MAC and the Pharmacodynamics of Inhaled Anesthetics

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MAC and the Pharmacodynamics of Inhaled
Anesthetics
Steven L. Shafer, M.D. Professor of Anesthesia,
Stanford University Adjunct Professor of
Biopharmaceutical Science, UCSF Editor in Chief,
Anesthesia Analgesia
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First There Was Ether
Dr. Crawford Long, Jefferson, GA, 1842
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Then Came Nitrous Oxide
Dr. Horace Wells, Hartford, CT, 1844
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Then There Was Ether, Again
Dr. William Morton, Boston, MA, 1846
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What Does Ether Do?
Guedels Signs of Ether Anesthesia
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Common Pharmacodynamic Properties of Inhaled
Anesthetics

• Initially cause excitement (patient is literally
  intoxicated)
• Higher doses cause loss of consciousness
• Even higher doses suppress movement response to
  noxious stimulation
• Higher doses depress myocardial contractility,
  cause vasodilation
• Blood pressure falls
• Higher doses suppress ventilation

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What is MAC

• A widely used measure of anesthetic potency
• The steady state expired gas concentration that
  suppresses a purposeful response to noxious
  stimulation in 50 of patients.

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Common Pharmacodynamic Properties of Inhaled
Anesthetics
Increasing Anesthetic Depth
MAC Fraction
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What is Anesthesia

• No universally accepted definition
• Usually thought to consist of
• Oblivion
• Amnesia
• Analgesia
• Lack of Movement
• Hemodynamic Stability

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Inhaled Anesthetics Are Complete Anesthetics
Oblivion
No Movement
Hemodynamic Response Attenuated
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Ether, Chloroform, Cyclopropane

• Ether Very slow onset, explosive
• Chloroform Slow onset, highly toxic
• Cyclopropane Fast onset, highly explosive

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Halothane, Methoxyflurane

• Halothane First modern anesthetic
• Rotted livers
• Metabolized by the liver
• Caused ventricular arrhythmia
• Methoxyflurane
• Rotted kidneys (released fluoride)

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Enflurane, Isoflurane,

• Introduced late 1970s, early 1980s
• Isoflurane is still widely used
• Pungent odor, rapid onset, rapid offset

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Sevoflurane, Desflurane

• Introduced in the 1990s
• Sevoflurane has fast onset, smells OK
• Desflurane has VERY fast onset / offset, very
  pungent

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Nitrous Oxide, Xenon

• Nitrous is still widely used
• Potent analgesic (NMDA antagonist)
• MAC 120
• Xenon
• Also a potent analgesia (NMDA antagonist)
• MAC is around 80
• Just an atom!
• Hmmmm what does that say about the site of
  action?

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What is Anesthesia?
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What is Anesthesia?
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Opioids and Hypnotics
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Inhalational anesthetic - opioid interaction
Adapted from Glass and Sebel
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What is Anesthesia?
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How Do Inhaled Anesthetics Work?

• Unknown!
• After 150 years, we still dont understand how
  inhaled anesthetics work.
• The biggest mystery in pharmacology

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Immobility is a SPINAL Effect
We know where, just not how
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However, the molecular site of action is unknown
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Intriguing Properties

• Meyer-Overton Hypothesis
• MAC correlates with lipophilicity
• Promiscuous receptor activity
• Low intersubject variability
• Conserved across species
• Additivity

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Anesthetic Structure
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Meyer Overton Observation
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Low Intersubject Variability

• For most intravenous hypnotics, the dose at which
  95 of the population is unresponsive is
  100-200 of the dose at which 5 of the
  population is unresponsive.
• For inhaled anesthetics, an ED95 is only about
  20 higher than an ED5.

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Promiscuous Pharmacology
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Conserved Across Species
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Age Affects MAC
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Where do Inhaled Anesthetics Act?

• GABA SHLA mouse has same MAC, picrotoxin has
  same effect on cyclopropane MAC as halothane MAC
• Nicotinic antagonists dont affect MAC,
  non-immobilizer is effective nicotinic antagonist
• Glycine ceiling effect of strychnine
• NMDA non-immobilizer blocks NMDA, MK-801
  insufficiently efficacious
• Kainate GluR6 knockout doesn't change MAC.
• AMPA GluR2 knockout doesn't change MAC.
• Adrenergic depletion of a2 receptors doesnt
  change MAC
• Serotonin ondansetron administration doesn't
  change MAC. Nonimmobilizer blocks 5-HT2C
• Potassium channels existing knockouts dont
  change MAC
• Opioids naloxone doesnt change MAC

Courtesy of Ted Eger
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Display of interactions
Immobility
Hypnosis
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Display of Hypothesis (IV Agents) What We
Predict
Immobility
Hypnosis
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Results
Human data Animal data Combined data
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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.

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Inhaled Anesthetic Interactions
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Interactions between inhaled agents and IV agents
are most often synergistic, making those
receptors less likely targets as sites of action
of inhaled agents.
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Human data Animal
data
Immobility
Immobility
Hypnosis
Hypnosis
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Human data Animal
data
Immobility
Immobility
Hypnosis
Hypnosis
Wrong MAC N2O estimate in rats or true antagonism?
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Human data Animal
data
Immobility
Immobility
Hypnosis
Hypnosis
there should be synergy with at least some
combinations...
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Different AnestheticsAct at Different Receptors
Courtesy of Ted Eger
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STRICTLY ADDITIVE INTERACTIONS
Courtesy of Ted Eger
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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.