.?
3.What is SAR.?
4.why SAR exists.?
5.What are the structural factors that influence the
physicochemical properties.?
6.How the physicochemical properties influence the
activity of a molecule.?
7.What are SAR studies and why are they done for a
chemical structure.?
8.When SAR studies are done.?
9.How SAR studies are done.?

33. Structure Activity Relationship
I-SynthesisOfNewCompoundsWithMoreSpecific
ActionsAndFewerAdverseEffects
Examples:-
1.Chlorpromazine & Trifluoperazine
2.Procaine & Procainamide
3.Benzyl Penicillin & ampicillin
4.Chlorothiazide & Bendoflumethiazide
5.Atropine & homatropine

34. II.Synthesis of structurally related competitive antagonist
•PABA & Sulfonamides
•Morphine & Naloxone

35. III-Understanding the Mechanism of Drug Action
Example:
Epinephrine & Isoprenaline

36. CHEMICAL STRUCTURE: ?
A chemical structure includes molecular
geometry, electronicstructure, and crystal
structure of a molecule.
BIOLOGICAL ACTIVITY:?
Biological activity is an expression describing
the beneficial or adverse effects of a drug on
living matter.
36

37. WHAT IS SAR?
•SAR is the relationship between chemical
structure and pharmacological activity of a
drug. The analysis of SAR enables the
determination of the chemical groups
responsible for evoking a target biological
effect in the organism.
WHY SAR EXIST ?:
The interaction of the drug molecule with a
protein depends on its chemical structure.

38. WHAT ARE SAR STUDIES.?
•The studies involving the modification of the
drug molecule in a systemic fashion and
determination of how these changes affect
biological activity.

39. WHY SAR STUDIES ARE DONE?
•IT HAS ADVANTAGES LIKE:
1.Increased potency .
2.Greater selectivity.
3.Increase or decrease the duration of action.
4.Low toxicity.
5.Increased stability.

40. WHEN SAR STUDIES ARE DONE?
Chemical compound
screening
Lead molecule
pruning
pharmacophore

41. SCREENING
Screening is the systematic examination of a
chemical molecule to identify the lead
molecule.
METHODS OF SCREENING:
1.Identification by random screening.
2.Identification by non random screening
studies.
3.Identification by observing side effect.

42. PRUNING
•Pruning is the refinement of lead structure .
•It is done to determine the pharmacophore.
PHARMACOPHORE:
A pharmacophore is a spatial arrangement of
functional groups essential for biological
activity.
It is a pattern that emerges from a set of
molecule with a common biological activity.

43. NEED OF SAR STUDY?
A study of the structure–activity relationship is
mainly done on lead molecule.
1.Itisusedtodeterminethepartsofthe
structureoftheleadcompoundthatare
responsibleforbothitsbeneficialbiological
activity,thatispharmacophoreandalsoits
unwantedsideeffects
43

44. 2.Thisisusedtodevelopanewdrugthathasincreased
activity.
3.Todeterminesomedifferentactivityfromanexisting
drugandfewerunwantedsideeffects.
4.Toknowthechangesinpharmacologicalpropertiesby
performingminorchangesinthedrugmolecule.
Contd…
44

45. EFECT OF CHEMICAL STRUCTURE
ON PHARMACOLOGICAL ACTION
1.Drugactionisaccordingtothetheoryproposed
byEARLICHi.e
2.Corporanonaguntnisifixata(Adrugwillnotwork
unlessitisbound)
3.Itmeansthedrugshouldbenon-uniformly
distributedinthebodyi.etowardsatargeted
portiontoelicitthepharmacologicalaction.
4.Inotherwordswhenthedrugmoleculegetclose
tothecellularmoleculesandbindswithittoalter
itsactivity.
45

46. Structure–activityrelationshipsareusuallydetermined
bymakingminorchangestothestructureofaleadto
produceanalogues
•Those changes are..
1.thesizeandshapeofthecarbonskeleton
2.thenatureanddegreeofsubstitutionand
3.thestereochemistryofthelead
46

47. 1.Pharmacodynamic: Substitution of a larger moiety(alylor methyl
cyclopropylgroup) for N-methyl group trnsform Morphine to
Nalorphine, Oxy morphine to Naloxone, Introduction of additional
double bond in 1,2 position of two steroid ring increases
Glucocorticoidactivity of Corticosteroids eg: Prednisolone.
2.Pharmacokinetic: Omeprazole-Esomeprazole(long t 1/2), etc.
3.To improve side effect profile eg: Phenytoin-FosPhenytoin,
Citalopram-Escitalopram,Amlodipine-S Amlodipine, etc.
47

48. CONCLUSION
1. SAR deals with the influence of the
functional groups present in the drug
on its biological activity
2. SAR studies are done to determine
the pattern of this influence which is
employed in the drug design and in the
synthesis of many drugs of desired
pharmacological activity.
48