This document contains information on general pharmacology principles including pharmacokinetics, pharmacodynamics, and dose-response relationships. It discusses [1] how drugs interact with receptors according to the law of mass action and receptor occupancy theory, [2] factors that influence dose-response curves including efficacy, potency, and antagonism, and [3] the relationship between therapeutic effects and toxic effects as characterized by the therapeutic index. Additional study resources on these topics are provided.

1. by Marc Imhotep Cray, M.D.
Basic Medical Sciences Professor
Companions
IVMS BASIC PHARM-
General Principles,
Pharmacokinetics and
Pharmacodynamics Ppt
General Principles,
Pharmacokinetics and
Pharmacodynamics Notes
Chemotherapy drugs in vials and an IV bottle. (Bill Branson Photographer;
image courtesy of National Cancer Institute Visuals Online.)
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2. Quantitative Aspects
I. Dose-effect Curve
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3. Example: Action at NMJ
• Repetitive slow stimulation of the ulnar nerve causes
release of ACh at thumb NMJs innervated by the
nerve, resulting in a reproducible twitch.
• Injection of an anticholinergic NMJ blocker results in
gradual blockade of neurotransmission.
• As [drug] rises in the tissue, thumb twitch is gradually
blocked.
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4. Block of Stimulation-Induced
(ACh-mediated) Thumb-Jerk
drug
Blockade develops as drug accumulates
at the NMJ and blocks ACh receptors.
0 100
Time
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5. Drug-Receptor Interactions
Obey the Law Of Mass Action
k1
• At equilibrium, D + R DR.
k2
• k2/k1 = Kd = the equilibrium dissociation
constant for the drug-receptor complex.
• Kd gives an idea of the binding affinity of D for
R.
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6. Concept: Fraction of Receptors
Occupied
• Y = fraction of receptors that are occupied.
• RT = total receptor concentration, a property of
the tissue.
• [D] is the concentration of free (unbound) drug.
• Y = [DR]/[RT] = [D]/(Kd + [D]).
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7. Receptor Occupancy Theory
Dependency of drug effect on concentration:
*In Classical Receptor Occupancy Theory, the
magnitude of the effect is assumed to be
directly proportional to Y:
*Effect = (Maximal Effect) X (Y)
Effect = (Maximal Effect) X ([D]/Kd + [D])
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8. Dose-Effect Curve: Graded Responses
• Plot of dose (arithmetic scale) vs. effect yields
a curved line (simple rectangular hyperbola).
• Plot using log of the dose yields a sigmoid
curve with a large linear component between
about 20% and 80% of the maximal effect - an
intuitively helpful graphical display of drug
action.
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9. Dose-Effect and Log Dose-
Effect Curves
Effect
ED50
Dose Log Dose
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10. Deficiencies of Classical Receptor
Occupancy Theory
• Does not allow maximum effect to occur
unless all receptors are occupied.
• Cannot relate the elicited effect as a function
of a biological stimulus governed by Y.
• Thus, does not account for the possibility of
amplification between receptor occupancy
and response.
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11. Dose-effect Curve:
Quantal Responses
• Graphically expresses the frequency that a
defined effect (e.g., blood pressure) occurs in a
population at a given dose.
• Can also express the cumulative frequency
with which an effect occurs in a population at a
given dose and all lower doses.
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12. Normal Distribution Curve
• For all-or-none (quantal) responses
• Shows the variation in minimum (threshold)
dose in individuals in a population.
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13. Frequency Distribution For Quantal
(all-or-none) Effects
Number Responding
for the First Time
More sensitive Less sensitive
Dose (mg/kg)
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14. 14

15. Drug-Receptor Interactions
• A typical D-R curve reveals potency, efficacy,
and slope.
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16. Representative Dose-Effect Curve
Maximum Effect
or Efficacy
Potency
Log Dose
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17. Drugs are described based on the
magnitude of two properties:
1) Affinity for the receptor. Affinity is related to
potency.
2) Efficacy once bound to the receptor.
Efficacy refers to the maximal effect the drug
can elicit.
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18. Agonists and Antagonists
• AGONIST - Has affinity for receptor and efficacy.
• ANTAGONIST - Has affinity but no efficacy.
• Competitive Antagonist
• Noncompetitive Antagonist
• Partial Agonist or Partial Antagonist - Has
affinity but lower efficacy than full agonist.
• Examples of typical curves...
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19. 19

20. Classes of Dose-Effect
Curves
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21. Full Agonists (i.e., equal
efficacies) that Differ In Potency:
A
B C
Compare the ED50s
Drug Concentration (log scale)
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22. Agonists That Differ in Efficacy
A
% Max response
B
C
Log Drug Concentration
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23. 23

24. Drug properties should be
compared in the same
system.
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25. Competitive Antagonism Shifts
The Agonist D-R Curve (Potency)
AG alone AG + ANT
Drug Concentration (log scale)
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26. Noncompetitive Antagonism
Decreases Agonist Efficacy
% Max response
Log Drug Concentration
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27. Competitive
antagonism is
Surmountable.
Antagonism: Noncompetitive
antagonism is NOT
surmountable: often
A = Agonist due to irreversible
B = Antagonist Binding.
Allosteric effects
occur when ligand B
Allosteric: binds to a different
site on the receptor
than agonist A.
A = Agonist Either antagonism
B = Ligand or potentiation is
possible.
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28. Factors Affecting Drug Response
• Resistance: used in context of antimicrobial
drugs.
• Tolerance: a decrease in drug response
during repeated administration.
• Tachyphylaxis: acute development of
tolerance due to rapid repeated admin. of
some drugs.
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29. Pharmacokinetic Tolerance
• Also called Drug Disposition Tolerance.
• Characterized by a decrease in [drug] at its site
of action.
• Barbiturates, Alcohol, and many others.
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30. Pharmacodynamic Tolerance
This is due to reduced responsiveness to the
drug at its site of action.
• Amphetamine
• Caffeine
• Nicotine
• Morphine, Barbiturates, Alcohol
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31. Drug Safety
• Therapeutic Index
•
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32. Therapeutic and Toxic Effects are
Dose-Related: Phenobarbital
Sleep Death
ED50 LD50
Dose of Phenobarbital
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33. Therapeutic Index (TI)
TI (preclinical) LD50
ED50
clinical TI TD50
ED50
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35. FOR ADDITIONAL STUDY:
PHARM2000
Medical Pharmacology and Disease-Based Integrated Instruction
Programmed Study: Pharmacology Content, Practice Questions, Practice Exams
Michael Gordon, Ph.D., site developer; email:
Michael Gordon
Chapter 1: General Principles--Introduction
Practice question set #1
Practice question set #2
Practice question set #3
Practice question set #4
Chapter 2: Pharmacokinetics
Practice question set #1
Practice question set #2
Practice question set #3
Practice question set #4
Practice question set #5
Practice question set #6
Flashcards
Problem set #1
Problem set #2
Practice Exam #1
Practice Exam #2
Chapter 3: Pharmacodynamics
Practice question set #1
Practice question set #2
Flashcards
Practice Exam 1 http://www.pharmacology2000.com/
Unit Practice Exam #1
Unit Practice Exam #2
Unit Practice Exam #3
Unit Practice Exam #4
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