Advances in the Clinical Pharmacology of Intravenous Anesthetics : Pharmacokinetic, Pharmacodynamic, Pharmaceutical, and Technological Considerations

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Advances in the Clinical Pharmacology of
Intravenous Anesthetics Pharmacokinetic,
Pharmacodynamic, Pharmaceutical, and
Technological Considerations

• R3 ???

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• Total intravenous anesthesia
• now an appealing, workable alternative to the
  inhalational anesthesia

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The "surfing" analogy in anesthesia drug
selection and administration

• anesthesia and reanimation
• necessitate a standard of precision and accuracy
  in drug administration
• anesthesiologist
• target drug level within a narrow therapeutic
  window
• adequate anesthesia vs rapid emergence

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• a "surfing" analogy
• surfer riding near the crest of wave
• target concentration that produce considerable
  drug effects and recover quickly drug
  administration is terminated
• large reduction in effects with small decrease in
  concentration

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Three approaches

• the pharmacodynamic approach
• feedback mechanism(propofol titration to EEG and
  muscle relaxant)
• the pharmacokinetic approach
• TCI
• the pharmaceutical approach
• unnecessary to hit the target with as much
  precisions and accuracy as with the other
  approaches

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Pharmacokinetic considerations

• pharmacologic modeling
• fitting mathematical equations to raw
  pharmacologic data
• a set of parameters that describe in quantitative
  terms a drug's disposition and effect in the body
  
• pharmacokinetic parameters clearance,
  distribution volumes, half life
• " what the body does to the drug"
• pharmacodynamic parameters potency
• " what the drug does to the body"

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• The goal of PK-PD modeling
• provide the practitioner with the knowledge
  necessary to formulate rational dosing scheme
• accurately predicting the time course and
  magnitude of drug effect in any type of patients
• to move dose-response analysis

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• pharmacokinetic component relationship between
  the drug dose and the time course of drug
  concentrations in the body
• pharmacodynamic component relationship between
  the drug concentration in the site of action and
  the drug effect
• prediction regarding latency to peak effect,
  magnitude of effect, duration of effect

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Context sensitive half-times a new
pharmacokinetic concept

• context sensitive half-times a new
  pharmacokinetic concept
• context the duration of the continuous infusion
  
• CSHT 50 decrement time
• alfentanil vs sufentanil vs fentanyl

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Pharmacodynamic considerations

• importance of pharmacodynamic drug interactions
  and synergy
• pharmacodynamic drug interaction frequently
  produced by design
• modern day anesthesia at least a two-drug
  process consisting of an analgesic and a hypnotic
  agent
• anesthesiology is the practice of pharmacologic
  synergism using CNS depressants

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• propofol-opioid interaction characterized using
  EC50 reduction study methodology
• opioid-propofol relation is highly nonlinear
• the dosage reduction of one drug produced by an
  increase in the other is not simply proportional
• the substantial pharmacodynamic synergy of the
  drug combination
• isobolographic drug interaction analysis
  rational selection of concentration target pairs
  for propofol and opioid

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• revolutionary advance in our understanding of IV
  anesthetic clinical behavior
• propofol 3.5ug/ml as loss of consciousness in
  50 pts 10-15ug/ml to supress to surgical stimuli
  1ug/ml in the presence of opioid adjuvant
• by using propofol-opioid ratio applicable to
  any anesthetic case
• function of opioid pharmacokinetics play a
  large part of selection of ratio
• long acting fentanyl congeners low opioid and
  high propofol
• short acting opioid low propofol

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• play in selecting the appropriate propofol-opioid
  ratio
• hemodynamically compromised pt VS pt prone to
  nausea and vomiting
• isobologram is only a single "slice" through a
  much larger drug ineraction "surface"
• response surface tool to visualize the nature
  of the synergy of two drug class

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Pharmaceutical considerations

• remifentanil a prototype designer drug
• by designing molecules with specialized
  structure-activity relationship
• lose its u-receptor agonist activity on ester
  hydrolysis
• very-short-acting pharmacokinetic activity

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• can be titrated up and down as necessary to meet
  the dynamic needs of the patient during rapid
  changing conditions of anesthesia and surgery
• when rapid recovery is desirable
• when the anesthetic requirement rapidly
  fluctuates
• when opioid titration is unpredictable or
  difficult
• when there is a substantial danger to opioid
  overdose
• when "high-dose" opioid technique is advantageous
  but not going to be mechanically ventilated

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• importance of formulation propofol as an
  example
• the formulation of a drug can have an important
  influence on the drug's clinical behavior
• propofol lipid emulsion formulation pain on
  injection serious allergic reactions inadvertent
  contamination
• prodrug non-lipid excipient lipid-based emulsion
• may alter pharmacokinetic and pharmacodynamic
  characteristic

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Technical advances

• calculating pump
• simply specifies a delivery rate as mg/hr or
  ug/kg/mim
• do not achieve the pharmacokinetic exactness
• patient-controlled analgesia machine

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• computer-controlled infusion pump
• by coding a pharmacokinetic model into a computer
  program and linking it into an electric pump
• design target concentration and calculate the
  necessary infusion rate by TCI system
• gradually decrease the rate of infusion based on
  the pharmacokinetics
• change the infusion rate frequently
• require knowledge of the therapeutic
  concentration for clinical application