Inhaled Anesthetic Agents: Mechanism of Action, Uptake, and Distribution

Mechanism of Action

Halogenated hydrocarbon volatile anesthetics (sevoflurane, isoflurane, desflurane) and nitrous oxide are the most commonly used inhaled anesthetic agents today.

Mechanism

• Inhaled anesthetics act through multiple complex mechanisms and pathways within the central nervous system (CNS).
  • The agents act by binding to target sites in proteins to enhance inhibitory receptors (gamma-amino butyric acid, glycine) and suppress excitatory transmission (block the action of glutamate at N-methyl D-aspartate (NMDA) receptors).¹
  • Hypnosis/sedation and amnesia are produced through effect sites in the brain. Immobility is produced by actions within the spinal cord.
  • Lipid solubility correlates to anesthetic potency (Meyer-Overton correlation).
  • There is currently no comprehensive theory of volatile anesthetics, and our understanding of the sequence of events, networks, and mechanisms is limited.
• Nitrous oxide is an inhaled anesthetic that works primarily by NMDA receptor antagonism.²

Properties of Gases

• The partial pressure of a gas is the fraction of the mixture that the agent comprises.
  • The partial pressure is directly proportional to tissue concentration which determines its clinical effect.
• Inhaled anesthetics function by achieving optimal and constant partial pressure at the CNS effect site (brain, spinal cord).
  • Equilibrium between alveolar partial pressures (PA) and arterial blood (Pa) results in steady-state partial pressures in the brain.³

• • PA (P_brain) = input (delivery) – uptake (into pulmonary circulation)

Uptake & Distribution (Pharmacokinetics)

F_i = concentration of inspired anesthetic in delivered gas flows
F_A = alveolar concentration
F_A/F_i = The rate of rise of concentration which determines the speed of inhalational induction

• An increased F_A/F_i results in faster induction.

Factors Affecting Anesthetic Delivery

1. Inspired concentration (F_i)

• • Increasing the concentration of the inhaled anesthetic increases F_A, but also the rate of rise of F_A/F_i via the concentration effect and the second gas effect (see below).

2. Alveolar ventilation

• • ↑ ventilation can counter uptake into circulation.
  • The effect is greater with soluble agents, which are subject to greater uptake.
  • Less pronounced with insoluble agents, where F_A/F_i quickly reaches 1.0.

3. Characteristics of anesthesia circuit

• • Circuit volume: ↓ delivery with h volume.
  • Gas flow: ↑ delivery with ↑ flow.
  • Solubility of agent into system components: ↓ delivery with ↑ absorption.

4. Characteristics of pulmonary system

• • Functional residual capacity (FRC): increased FRC will dilute the inspired gas due to a larger gas reservoir.
    • Larger FRC → slower induction.
  • V/Q mismatch: see below.

• Concentration effect
  • When the inhaled anesthetic represents a large fraction of the inhaled gas mixture, its rapid uptake results in a smaller relative anesthetic concentration drop, because the volume of the alveolar gas also decreases.⁵
  • This is only clinically relevant with nitrous oxide since it is used in high concentrations.
• Second-gas effect
  • The higher concentration of one inhaled anesthetic (usually nitrous oxide) will accelerate the increase in alveolar concentration of a coadministered inhaled agent.⁵

Uptake

• Uptake by the body (via the pulmonary circulation) delays the increase in FA.
• The greater the uptake, the slower the rise in FA/Fi.
• The three primary determinants of uptake include:

1. Solubility in blood:

• Expressed as blood: gas coefficient.
• A more soluble anesthetic will have a higher blood: gas coefficient.

2. Alveolar blood flow: if there is no pulmonary shunting, alveolar blood flow is equal to the cardiac output (CO).

• Increase in CO → more rapid uptake of agent → slower rise in F_A/F_i.
• Low CO → less uptake → ↑ rise in F_A/F_i → quicker induction.
• Change in CO has a more pronounced effect on soluble anesthetics, where uptake is greater.
• Note: as cerebral blood flow is well regulated, increasing CO will primarily deliver the anesthetic agent to other tissue sites.

3. The difference in partial pressures between alveoli and venous blood (P_A – P_v)

• Anesthetic flows across the alveolar-capillary interface are driven by the gradient in partial pressures. The net flow reverses during anesthetic elimination.
  • The larger the gradient, the greater the uptake into circulation.
• Primarily determined by tissue uptake (see “Distribution” below).
  • As soluble agents are taken up in tissues, venous partial pressure is initially low → increasing uptake → slowing the rise in F_A/F_i.
  • As tissue partial pressure approaches alveolar partial pressure, gradient will decrease → slowing the rate of uptake.

Inhalational Induction in Infants and Young Children

• The rapid wash-in (rise in F_A/F_i) of inhaled anesthetics in infants and young children can be explained by the following.⁴
  • Greater alveolar ventilation to FRC ratio (V_A/FRC ratio).
    • V_A/FRC ratio is approximately 5:1 in neonates compared to only 1.5:1 in adults.
    • Greater impact on more soluble agents (halothane)
  • Greater fraction of the cardiac output is distributed to the vessel-rich group (VRG).
    • VRG comprises approximately 18% of body weight in neonates compared to 8% in adults.
  • Reduced tissue/blood solubility
    • Tissue/gas solubilities of inhaled anesthetics in the VRG in neonates is approximately one-half those in adults.
    • It is explained by greater water content and decreased protein and lipid concentrations.
  • Reduced blood/gas solubility
    • Blood solubility of more soluble inhaled agents is about 18% less in neonates.
    • It is explained by decreased serum cholesterol and proteins (including albumin).
    • However, blood solubility of sevoflurane is similar in neonates and adults.

Effect of V/Q Mismatch on F_A/F_i

• Pulmonary dead space:
  • Increased dead space reduces effective alveolar ventilation, slowing induction.
  • Greater impact on less-soluble agents, where the limiting factor is alveolar ventilation.
• Shunt:
  • R → L (transpulmonary or intracardiac, i.e., one-lung ventilation, VSD):
    • Increases alveolar-arterial difference (↑ PA and ↓ Pa), slowing induction⁵
    • Greater impact on less-soluble agents
  • L → R:
    • Minimal effect on the speed of induction with inhaled anesthetics

Distribution

• Multicompartment model due to differing rates of uptake by tissue.
• Tissue uptake is determined by tissue solubility (tissue: blood coefficients), tissue perfusion, and partial pressure gradient (P_a: P_tissue).
• Four tissue groups:
  1. Vessel-rich group: brain, heart, lungs, kidney, liver, spinal cord
  • Rapidly reaches equilibrium (minutes)
  2. Muscle:
  • Equilibrates over hours
  3. Fat:
  • ↑ effective volume with soluble drugs
  • Slow uptake due to low perfusion and high volume
  • Equilibrates over days
  4. Vessel-poor group: bone, connective tissues

Minimal Alveolar Concentration (MAC)

• Definition: the steady-state alveolar concentration of the inhaled anesthetic at which 50% of healthy individuals do not respond to a surgical stimulus.⁶
• MAC values correspond to the potency of the inhaled anesthetic and vary between agents.
• MAC values are additive between the anesthetic agents.

Factors Affecting MAC

• Age: MAC increases by 30% from birth until 1-6 months of age and then decreases by 6-7% every decade after 20 years of age.⁷