713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY

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Pharmacodynamics Dose-response relationship
Topic 7

• 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY
• Dr. Korawuth Punareewattana

Faculty of Veterinary Medicine, Khon Kaen
University
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Pharmacodynamics (?????????????)

• Pharmacodynamics (PDs)
• is the science of drug action on the body or
• on microorganisms and other parasites within or
  on the body
• PDs study can be performed on many levels
• Molecular level
• Cellular level
• Tissue or organ level
• Whole body level

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Pharmacodynamics

• Pharmacodynamics consists of 2 elements
• The relationship between drug concentration and
  effect
• Mechanisms of drug action
• Receptor mediated (major)
• Signal transduction and Second messengers
• Non-receptor mediated (minor)

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Some terms involved

• Mechanism of action
• ???????????????
• Pharmacological effect
• ??????????????????
• Side effect
• ???????????
• Adverse effect
• ???????????, ??????????????????
• Undesirable effect
• Unwanted effect
• Toxic effect
• ????????

• Receptor ????????
• Affinity ??????????
• ?????????????????????????????
• Efficacy ????????????????
• Intrinsic activity
• Potency ????????????
• Ligand
• ?? ???? ????????? ????????? receptor
• Agonist
• Partial agonist
• Antagonist

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Pharmacodynamics

• Dose-Response Relationship
• The intensity and duration of a drugs effects
  are a function of the drug dose and drug
  concentration at the effect site

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Monitoring Dose-Response

• Level
• Molecular (e.g, enzyme inhibition)
• Cellular (in vitro tissue culture, blood cells)
• Tissue or organ (in vitro or in vivo)
• Organism
• Endpoint used to measure effect may be different
  at each level
• Overall effect
• sum of multiple drug effects and physiological
  response to drug effects

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Endpoints to Monitor Drug Effect
Farnesyltransferase Inhibitors for Cancer
LEVEL ENDPOINT
Molecular Farnesyltransferase inhibition
Cellular Proliferation rate or Apoptosis
Tumor Response (change in tumor size)
Organism Survival, quality of life
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Dose-Response Endpoints
Graded
Continuous scale (dose effect) Measured
in a single biologic unit Relates dose to
intensity of effect
Quantal
All-or-none pharmacologic effect Population
studies Relates dose to frequency of effect
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Graded Dose Response example Erythropoietin and
Anemia (Linear dose-response plot)
Peak Hematocrit Increment
Erythropoietin Dose units/kg
Eschbach et al. NEJM 31673-8, 1987
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Drug-Receptor Interactions
Drug
Drug-Receptor Complex
Ligand-binding domain
k1
Effector domain
k2
Receptor
Effect
(KD k2/k1)
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Dose-Effect Relationship
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Emax Model

• E is the drug effect
• Conc is the conc at the receptor
• Emax is the maximum drug effect
• EC50 is the conc at 50 of Emax

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Graded Dose-Effect Curve(Linear dose-response
plot)
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Log Transformation
Log Dose-Response Curve (LDR plot)
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Emax Model Predictions
EC20
EC80

• Emax 100
• EC50 1
• E0 0 (baseline)

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Properties of Log-Dose Response (LDR) Curves

• Describing the LDR-relationship over a wide
  range of doses
• Typically S-shaped or sigmoidal
• Frequently the same effect is produced by
  different drugs with an identical or at least
  similar mechanism.
• In such cases the LDR-curves of the drugs may be
  expected to run parallel to each other.
• Example from the next slide.
• The curves of drug A and B are parallel. At the
  same height or response of the plot, the dose of
  drug B will be twice as great as that of drug A.

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Properties of Log-Dose Response (LDR) Curves
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LDR and Identification of the site of drug action
Theophylline Dose-Effect
Relaxation
Control
PDE Inhibition
Theophylline µM
Rabe et al. Eur Respir J 8637-42, 1995
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Dose-Effect Parameters

• Graded dose-effect curves are also a good way to
  compare agents that produce the same effect.
• Drugs that produce the same effect differ in
  terms of potency and efficacy, which are
  parameters that can be assessed from the
  dose-response curves of the agents.

The sensitivity of an organ or tissue to the drug
POTENCY
EFFICACY
The maximum effect
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Efficacy and Potency
EFFICACY The maximum effect
POTENCY The sensitivity of an organ or tissue to
the drug
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LDR and Type of ligandsReceptor-Mediated Effects
Maximum Effect
Drug
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LDR and Drug interaction
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Drug Interactions

• Graded dose-effect curves are also useful for
  studying pharmacodynamic drug interactions.
• This plot shows the dose-effect curves for an
  agonist alone, in yellow,
• the agonist combined with a competitive
  antagonist in blue, and combined
• with a non-competitive antagonist in green.
• A competitive antagonist combines reversibly
  with the same binding site as
• the agonist or active drug and can be displaced
  from the binding site by an
• excess of the agonist. The maximal effect of the
  agonist can still be achieved
• if sufficient agonist is used.
• A competitive inhibitor lowers the potency of
  the agonist but
• does not alter its efficacy.
• A non-competitive antagonist binds irreversible
  to the receptor binding site or
• interacts with other components of the system to
  decrease or eliminate the effect
• of the drug binding to the receptor. A
  non-competitive antagonist prevents the agonist,
• at any concentration, from producing its maximum
  effect. Typically, the dose response
• curve with this type of antagonist reveals
  reduced apparent efficacy,
• but the potency is not altered.
• Using the dose-effect curve to study drug
  interactions can obviously be helpful in
• elucidating the mechanism of the drug
  interaction.

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Graded Dose-Effect Analysis

• Identify the therapeutic dose/concentration
• Define site of drug action (receptor)
• Classify effect produced by drug-receptor
  interaction (agonist, antagonist)
• Compare the relative potency and efficacy of
  drugs that produce the same effect
• Assess mechanism of drug interactions

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Quantal Dose-Effect Distribution
ED50
of Subjects
Threshold Dose
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Cumulative Dose-Effect Curve
Cumulative of Subjects
Dose
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Cumulative Dose-Effect Study
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Lidocaine Quantal Dose-Effect
Example
Achieving Complete Analgesia
Total Lidocaine Dose (mg)
Ferrante et al. Anesth Analg 8291-7, 1996
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Therapeutic and Toxic Effects
Therapeutic
Toxic
Responding
ED99
TD50
TD1
ED50
Dose
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Therapeutic Indices
Therapeutic Ratio
2.5
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Antihypertensive Dose-Effect
Identifying the dose-effect relationship is an
important component of early clinical trials
performed during the initial stages of drug
development.
Johnston Pharmacol Ther 5553-93, 1992
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Antihypertensive Drugs
Desirable Dose Range
Dose Range most often used
with Maximal Effect
Adverse Effects
Log Dose
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Role of Dose-Effect Studies

• Drug development
• Site of action
• Selection of dose and schedule
• Potency, efficacy and safety
• Drug interactions
• Patient management
• Therapeutic drug monitoring
• Risk-benefit (therapeutic indices)