Title: Fundamentals of Clinical Pharmacology in Anesthesia
1Fundamentals 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
2Outline
- Basic models of drug behavior
- Application of drug models target controlled
drug delivery - Drug Interaction Models
- Are mathematical models of drug behavior
clinically predictive?
3I wont be discussing
- Individual drug pharmacokinetics
- The role of pharmacokinetics and pharmacodynamics
in anesthetic drug development - Specific mathematical functions, other than some
fundamental definitions
4Basic Pharmacokinetic Models
5Simple Pharmacokinetic Model Volume of
Distribution
Volume
Amount
Concentrat
ion
Volume
6Simple Pharmacokinetic Model Clearance
7Simple Pharmacokinetic Model Half-Life
- The time required for drug concentrations to
decrease by 50.
8Comparative Pharmacokinetics of Duzitol
9Comparative Pharmacokinetics of Duzitol
10More complex PK ModelMulti-compartment
11More complex PK ModelMulti-compartment
100
Rapid
10
Concentration
Intermediate
Slow
1
0
120
240
360
480
600
Minutes since bolus injection
12More complex PK ModelMulti-compartment
13Opioid PK ExampleHalf-Lives (minutes)
14Opioid 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
15Integrative 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.
16Application of Drug ModelsTarget Controlled
Delivery
17Fentanyl Target 1 ng/ml
18Fentanyl TCI
19Fentanyl TCIPlasma Target
20Fentanyl TCIEffect Site Target
21Propofol PK/PD in the ICU
22Basic PharmacodynamicConcepts
23Pharmacodynamics
24Pharmacodynamics Potency
25Therapeutic Window
26Pharmacodynamics Efficacy
27Benzodiazepine Example
28The Effect Site
29Awake EEG
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
30Profound Opioid EEG Effect
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
31EEG Time Course with Fentanyl
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
32EEG Time Course with Alfentanil
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
33Extended PK/PD Concept The Effect Site
34PK/PD IntegrationEffect site concentrations
over time
35PK/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
36PK/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
37Drug Interaction Models
38Traditional View of Drug Interactions
Adapted from Tverskoy, Anesthesia and Analgesia
67342-345, 1988
39Usually interactions are represented in two
dimensions
Adapted from Glass and Sebel
40However, they are 3D surfaces(same model as on
prior slide)
McEwan et al.. Anesthesiology 78864, 1993.
41Basic 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
42Basis of Response Surface A Sigmoid in Every
Slice
43How a response surface relates to an isobole
44Simple Additivity
45Synergy
46Antagonism
47Agonist-Partial Agonist
48Agonist-Antagonist
49Agonist-Inverse Agonist
50Are Drug Models Predictiveof Drug Effect?
51The Aspect Data Base Evaluation
- Patient trials (movement)
- Thiopental
- Propofol
- Fentanyl/Alfentanil/Sufentanil
- Isoflurane
- Nitrous Oxide
- Volunteer trials (recall, sedation, eyelash)
- Propofol
- Isoflurane
- Alfentanil
- Midazolam
52The 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)
53Recall vs. Heart Rate, Blood Pressure(unstimulate
d)
54Recall vs. BIS, Blood Pressure(unstimulated)
55Recall vs. BIS, Blood Pressure(unstimulated)
56Predictors 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
57Sedation, BIS, and Propofol
Glass et al, Anesthesiology 86836-847, 1997
58Conscious/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
59PK for AAI, BIS, and Predicted Propofol
Concentrations(when combined with remifentanil)
Struys et al, Anesthesiology 99802-812
60Are 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.
61(No Transcript)