Quantitative aspects Dose Response Relationship

1. Drug Receptor Interaction:
Quantitative Aspects
DR. SAHIL KUMAR

2. OUTLINE
• Background
• Introduction
• Concentration-Binding Relationship
• Dose-Response Relationship
• Graded dose response curve
• Quantifying agonism
• Quantifying antagonism
• Quantal dose response curve
• Conclusion

3. BACKGROUND
“All substances are poisons.”
- Paracelsus
Biometrics.
DRUG EFFECT

4. INTRODUCTION
Quantifying Drug Receptor Interaction
Concentration –
Binding Relationship
Dose-Response
Relationship
(Affinity) (Efficacy, Potency)

5. Concentration – Binding Relationship

6. •Labelled with one or more radioactive
atoms (usually 3H, 14C or 125I) → incubate
samples → bound radioactivity measured.
•Non radioactive techniques.
•Non-invasive imaging techniques.
Concentration – Binding Relationship

7. Dose-Response Relationship
Description of the magnitude of the effect
of the drug as a function of dose.

8. Two types of dose-response relationships…
Relates dose to frequency
of “all or none response.”
Relates dose to gradual,
continuous increase in
response.

9. Graded Dose Response Curve (DRC)
Dose of Drug (mg/ml)
Response(%)
0 1 2 3 4 5 6 7
50%
100%
Maximal Response
Ceiling Dose

10. Why log DRC?

11. How to plot log DRC?

12. Normal DRC
• Inconvenient
• Hyperbola
• Very broad graph
• Difficult to analyze
• Difficulty in
comparison
Log DRC
• Convenient
• Sigmoid shaped
• Highly compressed graph
• Linear mid-portion easy
to analyze
• Mathematical advantages
on comparison of two
DRCs.

13. Information derived from a graded DRC:
Maximal (or ceiling) effect : Emax
Position of DRC: EC50 (or ED50), pD2 value
Slope of the curve/ regression coefficient
Comparison between curves.

15. pD2 Value
.

16. Quantifying agonism:
Some more parameters…
Potency Ratio
Selectivity ratio between different tissues
Potentiation

17. Quantifying Antagonism
•IC50 Value
Determination of types of drug antagonism:
Parallel shift of the log DRC.
Double reciprocal (Lineweaver & Burk) plot
Schild Plot and pA2 value.

18. Parallel shift of the log DRC
Dose Ratio : Factor by which conc. of agonist must be multiplied to
produce a given response in the presence of the antagonist.

19. Double reciprocal Plot

20. Schild Plot and pA2 value
Log
Negative log of molar conc
of antagonist which reduces
the effect of multiple doses
of an agonist to that of a
single dose.

21. Quantal Dose Response Curve
•Pharmacodynamic variation is both
individual and at population level.
•Variability in pharmacodynamic
response in the population analyzed
by a quantal dose response curve.

22. Frequency Distribution Curve
Dose
(ng/
kg/min)
No. of
subjects
responding
10 02
15 04
20 06
25 08
30 10
35 08
40 06
45 04
50 02

23. Summation of Frequency Histogram
Dose
(ng/
kg/min)
Cum. no. of
subjects
responding
10 02
15 04 + 02 = 06
20 06 + 06 = 12
25 08 + 12 = 20
30 10 + 20 = 30
35 08 + 30 = 38
40 06 + 38 = 44
45 04 + 44 = 48
50 02 + 48 = 50

24. Information derived from quantal DRC
Median Effective Dose (ED50)
Median Lethal Dose (LD50)
Evaluation of Drug Safety

25. LD50 Determination:
Graphical & Arithmetic methods

26. Evaluation of Drug Safety
• Therapeutic index
(LD50/ED50)

27. •Certain Safety Factor (CSF)

28. Therapeutic window

29. CONCLUSION

30. THANK YOU