Dose Response curve .powerpoint slides

Dose Response curve.powerpoint slides

1. Dose Response
Tammy Dugas, Ph.D.
Department of Pharmacology
675-7867; [email protected]
Room F5-28, BRI

2. What is Pharmacology?
•The investigation of the physiological
effects of drugs.

3. Related Areas of Study
•Toxicology: investigation of the toxic effects of
drugs and other chemicals.
•Pharmacodynamics: physiological effects of
drugs.
•Pharmacokinetics: drug absorption, distribution,
binding, metabolism, elimination.
•Pharmacy: preparation and dispensing of drugs.

4. Related Areas of Study
•Toxicology: investigation of the toxic effects of
drugs and other chemicals.
•Pharmacodynamics: physiological effects of
drugs = drug action over a period of time, that is
affected by absorption, distribution, localization
in the tissues, biotransformation, and excretion.
•Pharmacokinetics: drug absorption, distribution,
binding, metabolism, elimination.
•Pharmacy: preparation and dispensing of drugs.

5. Father of American Pharmacology
•John Jacob Abel (1857-1938):
–Studied in Germany under Oswald Schmiedeberg, who
trained more than 150 pharmacologists.
–Brought experimental pharmacology to the US.
–First chairman of a pharmacology department
(University of Michigan).
–Founder of the American Society for Pharmacology
and Experimental Therapeutics (ASPET) and the
Journal for Pharmacology and Experimental
Therapeutics.

6. Pharmacology is not a new science
•Aureolus Paracelsus (1493-1541): first to relate
dose and response; also, dose and toxicity.
“Grandfather of Pharmacology.”
•Pharmacology research emerged as an offshoot of
physiology:
–Francois Magendie (1783-1841): site of action of
the drug can be localized to a specific site in the
body.
–Claude Bernard (1813-1878): student of
Magendie.

7. Definitions:
•Dose: the amount of drug required to elicit
a biologic response.
•Dose-response relationship: the intensity of
the response elicited by a drug is
proportional to the dose administered.

8. Example: Dose-response curve
R
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Log concentration

9. Graded Dose-Response Relationship
•The response is measured on a continuous scale.
•The curve can be generated in a single subject.
•Can be used to determine maximum efficacy of a
drug.
%

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Log dose

10. Quantal Dose Response Relationship
•Response is an “either/or” event.
•Relates dose and response frequency in a
population.
N
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Dose

11. Quantal Dose Response Relationship
•Response is an “either/or” event.
•Relates dose and response frequency in a
population.
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Dose

12. How do we denote the clinical
effectiveness of a drug?
•Potency: Concentration of a drug required
to elicit a biologic effect.

13. How do we denote the clinical
effectiveness of a drug?
•Potency: Concentration of a drug required to elicit
a biologic effect.
–ED
50: Dose required to elicit 50% of the maximal
effect.
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Dose
50
100

14. How do we denote the clinical
effectiveness of a drug?
•Potency: Concentration of a drug required to elicit
a biologic effect.
–ED
50: Dose required to elicit a response in 50% of the
population.
%

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Dose
ED
50
50
100

15. How do we denote the clinical
effectiveness of a drug?
•Efficacy: The ability of the drug to elicit an
effect. It is the limit of the dose-response
curve on the response (y) axis.
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Log Dose

16. Drugs with Different Pharmacologic
Potencies and Maximal Efficacies
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Log concentration
Basic & Clinical Pharmacology, 7
th
ed.
A
B
C D

17. Two Types of Biologic Responses:
•Receptor mediated effects
•Nonreceptor mediated effects

18. A
BC
A
A A
C B

19. Drug response is directly proportional to
the percentage of receptors occupied.
Drug + Receptor Drug-receptor complex Response

20. Definitions:
•Agonist: A drug with affinity and efficacy.
•Antagonist: A drug that has affinity for a
receptor but elicits no effect, i.e., the drug
has affinity but no efficacy.

21. Agonist vs. Antagonist
Agonist Antagonist
Receptor Receptor
Activated receptor
Inactivate receptor

22. Definitions:
•Partial Agonist: Agonist with less than
maximal efficacy.
•Full Agonist: Agonist with maximal
efficacy.
•Inverse Agonist: Has the opposite effect of
a full agonist.
•Partial Inverse Agonist: An inverse agonist
with less than maximal efficacy.

23. Definitions:
•Competitive Antagonist: Competes with
the agonist for the same receptor.

•Noncompetitive Antagonist: May bind to
the same receptor or an associated
molecule.

24. Competitive Antagonism:
•Competes with the agonist for receptor
binding.
•Can be overcome by increasing the agonist
concentration.
•Displaces the dose response curve to the
right but does not alter maximal efficacy.

25. Competitive Antagonist
Agonist (g/ml)
Agonist
Agonist
+ antagonist
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26. Noncompetitive Antagonism
•Drug binds to the receptor or an associated
molecule.
•Is not overcome by increasing agonist
concentration.
•Dose response curve is shifted slightly to the
right.
•Maximal efficacy is decreased. (Prevents the
agonist at any concentration from reaching
maximal efficacy.)

27. Noncompetitive Antagonist
100
50
0
0.6 4.8 38.4
[Epinephrine] (M)
Epinephrine
Epinephrine
+ 2 x 10
-7
Dibenamine
Epinephrine
+ 4 x 10
-7 Dibenamine
P
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m
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x
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Agonist
Agonist +
antagonist (lo conc)
Agonist +
antagonist (hi conc)
Log Dose

28. Structure-Activity Relationship: The relationship
between chemical structure and pharmacologic
activity.

29. Structure-Activity Relationship: The relationship
between chemical structure and pharmacologic
activity.
•One goal in drug design is to define structural
requirements for good fit between drug and receptor.
•Small modifications of chemical structure can have
large effects on receptor binding and thus,
pharmacologic activity.
•Therapeutically useful drugs can be designed from small
modifications in antagonists known to elicit activity.
•SAR makes it possible to design drugs with better ratio
of therapeutic to toxic effects.

30. Types of receptor binding
•Covalent: Binding in which electrons are shared.
•Noncovalent:
•(reversible)
–Ionic: electrostatic attraction between charged ions.
–Hydrogen bonding: force of attraction between hydrogen and
electronegative atoms.
–van der Waals attraction: force of attraction between two
dispersed electron clouds. Weakest force of attraction
between atoms.
–Hydrophobic effect: rearrangement of nonpolar and polar
groups in a molecule. For example, in water, nonpolar groups
will likely be forced closer together.

31. A
BC
A
A A
C B

32. OH
OH
N
+
H
OH
H3C
H
H
X
AsymmetricAsymmetric
ReceptorReceptor
Flat area
Anionic
site

33. X
AsymmetricAsymmetric
ReceptorReceptor
Flat area
Anionic
site
OH
OH
N
+
OH
H
H3C
H
H

34. Specific Examples
OH
HO
OH
HO
Cl Cl
C(Cl)3
H
HO OH
CH3
CH3
O
OH
HO
OHO
Estradiol
Diethylstilbestrol
Bisphenol A
Genistein
p,p’-DDT

35. Dose-Response Curves for a
Homologous Series
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Molar concentration
Essentials of Pharmacology
Butyl
Hexyl
Heptyl
Octyl
Nonyl
Decyl

36. Paracelsus:
(1493-1541)
•“All substances are poisons; there is none
which is not a poison. The right dose
differentiates a poison from a remedy.”
Age of Enlightenment

37. Potency versus Toxicity
Potency: Dose required to elicit an effect.
A drug is considered potent if the dose
required to elicit an effect is small.
Margin of safety or therapeutic index:
Dosage range between that which produces
a lethal effect and the dose producing a
pharmacologic effect.

38. Potency versus Toxicity
Potency: Dose required to elicit an effect.
A drug is considered potent if the dose
required to elicit an effect is small.
Margin of safety or therapeutic index:
Dosage range between that which produces
a lethal effect and the dose producing a
pharmacologic effect.
TI = LD
50
/ED
50

39. Potency versus Toxicity
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100100
50 50
ED
50 LD
50
Log Dose