Anesthetic Drug Interactions: Implications for Dosing

1
Anesthetic Drug InteractionsImplications for
Dosing

• Steven L. Shafer, M.D.
• Professor of AnesthesiaStanford University
• Adjunct Professor of Biopharmaceutical
  SciencesUniversity of California at San Francisco

2
Acknowledgements
Don Stanski Jaap Vuyk Peter Glass Peter
Sebel Igor Kissin
Charles Minto Timothy Short Thomas Schnider Keith
Gregg Andrea Gentilini
3
Traditional View of Drug Interactions
Adapted from Tverskoy, Anesthesia and Analgesia
67342-345, 1988
4
Inhalational anesthetic - opioid interaction
Adapted from Glass and Sebel
5
Remifentanil MAC Reduction
Lang et al, Anesthesiology 85, 721-728, 1996
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Propofol/Alfentanil Interaction

• Adapted from Vuyk et al, Anesthesiology 838-22,
  1995
• Characterizes the concentrations for
• intubation
• maintenance
• on emergence
• Concentrations are 50 response level

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Optimal Propofol/Alfentanil

• Infusion rates for propofol and alfentanil
• Propofol levels during maintenance and at
  emergence from anesthesia
• Alfentanil concentrations during maintenance and
  at emergence
• Time from ending the infusion to awakening from
  anesthesia
• The percent decrease in concentration required
  for emergence from anesthesia

Stanski and Shafer Anesthesiology 831-5, 1995
8
EEG vs therapeutic ranges
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
9
Propofol / opioid technique
Stanski and Shafer Anesthesiology 831-5, 1995
Shafer SL, ASA Refresher Course, Chapter 19, 1996
10
Propofol/OpioidTime to Awakening
Alfentanil Technique
Remifentanil Technique
20
15
10
5
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Propofol/OpioidInfusion rates
Alfentanil Technique
Remifentanil Technique
400
300
Remifentanil (ng/kg/min)
Alfentanil (ng/kg/min)
200
Propofol (mg/kg/min)
Propofol (mg/kg/min)
100
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
12
Propofol/OpioidPropofol Levels (mg/ml)
Alfentanil Technique
Remifentanil Technique
6
4
Maintenance
Maintenance
2
Emergence
Emergence
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
13
Propofol/OpioidPercent Decrease on Emergence
Alfentanil Technique
Remifentanil Technique
100
75
Remifentanil
Propofol
50
Propofol
25
Alfentanil
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Propofol/Remifentanil TIVA

• Remifentanil
• 0.25 mg/kg/min
• Propofol
• 80 mg/kg/min
• Requires controlled ventilation

Shafer SL, ASA Refresher Course, Chapter 19, 1996

• Little tolerance for interruption of
  remifentanil or propofol infusion

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Propofol Anesthesia and Rational Opioid Selection
Determination of Optimal EC50-EC95
Propofol-Opioid Concentrations that Assure
Adequate Anesthesia and a Rapid Return on
Consciousness
Jaap Vuyk, M.D., Ph.D., Martijn J. Mertens, M.D.,
Erik Olofsen, M.Sc., Anton G.L. Burm, M.Sc,
Ph.D. James G. Bovill, M.D., Ph.D., F.F.A.R.C.S.I.
Anesthesiology 1997 871549-62
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Modeling of opioid/hypnotic interaction
Adapted from Vuyk et al, Anesthesiology 838-22,
1995
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Propofol/Alfentanil
60 min
10 min
600 min
300 min
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Propofol/Fentanyl
60 min
10 min
600 min
300 min
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Propofol/Sufentanil
60 min
10 min
600 min
300 min
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Propofol/Remifentanil
60 min
10 min
600 min
300 min
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10 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
30
60 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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300 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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600 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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Optimal Maintenance Propofol / Opioid
Concentrations
Sufentanil (ng/ml)
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Propofol/Opioid Recovery
40
35
30
25
Fentanyl
Minutes for Recovery
20
Alfentanil
15
Sufentanil
10
5
Remifentanil
0
0
120
240
360
480
600
Infusion Duration (minutes)
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Propofol/opioid vs Isoflurane/opioid
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Propofol/opioid vs Isoflurane/opioid
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Ketamine/Magnesium Interaction

• Preemptive Analgesia Ketamine and Magnesium
  Reduce Postoperative Morphine Requirements After
  Abdominal Hysterectomy
• Anesthesiology 1998 89A1163
• 4 groups
• Placebo, MgSO4 2 gms, ketamine 10 mg, or both
• Morphine sparing was measure of drug effect

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Lo, et al, Anesthesiology 1998 89 A1163
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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)
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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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Lowe Additivity
When normalized for potency, drug concentrations
can be simply added to calculate drug effect.
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Lowe Additivity
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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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Midazolam, Propofol, Alfentanil Interaction

• 400 patients undergoing gynecological surgery
• Dose response relationships established for loss
  of response to verbal command
• All drugs tested singly, in paired combinations,
  and the triple drug combination.

Minto et al, Anesthesiology 2000 921603-16
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Propofol-Midazolam Interaction for LOC
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Midazolam-Alfentanil Interaction for LOC
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Propofol-Alfentanil Interaction for LOC
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Three Drug Model Simple Additivity
All C
All A
All B
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Three Drug Model AB and AC Synergy, BC Additive
All C
All B
All A
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Three Drug Model Triple Synergy
All C
All B
All A
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Midazolam, Propofol, Alfentanil Interaction
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