Important Drug Interactions in Anesthesia

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Important Drug Interactions 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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Acknowledgements
Don Stanski Jaap Vuyk Peter Glass Peter
Sebel Igor Kissin Pamela Flood
Charles Minto Timothy Short Thomas Schnider Keith
Gregg Andrea Gentilini
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Conceptual Framework of Anesthetic Drug
Interaction
Hypnotics
Opioids,N2O
Conscious,Responsive
Cortex
AmbientStimuli
Unconscious,Unresponsive
SystemicOpioids
Pain projection
Midbrain, Thalamus
Severe
N2O
to cortex
None
Spinal
Local
Opioids
Anesthetics
Pain projection
Severe
to midbrain
Peripheral nerves, Spinal cord
None
Inspired by Glass PS.. Anesthesiology. 1998
885-6.
Pain
4
Simplistic View
AmbientStimuli
Afferent Stimuli
Pain projection
to cortex
Pain
Pain
5
Non-responsiveness
1
2
3
5
4
Hypnotic
Opioid
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Increasing Anesthetic Depth
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Increasing Anesthetic Depth
Tachycardia
Movement
Intubation
Hypnotic
Opioid
Incision
Verbal
Response
CallingName
Stimulus
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Inhalational anesthetic - opioid interaction
Adapted from Glass and Sebel
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Movement responseto Incision
Isoflurane
Fentanyl
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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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Any responseto Intubation
Propofol
Alfentanil
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EEG vs therapeutic ranges
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
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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
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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/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/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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10 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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600 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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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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Dynamic Ventilatory Control
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Model of Ventilatory DepressionRemifentanil 70
µg bolus
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Model of Ventilatory DepressionRemifentanil 12
µg/min infusion
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Propofol, Remifentanil,and Ventilation
Nieuwenhuijs et al, Anesthesiology. 98312-322,
2003
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Midazolam-Opioid Interactions(young volunteers)
Adapted from Kissen et al, Anesth Analg 7265-69,
1990
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Even actions on the same receptor can show synergy
Adapted from Tverskoy, Anesthesia and Analgesia
67342-345, 1988
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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.

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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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Midazolam, Propofol, Alfentanil Interaction
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Sequential Model of Drug Interaction
Hypnotics
Opioids,N2O
Conscious,Responsive
Cortex
AmbientStimuli
Unconscious,Unresponsive
SystemicOpioids
Pain projection
Midbrain, Thalamus
Severe
N2O
to cortex
None
Spinal
Local
Opioids
Anesthetics
Pain projection
Severe
to midbrain
Peripheral nerves, Spinal cord
None
Inspired by Glass PS.. Anesthesiology. 1998
885-6.
Pain
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Hierarchical Model of Drug Interaction
AmbientStimuli
Afferent Stimuli
Pain projection
to cortex
Pain
Pain
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Propofol-RemifentanilInteraction Surface
Laryngoscopy
Bouillon et al, Anesthesiology 2004
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Propofol-RemifentanilInteraction Surface
Laryngoscopy
Bouillon et al, Anesthesiology 2004
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Propofol-RemifentanilInteraction Surface BIS
Bouillon et al, Anesthesiology 2004
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Propofol-RemifentanilInteraction Surface BIS
Bouillon et al, Anesthesiology 2004
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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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Nicotine-Morphine
Flood and Daniel, Anesthesiology 2004, 1011417
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