General Principles of Drug Therapy
Integrated Scientific and Clinical Pharmacology
Pharmacodynamics II Dose-Response Relationships Marc Imhotep Cray, M.D. BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
General Principles of Drug Therapy
Dose-Response Relationships Time-Response Relationships Drugs as Agonist Drugs as Antagonist Signaling and Receptors The Future is Now: Biologics
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General Principles of Drug Therapy
Quantitative Aspects I. Dose-effect Curve
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General Principles of Drug Therapy
Example: Action at NMJ Repetitive slow stimulation of ulnar nerve causes release of ACh at thumb NMJs innervated by nerve, resulting in a reproducible twitch
Injection of an anticholinergic NMJ blocker (e.g. pancuronium) results in gradual blockade of neurotransmission
As [drug] rises in the tissue, thumb twitch is gradually blocked 4
General Principles of Drug Therapy
% Blockade
Block of Stimulation-Induced (ACh-mediated) Thumb-Jerk
drug
0
Blockade develops as drug accumulates at NMJ and blocks ACh receptors
Time
100 5
General Principles of Drug Therapy
Drug-Receptor Interactions Obey 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 6
General Principles of Drug Therapy
Concept: Fraction of Receptors Occupied Y = fraction of receptors that are occupied RT = total receptor concentration, a property of the tissue [D] is concentration of free (unbound) drug
Y = [DR]/[RT] = [D]/(Kd + [D])
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General Principles of Drug Therapy
Receptor Occupancy Theory Dependency of drug effect on concentration: *In Classical Receptor Occupancy Theory, the magnitude of 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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General Principles of Drug Therapy
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 maximal effect – an intuitively helpful graphical display of drug action
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General Principles of Drug Therapy
Effect
Effect
Dose-Effect and Log Dose-Effect Curves
Dose
ED50
Log Dose
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General Principles of Drug Therapy
Deficiencies of Classical Receptor Occupancy Theory Does not allow maximum effect to occur unless all receptors are occupied
Cannot relate elicited effect as a function of a biological stimulus governed by Y
Thus, does not account for possibility of amplification between receptor occupancy and response 11
General Principles of Drug Therapy
Dose-effect Curve: Quantal Responses  Graphically expresses frequency that a defined effect (e.g., blood pressure) occurs in a population at a given dose  Can also express cumulative frequency with which an effect occurs in a population at a given dose and all lower doses 12
General Principles of Drug Therapy
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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General Principles of Drug Therapy
Number Responding for the First Time
Frequency Distribution for Quantal (all-or-none) Effects
More sensitive
Less sensitive
Dose (mg/kg)
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General Principles of Drug Therapy
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General Principles of Drug Therapy
Representative Dose-Effect Curve Drug-Receptor Interactions: A typical D-R curve reveals potency, efficacy, and slope
Effect
Maximum Effect or Efficacy
Potency
Log Dose 16
General Principles of Drug Therapy
Drugs are described based on magnitude of two properties: 1) Affinity for the receptor  Affinity is related to potency 2) Efficacy once bound to the receptor  Efficacy refers to maximal effect drug can elicit
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General Principles of Drug Therapy
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...next slide 18
General Principles of Drug Therapy
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General Principles of Drug Therapy
Classes of Dose-Effect Curves
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General Principles of Drug Therapy
Full Agonists (i.e., equal efficacies) that Differ In Potency: A
B
C Compare the ED50s
Drug Concentration (log scale) 21
General Principles of Drug Therapy
% Max response
Agonists That Differ in Efficacy
A B
C
Log Drug Concentration
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General Principles of Drug Therapy
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General Principles of Drug Therapy
Drug properties should be compared in the same system
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General Principles of Drug Therapy
Competitive Antagonism Shifts The Agonist D-R Curve (Potency)
AG alone
AG + ANT
Drug Concentration (log scale) 25
General Principles of Drug Therapy
% Max response
Noncompetitive Antagonism Decreases Agonist Efficacy
AG alone AG + NC ANT AG + higher dose NC ANT
Log Drug Concentration 26
General Principles of Drug Therapy
Competitive antagonism is Surmountable.
Antagonism: A = Agonist B = Antagonist
Allosteric: A = Agonist B = Ligand
Noncompetitive antagonism is NOT surmountable: often due to irreversible Binding Allosteric effects occur when ligand B binds to a different site on the receptor than agonist A Either antagonism or potentiation is possible 27
General Principles of Drug Therapy
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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General Principles of Drug Therapy
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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General Principles of Drug Therapy
Pharmacodynamic Tolerance
This is due to reduced responsiveness to the drug at its site of action Amphetamine Caffeine
Nicotine Morphine, Barbiturates, Alcohol 30
General Principles of Drug Therapy
Drug Safety
Therapeutic Index
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General Principles of Drug Therapy
Therapeutic and Toxic Effects are Dose-Related: Ex. Phenobarbital
Sleep
ED50
Death
LD50
Dose of Phenobarbital 32
General Principles of Drug Therapy
Therapeutic Index (TI)
TI (preclinical)
LD50 ED50
clinical TI
TD50 ED50 33
General Principles of Drug Therapy
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General Principles of Drug Therapy
The End!!!
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