General Anesthetic Pharmacology - Quick Reference

Potency, MAC, and Meyer-Overton Rule

• General anesthetics cause reversible CNS depression: loss of consciousness, amnesia, immobility; other effects (analgesia, muscle relaxation) depend on agent and context.

• The Minimum Alveolar Concentration (MAC): the alveolar partial pressure that abolishes movement to a surgical incision in 50% of patients.

  • Potency inversely related to MAC: smaller MAC = more potent.

  • The Meyer-Overton rule links potency to lipid solubility: higher oil/gas partition coefficient predicts higher potency.

  • Practical relation: $\text{MAC} \propto \frac{1}{(\text{oil/gas})} \quad\text{and}\quad \text{MAC} \approx \frac{1.3}{(\text{oil/gas})}$ (approximate constant across agents).

• Analgesia vs surgical anesthesia: higher partial pressures may be needed for nociception blockade than for immobility; analgesic index = MAC / AP50.

Partition Coefficients and Their Significance

• Solubility in solvent(s) predicts behavior:

  • Oil/gas partition coefficient ((oil/gas)) → potency: higher = more potent.

  • Blood/gas partition coefficient ((blood/gas)) → rate of induction/recovery: lower = faster kinetics.

• Tissue/blood partition coefficients describe tissue solubility:

  • (tissue/blood) = [A]{tissue} / [A]{blood} at equilibrium.

  • Higher values → greater tissue uptake and longer equilibration, especially for fat.

• Rule of thumb: high oil/gas often comes with higher blood/gas, trading potency for speed.

• Box concept: converting partial pressures to tissue concentrations relies on solvent/gas coefficients and partitioning.

Uptake Model and Kinetics Overview

• Body modeled in compartments, in parallel:

  • Vessel-rich group (VRG): brain, liver, kidneys; high perfusion, low capacity.

  • Muscle group (MG): muscle/skin; moderate perfusion, moderate capacity.

  • Fat group (FG): adipose tissue; low perfusion, very high capacity.

  • Vessel-poor group (VPG): bone/cartilage/ligaments; negligible capacity/perfusion (often ignored).

• Key idea: induction and recovery depend on how fast partial pressures equilibrate between alveoli, blood, and tissues.

• Time constants and equilibration:

  • For a compartment, equilibration follows a time constant: $\tau = \frac{V<em>{\text{cap}}}{\dot{Q}}$ where V{cap} is tissue capacity and \dot{Q} is tissue perfusion.

  • 63% equilibration at t = \tau; 95% by ~3\tau.

  • Alveolar-to-inspired (Palv vs PI) equilibration has its own time constant: $\tau<em>{\text{alv}} = \frac{FRC}{\dot{V}</em>A}$

• Two rate-limiting steps define uptake:

  • Alveolar partial pressure to inspired partial pressure: {Palv → PI} is slow for some agents (ventilation-limited) and faster for others (perfusion-limited).

  • Tissue equilibration to arterial partial pressure: {Ptissue → Part} is generally fast for VRG but slow for FG.

Ventilation-Limited vs Perfusion-Limited Anesthetics

• Ventilation-limited (high blood/gas): e.g., diethyl ether, halothane, isoflurane.

  • Slow {Palv → PI} and slower induction/recovery; susceptible to changes in ventilation and CO.

• Perfusion-limited (low blood/gas): e.g., nitrous oxide, desflurane, sevoflurane.

  • Rapid {Palv → PI} and faster equilibration; ind/rec less sensitive to CO but still influenced by ventilation.

• Practical implication: agents with low blood/gas solubility induce and wake faster; agents with high blood/gas solubility have slower kinetics but may allow more stable maintenance.

Alveolar and Tissue Equilibration Dynamics

• Alveolar-to-inspired equilibration (Palv ↔ PI): faster for low blood/gas agents; slower for high blood/gas agents.

  • When Palv approaches PI, induction accelerates; if Palv lags, uptake slows progress toward CNS depth.

• Tissue-to-arterial equilibration (Ptissue ↔ Part): tissue groups equilibrate with arterial blood at rates determined by tissue volume and blood flow; VRG equilibrates fastest, FG slowest.

• The rate at which CNS partial pressure (Pbrain, a proxy for CNS depth) reaches the arterial level depends on two factors:

  • For VRG, rapid due to high perfusion and proximity to blood supply.

  • For FG, very slow due to large capacity and low perfusion.

• Key takeaway: induction is often limited by {Palv → PI} for perfusion-limited agents and by {Pbrain → Part} for some ventilation-limited agents; initial changes in ventilation or CO have greatest impact early in anesthesia.

Effects of Physiologic Variables on Induction

• Ventilation changes:

  • Hypoventilation slows induction by reducing Palv rise; more pronounced for ventilation-limited agents.

  • Hyperventilation speeds Palv rise; effect varies with agent type.

• Cardiac output changes:

  • Decreased CO speeds Palv rise for ventilation-limited agents (less uptake) but may accelerate CNS uptake for perfusion-limited agents due to altered MVR dynamics.

  • Increased CO can slow induction by increasing anesthetic uptake into tissues and reducing Palv rise rate.

• Age effects (children vs adults):

  • Children have higher ventilation and higher VRG fraction, which tends to speed induction, but higher CO can slow it; net effect often faster induction in children for many agents.

• Pathologic states:

  • Hemorrhagic shock, COPD, V/Q mismatch alter uptake/distribution and thus depth of anesthesia; predictions rely on the uptake model.

Recovery from Anesthesia

• Recovery is the reverse of induction; VRG unloads fastest, FG unloads slowly.

• Recovery rate depends on agent’s blood/gas partition coefficient: lower (blood/gas) → faster recovery; higher capacity tissues slow recovery after long procedures.

• Diffusion/solubility effects mean redistribution from VRG to MG/FG can prolong recovery after extended anesthesia.

• Diffusion hypoxia: when nitrous oxide is discontinued, rapid loss of N2O from blood into alveoli displaces O2, risking hypoxia; counteract with abrupt administration of 100% O2 for several minutes.

Inhaled Anesthetic Agents: Key Properties and Practical Notes

• Nitrous oxide (N2O)

  • Low blood/gas solubility → very fast equilibration (rapid induction/recovery).

  • High MAC, so cannot produce full anesthesia alone; often used with other agents (balanced anesthesia).

  • Oil/gas partition coefficient modest; contributes analgesia with other agents.

  • Diffusion hypoxia risk on discontinuation; mitigate with 100% O2.

• Halothane

  • High oil/gas (potent), but relatively high blood/gas (slower induction/recovery).

  • Nonirritant odor; pediatric use is common but hepatotoxicity risk exists; rare malignant hyperthermia.

• Isoflurane

  • Potent with moderately high oil/gas; relatively low blood/gas → relatively rapid emergence; good maintenance agent.

• Enflurane

  • Similar to isoflurane but with some different defluorination profile and potential for seizures in rare cases.

• Desflurane

  • Very low blood/gas, very low induction time; potential airway irritation; not ideal for induction but excellent for maintenance due to rapid emergence.

• Sevoflurane

  • Low blood/gas and good potency; pleasant odor; widely used for induction; generally well tolerated; caveat: potential nephrotoxicity with degradation products when exposed to some CO2 absorbers.

• Diethyl ether and methoxyflurane

  • Historically potent but high blood/gas leading to slow induction and flammability; largely out of routine use in developed regions.

Practical Equations and Concepts to Remember (LaTeX)

• Potency relation (Meyer-Overton): $\text{MAC} \approx \frac{1.3}{(\text{oil/gas})}$

Potency, MAC, and Meyer-Overton Rule

• General anesthetics cause reversible CNS depression: loss of consciousness, amnesia, immobility; other effects (analgesia, muscle relaxation) depend on agent and context.

• The Minimum Alveolar Concentration (MAC): the alveolar partial pressure that abolishes movement to a surgical incision in 50% of patients.

  • Potency inversely related to MAC: smaller MAC = more potent.

  • The Meyer-Overton rule links potency to lipid solubility: higher oil/gas partition coefficient predicts higher potency.

  • Practical relation: $\text{MAC} \propto \frac{1}{(\text{oil/gas})} \quad\text{and}\quad \text{MAC} \approx \frac{1.3}{(\text{oil/gas})}$ (approximate constant across agents).

• Analgesia vs surgical anesthesia: higher partial pressures may be needed for nociception blockade than for immobility; analgesic index = MAC / AP50.

Partition Coefficients and Their Significance

• Solubility in solvent(s) predicts behavior:

  • Oil/gas partition coefficient ((oil/gas))

    • Potency: higher = more potent.

  • Blood/gas partition coefficient ((blood/gas))

    • Rate of induction/recovery: lower = faster kinetics.

• Tissue/blood partition coefficients describe tissue solubility:

  • (tissue/blood) $= [A]<em>{\text{tissue}} / [A]</em>{\text{blood}}$ at equilibrium.

  • Higher values

    • Greater tissue uptake and longer equilibration, especially for fat.

• Rule of thumb: high oil/gas often comes with higher blood/gas, trading potency for speed.

• Box concept: converting partial pressures to tissue concentrations relies on solvent/gas coefficients and partitioning.

Uptake Model and Kinetics Overview

• Body modeled in compartments, in parallel:

  • Vessel-rich group (VRG): brain, liver, kidneys; high perfusion, low capacity.

  • Muscle group (MG): muscle/skin; moderate perfusion, moderate capacity.

  • Fat group (FG): adipose tissue; low perfusion, very high capacity.

  • Vessel-poor group (VPG): bone/cartilage/ligaments; negligible capacity/perfusion (often ignored).

• Key idea: induction and recovery depend on how fast partial pressures equilibrate between alveoli, blood, and tissues.

• Time constants and equilibration:

  • For a compartment, equilibration follows a time constant: $\tau = \frac{V<em>{\text{cap}}}{\dot{Q}}$ where $V</em>{\text{cap}}$ is tissue capacity and $\dot{Q}$ is tissue perfusion.

  • 63% equilibration at $t = \tau$; 95% by $\approx 3\tau$.

  • Alveolar-to-inspired (Palv vs PI) equilibration has its own time constant: $\tau<em>{\text{alv}} = \frac{\text{FRC}}{\dot{V}</em>A}$.

• Two rate-limiting steps define uptake:

  • Alveolar partial pressure to inspired partial pressure: {Palv → PI} is slow for some agents (ventilation-limited) and faster for others (perfusion-limited).

  • Tissue equilibration to arterial partial pressure: {Ptissue → Part} is generally fast for VRG but slow for FG.

Ventilation-Limited vs Perfusion-Limited Anesthetics

• Ventilation-limited (high blood/gas): e.g., diethyl ether, halothane, isoflurane.

  • Slow {Palv → PI} and slower induction/recovery; susceptible to changes in ventilation and CO.

• Perfusion-limited (low blood/gas): e.g., nitrous oxide, desflurane, sevoflurane.

  • Rapid {Palv → PI} and faster equilibration; ind/rec less sensitive to CO but still influenced by ventilation.

• Practical implication: agents with low blood/gas solubility induce and wake faster; agents with high blood/gas solubility have slower kinetics but may allow more stable maintenance.

Alveolar and Tissue Equilibration Dynamics

• Alveolar-to-inspired equilibration (Palv ↔ PI): faster for low blood/gas agents; slower for high blood/gas agents.

  • When Palv approaches PI, induction accelerates; if Palv lags, uptake slows progress toward CNS depth.

• Tissue-to-arterial equilibration (Ptissue ↔ Part): tissue groups equilibrate with arterial blood at rates determined by tissue volume and blood flow; VRG equilibrates fastest, FG slowest.

• The rate at which CNS partial pressure (Pbrain, a proxy for CNS depth) reaches the arterial level depends on two factors:

  • For VRG, rapid due to high perfusion and proximity to blood supply.

  • For FG, very slow due to large capacity and low perfusion.

• Key takeaway: induction is often limited by {Palv → PI} for perfusion-limited agents and by {Pbrain → Part} for some ventilation-limited agents; initial changes in ventilation or CO have greatest impact early in anesthesia.

Effects of Physiologic Variables on Induction

• Ventilation changes:

  • Hypoventilation slows induction by reducing Palv rise; more pronounced for ventilation-limited agents.

  • Hyperventilation speeds Palv rise; effect varies with agent type.

• Cardiac output changes:

  • Decreased CO speeds Palv rise for ventilation-limited agents (less uptake) but may accelerate CNS uptake for perfusion-limited agents due to altered MVR dynamics.

  • Increased CO can slow induction by increasing anesthetic uptake into tissues and reducing Palv rise rate.

• Age effects (children vs adults):

  • Children have higher ventilation and higher VRG fraction, which tends to speed induction, but higher CO can slow it; net effect often faster induction in children for many agents.

• Pathologic states:

  • Hemorrhagic shock, COPD, V/Q mismatch alter uptake/distribution and thus depth of anesthesia; predictions rely on the uptake model.

Recovery from Anesthesia

• Recovery is the reverse of induction; VRG unloads fastest, FG unloads slowly.

• Recovery rate depends on agent’s blood/gas partition coefficient: lower (blood/gas)

  • Faster recovery; higher capacity tissues slow recovery after long procedures.

• Diffusion/solubility effects mean redistribution from VRG to MG/FG can prolong recovery after extended anesthesia.

• Diffusion hypoxia: when nitrous oxide is discontinued, rapid loss of N2O from blood into alveoli displaces O2, risking hypoxia; counteract with abrupt administration of 100% O2 for several minutes.

Inhaled Anesthetic Agents: Key Properties and Practical Notes

• Nitrous oxide (N2O)

  • Low blood/gas solubility

    • Very fast equilibration (rapid induction/recovery).

  • High MAC, so cannot produce full anesthesia alone; often used with other agents (balanced anesthesia).

  • Oil/gas partition coefficient modest; contributes analgesia with other agents.

  • Diffusion hypoxia risk on discontinuation; mitigate with 100% O2.

• Halothane

  • High oil/gas (potent), but relatively high blood/gas (slower induction/recovery).

  • Nonirritant odor; pediatric use is common but hepatotoxicity risk exists; rare malignant hyperthermia.

• Isoflurane

  • Potent with moderately high oil/gas; relatively low blood/gas

    • Relatively rapid emergence; good maintenance agent.

• Enflurane

  • Similar to isoflurane but with some different defluorination profile and potential for seizures in rare cases.

• Desflurane

  • Very low blood/gas, very low induction time; potential airway irritation; not ideal for induction but excellent for maintenance due to rapid emergence.

• Sevoflurane

  • Low blood/gas and good potency; pleasant odor; widely used for induction; generally well tolerated; caveat: potential nephrotoxicity with degradation products when exposed to some CO2 absorbers.

• Diethyl ether and methoxyflurane

  • Historically potent but high blood/gas leading to slow induction and flammability; largely out of routine use in developed regions.

Practical Equations and Concepts to Remember (LaTeX)

• Potency relation (Meyer-Overton): $\text{MAC} \approx \frac{1.3}{(\text{oil/gas})}$

• Time constants and equilibration (tissue compartments):

  • $\tau = \frac{V_{\text{cap}}}{\dot{Q}}$

  • For a compartment: $P<em>{\text{comp}}(t) = P</em>{\text{flow}} \left(1 - e^{-t/\tau}\right)$

• Alveolar-to-inspired equilibration: $\tau<em>{\text{alv}} = \frac{\text{FRC}}{\dot{V}</em>A}$

• Tissue equilibration (relative capacity): $\tau<em>{\text{tissue}} = \frac{V</em>{\text{vol}}}{\dot{Q}}$ and the tissue/blood partition concept: $(tissue/blood) = \frac{[A]<em>{\text{tissue}}}{[A]</em>{\text{blood}}}$

• Concentration vs partial pressure in tissue (Box 17-2 concept): $[A]<em>{\text{solution}} = \frac{P</em>{\text{solvent}} (\text{solvent/gas})}{24.5} \quad (\text{units: M})$

• Diffusion hypoxia mitigation: give 100% O2 for several minutes after nitrous oxide anesthesia.

Quick Clinical Takeaways

• Expect faster induction with agents having low (blood/gas) and/or low MAC; slower with high (blood/gas) and high MAC agents.

• In pediatric patients, induction can be faster overall due to higher VRG perfusion and ventilation, but caution for rapid changes in depth.

• To speed induction, controlled overpressure (higher PI briefly) can be used, but must be reduced to avoid overshoot and cardio-respiratory depression.

• When using nitrous oxide, plan for diffusion hypoxia post-termination and administer 100% O2 briefly.

• Balanced anesthesia (combining agents) allows leveraging favorable properties of each drug (e.g., rapid induction with N2O + low-solubility maintenance with sevoflurane/desflurane).

• Alveolar-to-inspired equilibration: $\tau<em>{\text{alv}} = \frac{\text{FRC}}{\dot{V}</em>A}$

• Tissue equilibration (relative capacity): $\tau<em>{\text{tissue}} = \frac{V</em>{\text{vol}}}{\dot{Q}}$ and the tissue/blood partition concept: $(tissue/blood) = \frac{[A]<em>{\text{tissue}}}{[A]</em>{\text{blood}}}$

• Concentration vs partial pressure in tissue (Box 17-2 concept): $[A]<em>{\text{solution}} = \frac{P</em>{\text{solvent}} (\text{solvent/gas})}{24.5} \quad (\text{units: M})$

• Diffusion hypoxia mitigation: give 100% O2 for several minutes after nitrous oxide anesthesia.

Quick Clinical Takeaways

• Expect faster induction with agents having low (blood/gas) and/or low MAC; slower with high (blood/gas) and high MAC agents.

• In pediatric patients, induction can be faster overall due to higher VRG perfusion and ventilation, but caution for rapid changes in depth.

• To speed induction, controlled overpressure (higher PI briefly) can be used, but must be reduced to avoid overshoot and cardio-respiratory depression.

• When using nitrous oxide, plan for diffusion hypoxia post-termination and administer 100% O2 briefly.

• Balanced anesthesia (combining agents) allows leveraging favorable properties of each drug (e.g., rapid induction with N2O + low-solubility maintenance with sevoflurane/desflurane).