Fundamentals of Clinical Pharmacology in Anesthesia

1
Fundamentals of Clinical Pharmacology in
Anesthesia
Steven L. Shafer, M.D. Palo Alto VA Health Care
System Stanford University School of
Medicine University of California at San Francisco
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Outline

• Basic models of drug behavior
• Application of drug models target controlled
  drug delivery
• Drug Interaction Models
• Are mathematical models of drug behavior
  clinically predictive?

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I wont be discussing

• Individual drug pharmacokinetics
• The role of pharmacokinetics and pharmacodynamics
  in anesthetic drug development
• Specific mathematical functions, other than some
  fundamental definitions

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Basic Pharmacokinetic Models
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Simple Pharmacokinetic Model Volume of
Distribution
Volume
Amount

Concentrat
ion
Volume
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Simple Pharmacokinetic Model Clearance
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Simple Pharmacokinetic Model Half-Life

• The time required for drug concentrations to
  decrease by 50.

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Comparative Pharmacokinetics of Duzitol
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Comparative Pharmacokinetics of Duzitol
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More complex PK ModelMulti-compartment
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More complex PK ModelMulti-compartment
100
Rapid
10
Concentration
Intermediate
Slow
1
0
120
240
360
480
600
Minutes since bolus injection
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More complex PK ModelMulti-compartment
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Opioid PK ExampleHalf-Lives (minutes)
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Opioid Pharmacokinetics
100
10
Percent of peak plasma opioid concentration
fentanyl
1
sufentanil
alfentanil
0.1
0
120
240
360
480
600
Minutes since bolus injection
15
Integrative PK modelContext-Sensitive Half-Time
120
fentanyl
90
alfentanil
Minutes required
60
sufentanil
30
0
0
120
240
360
480
600
Minutes since beginning of infusion
Hughes MA, Glass PS, Jacobs JR. Anesthesiology.
1992 76334-41.
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Application of Drug ModelsTarget Controlled
Delivery
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Fentanyl Target 1 ng/ml
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Fentanyl TCI
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Fentanyl TCIPlasma Target
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Fentanyl TCIEffect Site Target
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Propofol PK/PD in the ICU
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Basic PharmacodynamicConcepts
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Pharmacodynamics
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Pharmacodynamics Potency
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Therapeutic Window
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Pharmacodynamics Efficacy
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Benzodiazepine Example
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The Effect Site
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Awake EEG
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
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Profound Opioid EEG Effect
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
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EEG Time Course with Fentanyl
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
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EEG Time Course with Alfentanil
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
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Extended PK/PD Concept The Effect Site
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PK/PD IntegrationEffect site concentrations
over time
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PK/PD Concept20 Plasma Decrement Time
60
fentanyl
40
Minutes required
alfentanil
20
sufentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
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PK/PD Concept80 Decrement Time
300
fentanyl
240
alfentanil
180
Minutes required
120
sufentanil
60
0
0
120
240
360
480
600
Minutes since beginning of infusion
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Drug Interaction Models
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Traditional View of Drug Interactions
Adapted from Tverskoy, Anesthesia and Analgesia
67342-345, 1988
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Usually interactions are represented in two
dimensions
Adapted from Glass and Sebel
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However, they are 3D surfaces(same model as on
prior slide)
McEwan et al.. Anesthesiology 78864, 1993.
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Basic Concentration vs Response Relationship
1
0.8
0.6
50 Probability
Probability of no response
0.4
C
0.2
50
0
0.1
1
10
100
Drug concentration
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Basis of Response Surface A Sigmoid in Every
Slice
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How a response surface relates to an isobole
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Simple Additivity
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Synergy
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Antagonism
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Agonist-Partial Agonist
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Agonist-Antagonist
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Agonist-Inverse Agonist
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Are Drug Models Predictiveof Drug Effect?
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The Aspect Data Base Evaluation

• Patient trials (movement)
• Thiopental
• Propofol
• Fentanyl/Alfentanil/Sufentanil
• Isoflurane
• Nitrous Oxide
• Volunteer trials (recall, sedation, eyelash)
• Propofol
• Isoflurane
• Alfentanil
• Midazolam

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The Aspect Data Base Evaluation

• Aspect Investigators
• Peter Sebel (Emory)
• Peter Glass (Duke)
• Carl Rosow (Harvard/MGH)
• Lee Kearse (Harvard/MGH)
• Marc Bloom (University of Pittsburgh)
• Ira Rampil (University of California, San
  Francisco)
• Randy Cork (University of Arizona)
• Mark Jopling (Ohio State University)
• N. Ty Smith (University of California, San Diego)
• Paul White (University of Texas at Dallas)

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Recall vs. Heart Rate, Blood Pressure(unstimulate
d)
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Recall vs. BIS, Blood Pressure(unstimulated)
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Recall vs. BIS, Blood Pressure(unstimulated)
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Predictors of Movement
Measure
Pk
0.74
Blood propofol
0.76
Effect-site propofol
Bispectral Index
0.86
Relative delta power
0.79
Relative beta power
0.83
95 SEF (Hz)
0.81
Median Frequency (Hz)
0.8
Leslie et al, Anesthesiology 8452-63, 1996
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Sedation, BIS, and Propofol
Glass et al, Anesthesiology 86836-847, 1997
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Conscious/Unconscious Prediction (Pk)
Target
Measured
Agent (n)
BIS
Concentration
Concentration
Propofol (399)
0.976 0.006
0.936 0.010
0.937 0.013
Isoflurane (70)
0.959 0.021
0.965 0.015
0.967 0.016
Midazolam (50)
0.885 0.047
0.859 0.045
0.886 0.048
Significantly different from Pk value for Target
Concentration (p lt 0.001),
and Measured concentration (p lt 0.01)
Glass et al, Anesthesiology 86836-847, 1997
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PK for AAI, BIS, and Predicted Propofol
Concentrations(when combined with remifentanil)
Struys et al, Anesthesiology 99802-812
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Are drug models predictive?

• Mathematical models of drug behavior
  incorporating effect site concentrations and drug
  interactions predict anesthetic drug effect
  (e.g., loss of response to stimulation) as well
  as
• Measured concentrations
• BIS
• AAI
• Ive learned of only 1 counter example, which was
  reported at a meeting I attended in April, and
  has not been published.

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