Inhaled Anesthetics

The popularity of inhaled anesthetics for establishing general anesthesia is based on their ease of administration (via inhalation) and the ability to monitor their effects (clinical signs and end-tidal concentrations) (Fig. 17-1) (Ebert TJ, Linderman L. Inhaled anesthetics. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Ortega R, Stock MC, eds. Clinical Anesthesia. Philadelphia: Lippincott Williams & Wilkins; 2013:445–477). The most popular potent inhaled anesthetics used in adult surgical procedures are sevoflurane, desflurane, and isoflurane (see Fig. 17-1). Sevoflurane is the most commonly used inhaled anesthetic for pediatric patients.

I. Pharmacokinetic Principles

Drug pharmacology is classically divided into pharmacodynamics (what the body does to a drug) and pharmacokinetics (what the drug does to the body). Drug pharmacokinetics has four phases: absorption (uptake), distribution, metabolism, and excretion (elimination).
Unique Features of Inhaled Anesthetics
- Speed, Gas State, and Route of Administration. The inhaled anesthetics are among the most rapidly acting drugs in existence, and when administering a general anesthetic, this speed provides a margin of safety and also means efficiency.
- Technically, nitrous oxide and xenon are the only true gases; the other inhaled anesthetics are vapors of volatile liquids (for simplicity, all of them are referred to as gases).
- A unique advantage of anesthetic gases is the ability to deliver them to the bloodstream via the patient’s lungs.
Physical Characteristics of Inhaled Anesthetics (Tables 17-1 and 17-2)
- The goal of delivering inhaled anesthetics is to produce the anesthetic state by establishing a specific concentration (partial pressure) in the central nervous system (CNS). This is achieved by establishing the desired partial pressure in the lungs that ultimately equilibrates with the brain and spinal cord.
- At equilibrium, the CNS partial pressure equals the blood partial pressure, which equals alveolar partial pressure.
Gases in Mixtures. For any mixture of gases in a closed container, each gas exerts a pressure proportional to its fractional mass (partial pressure).
Gases in Solutions
- The concentration of any one gas in a mixture of gases in solution depends on (i) its partial pressure in the gas phase in equilibrium with the solution and (ii) its solubility within that solution.
- The concentration of anesthetic in the target tissue depends on the partial pressure at equilibrium and the target tissue solubility.
- Because inhaled anesthetics are gases and because partial pressures of gases equilibrate throughout a system, monitoring the alveolar concentration of inhaled anesthetics provides an index of their effects on the brain.
Anesthetic Transfer: Machine to Central Nervous System (Table 17-3)
Uptake and Distribution
- F_A/F_I. A common way to assess anesthetic uptake is to follow the ratio of the alveolar anesthetic concentration (F_A) to the inspired anesthetic concentration (F_I) over time (F_A/F_I) (Fig. 17-2).
- Distribution (Tissue Uptake). Factors that increase or decrease the rate of increase of F_A/F_I determine the speed of induction of anesthesia (see Fig. 17-2 and Table 17-3).
- Metabolism plays little role in opposing induction but may have some significance in determining the rate of recovery.
Overpressurization and Concentration Effect
- Overpressurization (delivering a higher F_I than the F_A actually desired for the patient) is analogous to an intravenous bolus and thus speeds the induction of anesthesia.
- Concentration effect (the greater the F_I of an inhaled anesthetic, the more rapid the rate of increase of the F_A/F_I) is a method used to speed the induction of anesthesia (Fig. 17-3).
Second Gas Effect
- A special case of the concentration effect is administration of two gases simultaneously (nitrous oxide and a potent volatile anesthetic) in which the high volume uptake of nitrous oxide increases the F_A (concentrates) of the volatile anesthetic.
Ventilation Effects
- Inhaled anesthetics with low blood solubility have a rapid rate of increase in the F_A/F_I with induction of anesthesia such that there is little room to improve this rate of increase by increasing or decreasing ventilation (see Fig. 17-3).
- To the extent that inhaled anesthetics depress ventilation with an increasing F_I, alveolar ventilation decreases, as does the rate of increase of F_A/F_I (negative feedback that results in apnea and may prevent an overdose).
Perfusion Effects
- As with ventilation, cardiac output does not greatly affect the rate of increase of the F_A/F_I for poorly soluble anesthetics.
- Cardiovascular depression caused by a high F_I results in depression of anesthetic uptake from the lungs and increases the rate of increase of F_A/F_I (positive feedback that may result in profound cardiovascular depression).
Exhalation and Recovery
- Recovery from anesthesia, similar to induction of anesthesia, depends on the drug’s solubility (primary
  determinant of the rate of decrease in F_A), ventilation, and cardiac output (Fig. 17-4).
- The “reservoir” of anesthetic in the body at the conclusion of anesthesia is determined by the solubility of the inhaled anesthetic and the dose and duration of the drug’s administration (can slow the rate of decrease in the F_A).
- Pharmacokinetic differences between recovery and induction of anesthesia include the absence of overpressurization (cannot give less than zero) during recovery and the presence of tissue anesthetic concentrations present at the start of recovery (tissue concentration of zero at the start of anesthesia induction).

Figure 17-1. Chemical structure of inhaled anesthetics. Whereas halothane (no longer commercially available) is an alkane, all of the other volatile anesthetics are ether derivatives. Isoflurane, enflurane, and desflurane are methyl ethyl ether derivatives, and sevoflurane is a methyl isopropyl ether. Isoflurane and enflurane are isomers, and desflurane differs from isoflurane in the substitution of a fluorine for a chlorine atom.

Table 17-1 Physiochemical Properties of Volatile Anesthetics

Property	Sevoflurane	Desflurane	Isoflurane	Enflurane	Nitrous Oxide
Boiling point (ºC)	59	24	49	57	–88
Vapor pressure at 20ºC (mm Hg)	157	669	238	172	38,770
Molecular weight (g)	200	168	184	184	44
Oil:gas partition coefficient	47	19	91	97	1.4
Blood:gas partition coefficient	0.65	0.42	1.46	1.9	0.46
Brain:blood solubility	1.7	1.3	1.6	1.4	1.1
Fat:blood solubility	47.5	27.2	44.9	36	2.3
Muscle:blood solubility	3.1	2.0	2.9	1.7	1.2
MAC in oxygen, 30–60 years old, 37ºC, P_B760 (%)	1.8	6.6	1.17	1.63	104
MAC in 60%–70% nitrous oxide (%)	0.66	2.38	0.56	0.57
MAC, >65 years old (%)	1.45	5.17	1.0	1.55
Preservative	No	No	No	No	No
Stable in moist carbon dioxide absorbent	No	Yes	Yes	Yes	Yes
Flammability (%) (in 70% nitrous oxide/30% oxygen)	10	17	7	5.8
Recovered as metabolites (%)	2–5	0.02	0.2	2.4
MAC = minimum alveolar concentration.

Table 17-2 Tissue Groups and Pharmacokinetics

Group	% Body Mass	% Cardiac Output	Perfusion (mL/min/100 g)
Vessel rich	10	75	75
Muscle	50	19	3
Fat	20	6	3

Table 17-3 Factors That Increase or Decrease the Rate of Increase of Alveolar Anesthetic Concentration (F_A)/Inspired Anesthetic Concentration (F_I)

Increase	Decrease
Low blood solubility	High blood solubility	The lower the blood:gas solubility, the faster the increase in F_A/F_I.
Low cardiac output	High cardiac output	The lower the cardiac output, the faster the increase in the F_A/F_I.
High minute ventilation	Low minute ventilation	The higher the minute ventilation, the faster the increase in F_A/F_I.
High pulmonary arterial to venous partial pressure	Low pulmonary arterial to venous partial pressure	At the beginning of induction, the pulmonary to venous blood partial pressure gradient is zero, but it increases rapidly, and F_A/F_I increases rapidly. Later during induction and maintenance, the pulmonary venous blood partial pressure increases more slowly, so F_A/F_I increases more slowly.

Figure 17-2. The increase in the alveolar anesthetic concentration (F_A) toward the inspired anesthetic concentration (F_I) is most rapid with the least-soluble anesthetics (nitrous oxide, desflurane, and sevoflurane) and intermediate with the more soluble anesthetics (isoflurane and halothane). After 10 to 15 minutes of administration (about three time constants), the slope of the curve decreases, reflecting saturation of vessel-rich group tissues and subsequent decreased uptake of the inhaled anesthetic.