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Models of Drug Behavior

Please Fasten Safety Belts Prior to Take Off. Outline. Basic models of drug behaviorApplication of drug models: target controlled drug deliveryModels of drug interactionAre mathematical models of drug behavior clinically predictive?Future Directions. I won't be discussing. Individual drug pharmacokineticsThe role of pharmacokinetics and pharmacodynamics in anesthetic drug developmentSpecific mathematical functions, other than some fundamental definitions.

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Models of Drug Behavior

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    1. Models of Drug Behavior

    2. Please Fasten Safety Belts Prior to Take Off

    3. Outline Basic models of drug behavior Application of drug models: target controlled drug delivery Models of drug interaction Are mathematical models of drug behavior clinically predictive? Future Directions

    4. I won’t be discussing Individual drug pharmacokinetics The role of pharmacokinetics and pharmacodynamics in anesthetic drug development Specific mathematical functions, other than some fundamental definitions

    5. Basic Models of Drug Behavior

    6. Simple Pharmacokinetic Model: Volume of Distribution

    7. Simple Pharmacokinetic Model: Clearance

    8. The time required for drug concentrations to decrease by 50%. Simple Pharmacokinetic Model: Half-Life

    9. Comparative Pharmacokinetics of Duzitol

    11. More complex PK Model: Multi-compartment

    12. More complex PK Model: Multi-compartment

    13. Comparative Pharmacokinetics of Duzitol

    14. Comparative Pharmacokinetics of Duzitol

    16. Opioid Half-Lives (minutes)

    17. Opioid Pharmacokinetics

    18. Integrative PK model: Context-Sensitive Half-Time

    19. PK/PD Concept: 20% Plasma Decrement Time

    20. PK/PD Concept: 80% Decrement Time

    22. Awake EEG

    23. Profound Opioid EEG Effect

    24. EEG Time Course with Fentanyl

    25. EEG Time Course with Alfentanil

    26. Extended PK/PD Concept: The “Effect Site”

    27. Normalized Effect Site Opioid Concentrations

    28. Morphine Onset

    29. Simulation of Morphine Time Course

    30. Morphine Pharmacokinetics

    31. Morphine vs. Fentanyl PK

    32. Morphine vs. Fentanyl PK

    33. Morphine vs. Fentanyl Onset

    34. Morphine vs. Fentanyl Onset

    35. Morphine vs. Fentanyl PK

    36. Comparative Hydromorphone PK

    37. Comparative Hydromorphone PK

    38. Hydromorphone Onset

    39. Hydromorphone Onset

    40. Comparative Hydromorphone PK

    41. Comparative Sufentanil PK

    42. Comparative Sufentanil PK

    43. Sufentanil Onset

    44. Sufentanil Onset

    45. Meperidine Onset

    46. Meperidine Onset

    47. Comparative Onset of Alfentanil and Remifentanil

    48. Methadone Onset

    49. Methadone Onset

    50. Methadone PK

    51. Methadone PK

    52. Application of Drug Models: Target Controlled Delivery

    53. Fentanyl: Target = 1 ng/ml

    54. Fentanyl TCI

    55. Fentanyl TCI Plasma Target

    56. Fentanyl TCI Effect Site Target

    57. Remifentanil: Plasma Control

    58. Remifentanil: Effect Site Control

    60. Propofol: Plasma Control

    61. Propofol: Effect Site Control

    65. Target Controlled Lidocaine Used at Stanford Pain Clinical for patients with neuropathic pain.

    66. CSF Targeted Epidural Clonidine

    67. Models of Drug Interaction

    70. Propofol/Alfentanil Interaction Adapted from Vuyk et al, Anesthesiology 83:8-22, 1995 Characterizes the concentrations for intubation maintenance on emergence Concentrations are 50% response level

    75. Usually interactions are represented in two dimensions

    76. However, they are 3D surfaces: (same model as on prior slide)

    83. 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.

    91. Propofol-Remifentanil Interaction Surface: Laryngoscopy

    92. Propofol-Remifentanil Interaction Surface: BIS

    93. Dynamic Ventilatory Control

    94. Model of Ventilatory Depression Remifentanil 70 µg bolus

    95. Model of Ventilatory Depression Remifentanil 12 µg/min infusion

    96. Are Drug Models Predictive of Drug Effect?

    97. The Aspect Data Base Patient trials (movement): Thiopental Propofol Fentanyl/Alfentanil/Sufentanil Isoflurane Nitrous Oxide Volunteer trials (recall, sedation, eyelash): Propofol Isoflurane Alfentanil Midazolam

    98. The Aspect Data Base 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)

    99. Recall vs. Heart Rate, Blood Pressure (unstimulated)

    100. Recall vs. BIS, Blood Pressure (unstimulated)

    101. Recall vs. BIS, Blood Pressure (unstimulated)

    102. Predictors of Movement

    105. PK for AAI, BIS, and Predicted Propofol Concentrations (when combined with remifentanil)

    106. Propofol-Remifentanil Interaction (loss of response to laryngoscopy)

    107. 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 I am aware of only one counter example, which has not been published.

    108. Models of Drug Behavior: Future Directions

    109. Jan Hendrickx Interaction Analysis Literature search All interaction studies involving 2 or more drugs: GABA propofol, etomidate, methohexital, thiopental, midazolam, diazepam NMDA ketamine Alpha2 clonidine, dexmedetomidine Opioids morphine, alfentanil, fentanyl, sufentanil, remifentanil Dopamine droperidol Na+ channel lidocaine

    110. Endpoints considered Humans Hypnosis Verbal/Syringe Pain/Movement Incision/Tetanus Animals Hypnosis Righting reflex Pain/Movement Tail clamp/Tetanus

    113. Results

    114. Conclusion Additivity usually applies when anesthetics act identically at a single site additivity supports, but does not prove, a single site of action. Additivity is the exception for the interaction of intravenous drugs that are known to target different receptors relevant to the anesthetic state.

    115. What are the implications for the mechanisms of action of inhaled anesthetics? What do we learn from existing interaction data with inhaled anesthetics, and what future research can be done?

    119. Different Anesthetics Act at Different Receptors

    120. STRICTLY ADDITIVE INTERACTIONS

    121. Conclusion For years, we have pursued protein based mechanisms of anesthetic action, focused on ion channels No single ion channel can explain the inhaled anesthetic action It has been postulated that multiple discrepant effects on proteins may be responsible for inhaled anesthetic action. STRICT ADDITIVITY has pushed us back to a unitary site of inhaled anesthetic action.

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