Pharmacodynamics II- Dose Response Relationships

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

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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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