2. Inhaled anesthetics

• Anesthesia


  Reversible depression of the CNS sufficient to permit surgery to be performed without movement, obvious distress, or recall
• Components of anesthesia


  • Sedation
  • Immobilization in response to a noxious stimulus
  • Amnesia
  • Attenuation of autonomic responses to noxious stimulation
  • Analgesia
• Stages of anesthesia


  • Stage 1: Analgesia
  • Stage 2: Disinhibition
  • Stage 3: Surgical Anesthesia
  • Stage 4: Medullary Depression
• Medical gases


  • Oxygen (O2)
  • Nitrous Oxide (N2O or Laughing Gas)
  • Air (N2 + O2 + trace gases)
  • Heliox (HeO2)
  • Nitrox (N2O2)
• Oxygen (O2)


  99% pure oxygen, compressed gas or refrigerated liquid, stored in green cylinder
• Nitrous Oxide (N2O)


  "Laughing gas", stored in blue cylinder, liquid form at room temperature
• Air


  Created by mixing O2 and N2, stored in yellow cylinder
• Cylinder Index System includes Diameter Index Safety System (DISS) and Pin Index Safety System (PISS)
• Nitrous oxide was first synthesized in 1772 by Joseph Priestley
• Diethyl ether was first used for anesthesia on October 16, 1846, "Ether Day"
• Three broad classes of inhaled anesthetics


  • Ethers
  • Alkanes
  • Gases
• Potent


  Inhaled anesthetics only require 1-2% mixed with O2 to exert a clinically desired effect
• Volatile


  Inhaled anesthetics have a propensity to move from liquid to gas
• Vapor pressure


  Partial pressure of a vapor in equilibrium with a liquid
• Solubility


  Amount of gas that can be dissolved into a solvent at equilibrium, described by partition coefficient
• Blood:gas partition coefficient (λBG) is critically important to alveolar uptake of inhaled anesthetics
• Partial pressure gradients propel inhaled anesthetic across various barriers (breathing circuit → FI → FA → Fa → FBr)
• Blood/gas solubility coefficient (λ)


  Ratio of the concentration in blood to the concentration in gas, when the partial pressure in both compartments is at equilibrium
• The higher the blood/gas partition coefficient, the slower the onset of an inhaled anesthetic due to greater uptake into blood and tissue
• Solubility describes the affinity of a gas for a given substance, for inhaled anesthetics blood acts as a pharmacologically inactive reservoir
• Concentration of gases


  Equivalent to partial pressure or gas tension
• The principal objective of inhalation anesthesia is to achieve a constant and optimal brain partial pressure of the inhaled anesthetic
• Determinants of alveolar partial pressure


  • FGF
  • Administered dose (vaporizer %)
  • Breathing circuit
  • Lung exchange
  • CO
  • Blood:gas partition coefficient
  • Ventilation
  • FRC
• A high FI is required during the initial phases of anesthesia to offset uptake and accelerate induction
• Factors affecting uptake of volatile anesthetics


  • B:G coefficients
  • CO or alveolar Blood Flow
  • Alv/v partial pressure difference
  • Shunts
  • R to L vs. L to R
• Increased ventilation and increased concentration of anesthetic can speed induction through the concentration effect and second gas effect
• Blood distributes the anesthetic around the body according to regional perfusion, with the vessel-rich group (brain, heart, kidney, liver, endocrine glands) receiving 75% of cardiac output but only 10% of total body weight
• Elimination of inhaled anesthetics is exclusively through the lungs, as the reverse of uptake
• Metabolism of inhaled anesthetics occurs via cytochrome P450 enzyme 2E1 in the liver, kidney, and lung, with varying degrees of toxicity from metabolites
• Mechanism of action of inhaled anesthetics


  Potentiate inhibitory GABA and glycine receptors, inhibit excitatory NMDA and nicotinic acetylcholine receptors, decreasing nervous system excitability
• Enflurane


  Renal injury
• Sevoflurane


  Results in the largest level of serum F- ions, but is safe
• Sevoflurane's safety is probably due to uniquely low B:G λ
• Mechanism of action of inhalational anesthetics


  • Unknown
  • N2O is believed to inhibit NMDA excitatory receptors in brain
  • Some VA appear to interact with GABA
  • Others block excitatory channels and activate inhibitory channels
  • There does not seem to be a single site of action that is shared by all agents
• Mechanism of action of inhalational anesthetics


  • VA site of action is most likely GABAA
  • They potentiate inhibitory Cl- currents though GABAA receptors by increasing the efficacy of GABAA
  • Produces a decrease in neuronal excitability
  • Glycine receptors when activated open a Cl- permeable channel that hyperpolarizes neurons
  • Decrease nervous system excitability
• Mechanism of action of inhalational anesthetics


  • VA may also inhibit nAChRs, because their activation in the brain aids in function of learning, memory, and attention. Thus, inhibiting nAChR may contribute to cognitive components of anesthesia
  • VA may inhibit NMDA receptors responsible for learning and memory
  • VA have been shown to inhibit excitatory neurotransmitter release, reducing CNS excitability
• Compared to IV anesthetics, inhaled anesthetics are generally more promiscuous in the molecular targets, lacking the receptor-specific, and even subtype-specific, effects of certain IV anesthetics
• Evidence exists that loss of consciousness and immobility are the result of two or more separate mechanisms rather than one
• Minimal Alveolar Concentration (MAC)


  • The concentration that prevents skeletal muscle movement in response to a painful noxious stimulus (i.e. skin incision) in 50% of patients
  • Roughly additive when VA are used with N2O
  • Considered the ED50 of an inhaled anesthetic
  • Analogous to the EC50 for IV drugs
• MAC values


  • Halothane 0.75%
  • Isoflurane 1.15%
  • Enflurane 1.6%
  • Sevoflurane 2.1%
  • Desflurane 6.0%
  • Nitrous Oxide 105%