Wayne E. Ellis, Ph.D., CRNA

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Anesthesia Agents 1

• Wayne E. Ellis, Ph.D., CRNA

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Primary Goals of Anesthesia

• Unconsciousness
• Amnesia/Hypnosis
• Analgesia
• Inhibition of Noxious Reflexes
• Skeletal Muscle Relaxation

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History that you must know!!

• Who and When
• Ether
• Chloroform
• Cyclopropane
• Diethyl ether
• Halothane
• Methoxyflurane
• Isoflurane

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• While the saying "it does not matter what is in
  the can, but who tips the can" certainly has
  merit, one should base their decision on
  selection of one of the inhaled anesthetics on
  sound reasoning Adriani, 1950

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Ron Miller

• One should also keep in mind most of the effects
  of these agents are dose dependent

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What Is Anesthesia

• State of
• No memory
• No pain
• No sympathetic response
• In Nature
• Deep sleep
• Fainting
• Death

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Effects of Agents

• Most dependent
• Exposure Time
• Exposure Concentration
• Body Reservoirs

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Role of Inhalation Agents

• Changed since introduction of original agents
• Total anesthetic to part of the pot
• Combinations include
• Narcotics, benzodiazepines, and muscle relaxants
• Use Lower doses
• Less side effects
• Faster wake-up

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Measuring an Effective Anesthetic

• Lack of purposeful response to painful stimuli
• Surgical incision mammal
• Tail clamp rodents
• Heat rodents, fruit flies
• Loss of righting reflex rodents
• Loss of spontaneous movement
• Swimming, flying, or crawling

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Mechanism of Inhalation Agents

• Meyer Overton Rule
• Membrane Expansion Theory
• Based on lipophilic nature of anesthetics
• Anesthesia occurs after a sufficient number of
  lipid soluble anesthetic molecules are dissolved
  in lipid cell membranes. The membrane expands as
  a result of the increased volume.
• The most potent volatile anesthetic was
  methoxyflurane highest oil gas partition
  coefficient

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Myer-Overton Rule

• Agreement
• Halogenated alkanes, ethers (halothane,
  isoflurane)
• Alkanes, ethers, alcohols (Cyclopropane, Etoh)
• Some other gases (Xenon)
• Disagreement
• Perfluorocarbon (C2F6)
• Gases (Helium, Neon)
• Long chain alcohols and alkanes (Cgt 12 14)

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Theories of Narcosis

• Influence of physical and physiologic principles
  on anesthetic requirements
• Understand effects of
• Temperature
• Aging
• Pressure
• Ion concentrations

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Lipid Theory

• Nonspecific mechanism of action
• Lipid solubility
• Pressure reversal
• Not favored
• Little physical evidence
• Anesthetic to lipid ration is low
• Specificity issues lipids are ubiquitous

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Clathrate Theory

• When drugs interact with water molecules, they
  form hydrated micro crystals called clathrates
• Hypothesized to decrease receptor function
• This theory applies to hydrophilic molecules

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Protein based theories

• Anesthetics bind to sites on proteins
• Conformational change induced or prevented
• Change kinetics of conformational change
• Compete with ligands
• Protein receptor sites
• Competitive inhibition
• Interaction with voltage-gated channel proteins

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Protein Targets

• Ion channels
• Ligand gated
• Voltage gated
• Calcium, sodium, potassium
• G-protein gated
• Enzymes like kinases
• Effector enzymes
• G proteins

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Neurotransmitters

• Inhibitory receptor glycine
• Excitatory receptor nicotinic
• Excitatory receptor serotonin (5HT3)
• Excitatory receptor glutamate (NMDA)
• Inhibitory receptor GABA

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Glycine

• Acts by binding to a ligand-gated chloride
  channel
• Potentiated
• Volatile anesthetics
• Propofol
• Barbiturates
• Not applicable
• Ketamine
• Etomidate

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Nicotinic

• Inhibited by
• Volatile Anesthetics
• Alcohols (long chain)
• Barbiturates
• Not applicable to ketamine

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Serotonin

• Potentiated by the volatile anesthetics
• Inhibited by
• Ketamine
• Sodium Thiopental

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Glutamate

• Mediate synaptic transmission in the spinal cord
  by regulating calcium
• Types
• Inotropic (neurotransmitter gated)
• NMDA receptors
• KA (Kainate) receptors
• AMPA (quisqualate) receptors
• Metabotropic (G-protein associated)

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NMDA (N-methyl-D-aspartate) Receptor

• Inhibition
• Ketamine
• Volatile Anesthetics
• Etoh
• Phencyclidine
• STP

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Alpha2 (a2) Adrenoceptors

• Agonists
• Clonidine
• Xylazine
• Tranquilizing, sedative , and
• Presynaptic inhibition of neurotransmission

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GABA (Gamma-aminobutyric acid) Receptors

• Widely found in CNS
• Concentrated in the basal ganglia, cerebellum,
  hippocampus, hypothalamus, substantial gelatinosa
• GABA-a and GABA-b
• Inhibitory actions
• Act via chloride channel

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GABA-a

• Inhibitory activity potentiated by
• Volatile anesthetics
• Barbiturate
• Propofol
• Benzodiazepines
• Anesthetic steroids
• Exception is Ketamine

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Second Messenger Systems

• G-proteins mediated
• Phosphatidylinositol mediated
• Calcium mediated
• cAMP mediated
• cGMP mediated

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Protein Theories

• Favored
• Many proteins have binding sites for anesthetics,
  some are stereo specific
• Reasonable concentration ranges
• If binding at specific site, effect is possible
• Disfavored
• Antagonist
• Specificity
• Chirality

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?What is it?

• Multiple mechanisms for different agents
• Multiple sites of action
• Multiple actions on same target
• Each anesthetic has a specific spectrum of action
• Different effects on same target in different
  location

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?What is it?

• General Anesthesia may be different states caused
  by multiple actions on multiple sites or
  combinations thereof.
• General Anesthesia is not an identical state
  achieved by a common action on one cell site
• General Anesthesia has similar effects achieved
  by different substances by different actions

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Understanding General Anesthesia

• Requires an understanding of
• Sleep
• Memory
• State of Consciousness
• Pain

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Potency / MAC

• Potency is directly related to lipid solubility.
• MAC Minimal Alveolar Concentration at 1
  atmosphere that produce immobility in 50 of
  patients exposed to noxious stimulus.
• MAC is inversely proportional to potency.
• The lower the MAC the greater the potency.
• 1 MAC prevents movement in 50 of patients ED50
  of drug.
• 1.3 MAC prevents movement in 95 of patients
  ED95 of drug.

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Factors That Increase MAC

• Term infant to 6months of age
• Hyperthermia
• Hypernatremia
• CNS excitation with cocaine MAO inhibitors

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Factors That Decrease MAC

• Hypothermia
• Prematurity
• Increasing age
• CNS depressants
• Acute ethanol intoxication
• Alpha-2 agonists (Clonidine)
• Pregnancy
• Hypercalcemia
• Hyponatremia
• Acute alcohol intoxication

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Vapor Pressures

• Enflurane - 172mmHg
• Sevoflurane - 170mmHg
• Halothane - 244mmHg
• Isoflurane - 240mmHg
• Desflurane - 669mmHg

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Effects On Renal System

• Decreased renal blood flow
• Decreased Glomerular Filtration Rate
• Decreased urine output

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  Effects on Cardiac System

• SVR mostly decreased by Isoflurane/Desflurane
• Most Myocardial depression occurs with
  Halothane/Enflurane
• Halothane/sevoflurane mostly depress baroreceptor
  reflex (no HR increases despite decreased BP)
• Isoflurane/Desflurane least depress baroreceptor
  reflex (HR increases with decreased BP)  

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Anesthetic Concerns

• Lipid Solubility
• Volatility
• Speed of uptake
• Speed of elimination
• Metabolism
• Toxicity

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Lipid solubility and volatility

• I gt Br gt Cl gt F
• Larger the halogen
• More lipid soluble
• Less volatile
• Anesthetics work
• How long to get to susceptible tissues
• How long stay there
• How fast removed

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Metabolism Of Volatile Anesthetics

• Methoxyflurane gt Halothane gt Sevoflurane gt
  Enflurane gt Isoflurane gt Desflurane
• Desflurane almost totally inert to metabolism
• Metabolism
• Cytochrome P450 enzymes in liver
• Oxidize anesthetics

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Metabolism Toxicity

• Liver most susceptible to toxicity
• Halothane
• Chloroform
• Halothane is only anesthetic that undergoes
  metabolic reduction
• Penthrane (Methoxyflurane) Kidneys

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?What is it?

• General Anesthesia may be different states caused
  by multiple actions on multiple sites or
  combinations thereof.
• General Anesthesia is not an identical state
  achieved by a common action on one cell site
• General Anesthesia has similar effects achieved
  by different substances by different actions

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Anesthetic Action

• Based on lipid solubility
• Direct interaction of the anesthetic leads to
  indirect action on protein
• Involving
• Size (thickness/volume)
• Shape (curvature)
• Phase Transition
• Fluidity
• Ionic permeability and dielectric properties

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Pharmacokinetics of Inhaled Agents

• Factors determining the partial pressure of
  anesthetic gas in the arterial blood and brain
  are
• Concentration of agent in inspired gas
• Alveolar Ventilation
• Transfer of gas from alveoli to arterial blood
• Loss of agent (uptake) to tissue

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Effects of Agents

• Exposure Time
• Exposure Concentration
• Body Reservoirs

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Anesthetic Partial Pressure Gradients May Exist
Between

• Vaporizer
• Inflow
• System
• Alveoli
• Blood
• Tissue

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Wash-in of Inhaled Anesthetics

• Definition
• The increase in the ratio of the anesthetic
  partial pressure in the alveoli to that in the
  inspired fresh gas.
• FA/Fi depends on a balance of the rate of
  delivery to and uptake from the lungs.

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Wash-in of Inhaled Anesthetics

• Factors Affecting Wash-in
• Inspired Concentration - Fi
• Alveolar Ventilation
• FRC
• Cardiac Output
• Solubility
• Alveolar to venous partial pressure gradient

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Inspired Concentration

• Driving force of anesthetic into the lungs
• The greater the inspired concentration (Fi), the
  greater the driving force and the more rapid the
  increase in FA/Fi

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Alveolar Ventilation

• Changes in alveolar ventilation lead to parallel
  changes in FA/Fi.
• Effects of ventilation vary depending on
  solubility of agent.
• Effects of hyperventilation
• Spontaneous vs. Controlled Ventilation

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Functional Residual Capacity

• Contributes to wash-in in an inverse manner
• The greater the FRC the slower the rate of rise
  FA/Fi

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Cardiac Output

• Removal of anesthetic from the lung depends on
  pulmonary blood flow
• The greater the CO the greater the uptake
• Increased uptake slows the rate of rise of FA/Fi

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Solubility

• Definition - the ratio of concentrations of the
  anesthetic in two phases when the partial
  pressure has equilibrated.
• Expressed as a partition coefficient
• Partition coefficient reflects the solubility of
  an anesthetic in one phase compared to its
  solubility in a second phase

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Solubility (Speed)

• The lower the solubility of agent
• The quicker the agent diffuses into brain tissue
  with induction
• The quicker the agent diffuses from brain tissue
  back into the lungs with emergence
• The higher the solubility of agent
• The slower the agent diffuses into brain tissue
  with induction
• The slower the agent diffuses from brain tissue
  back into the lungs with emergence

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Lipid solubility and volatility

• I gt Br gt Cl gt F
• Larger the halogen
• More lipid soluble
• Less volatile
• Anesthetics work
• How long to get to susceptible tissues
• How long stay there
• How fast removed

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Partition Coefficients
Agent Blood/ Gas Brain/ Gas Muscle/ Blood Fat/ Blood Oil/ Gas
N2O 0.47 1.1 1.2 2.3 1.40
Halothane 2.4 1.9 3.5 60 224
Enflurane 1.8 1.3 1.7 36 98.5
Isoflurane 1.4 1.6 4.0 45 90.8
Desflurane 0.45 1.3 2.0 27.2 18.7
Sevoflurane 0.65 1.7 3.1 47.5 53.4
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Inhaled Agents Blood/gas Partition Coefficient
(Solubility)

• Desflurane 0.42 (Fast onset)
• Nitrous Oxide 0.47 (Fast onset)
• Sevoflurane 0.69 (Medium Fast)
• Isoflurane 1.43 (Medium)
• Ethrane 1.9 (Medium)
• Halothane 2.4 (Slow)
• Penthrane 13.0 (Very slow)

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Year of Introduction Solubility
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(A-v) Partial Pressure Gradient

• With no obstruction of diffusion the alveolar
  tension of agent is the same as the arterial
  tension
• Difference between alveolar and venous partial
  pressure is then due to tissue uptake

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Tissue Groups

• Vessel- rich
• Muscle
• Fat
• Vessel-poor

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Theories of Narcosis

• Effects of
• Temperature
• Aging
• Pressure
• Ion concentrations
• Influence of physical and physiologic principles
  on anesthetic requirements

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Temperature

• MAC decreases with decreasing body temperature
• Variable from agent to agent
• Cyclopropane 2/degree
• Halothane 5/degree

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Pressure

• Not correlated across species

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Age

• MAC
• Maximal at 6 months of age
• Gradually decreases as age increases
• Octogenarian has approximately 1/2 infant
  requirement
• For all potent inhalation agents
• Not directly related to potency of agent
• Elder has increased susceptibility to CNS
  depressants

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Ion Concentration

• Hypernatremia
• Increases sodium in CSF
• Increases Halothane MAC up to 43
• Hyperkalemia
• Does not alter CSF potassium
• Does not alter MAC
• Calcium
• Increased serum and CSF levels without change in
  MAC

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CNS Actions

• Altering neuronal activity
• Brain stem reticular formation
• Alters state of consciousness and alertness
• Regulates motor activity
• Theory
• Decrease tone in ascending reticular system
• Effects of agents variable

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Amnesia Inhaled Agents

• Will not cause retrograde amnesia (amnesia of
  occurrences 30-60 before surgery)
• Causes antegrade amnesia (amnesia of occurrences
  when inhalation given, gt 0.5 MAC)
• Should not cause prolonged impairment of memory

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Neuronal Transmission

• Peripheral
• No depression by ether, penthrane, or halothane
• Can increase sensitivity of nocioceptors
• Selective highly sensitive neurons
• Sensitive to potent inhalation anesthetics
• Inhibited firing activity

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Axonal vs. Synaptic Transmission

• Concentrations that alter synaptic transmission
  have smaller effect on axonal transmission
• Chloroform and ether
• Amplitude of action potential by 1/2
• 3-4 x the concentration required to reduce
  synaptic transmission by 1/2
• Concentrations close to MAC do not alter action
  potential propagation in mammals
• Produce a 50-100 block of postsynaptic
  potentials

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Axonal vs. Synaptic Transmission

• At clinical concentrations
• Alter transmission through axon
• Enhanced excitability of axons
• Initial exposure
• Excitation during induction
• Frequency of transmission may alter potency
• Inhalation agents may change frequency of firing