Pharmacology of Inhalational Anesthetics

Agent

Vapor pressure (20 °C)

Blood: gas partition coefficient^a

Fat: blood partition coefficient

Metabolism

Pungency^b

N₂O

38,770 mmHg

0.46

2.3

None

Desflurane

669 mmHg

0.42

0.02 %

High

Sevoflurane

157 mmHg

0.65

5 %

Low

Isoflurane

238 mmHg

1.46

0.2 %

High

^aThe low blood: gas partition coefficients (i.e. low solubility in blood) of nitrous oxide, desflurane, and sevoflurane speed induction and emergence

^bDue to their low pungencies, nitrous oxide and sevoflurane are excellent agents for inhalational induction of anesthesia by mask

Inspired concentration : A high inspired concentration of the anesthetic speeds induction by providing a large gradient between the partial pressure of the agent in the alveoli and the blood. This concentration gradient increases the arterial concentration of the agent, thereby speeding induction of the anesthetic effect. The reverse of this phenomenon is seen on emergence, when an inspired concentration of zero favors passage of volatile agent out of the blood into the alveoli (see Fig. 5.1).

Figure 5.1

Ratio of concentration of anesthetic in alveolar gas to inspired gas. Graph shows how the ratio between the inspired (FI) and alveolar (FA) concentrations of inhalational anesthetics changes with time of administration. The least soluble drugs approach equilibrium (FA/FI) the fastest (From Modern Anesthetics: Handbook of Experimental Pharmacology, by Helmut Schwilden, Springer 2008. Used with Permission)

Fresh gas flow rate : A higher fresh gas flow rate into the anesthesia machine circuit speeds induction. By more completely and rapidly replacing expired gases (which contain less anesthetic agent), a consistently high inspired concentration is provided. Similarly, a high inflow rate of anesthetic-free fresh gas during emergence quickly flushes the anesthetic agent out of the circuit, enhancing the elimination of inhaled anesthetic from the lungs.

Minute ventilation : High minute ventilation (respiratory rate x tidal volume) increases the rate of induction and emergence by rapidly providing fresh inhalational agent during induction and rapidly removing it during emergence. This is clinically relevant during inhalational inductions and during the emergence of most patients. For example, a patient with high minute ventilation (i.e. an infant) will have a faster inhalational induction and emergence than a patient with lower minute ventilation (e.g., an elderly patient). Ventilation has a greater effect on high-solubility agents (such as diethyl ether) and a lesser effect on relatively insoluble agents (such as nitrous oxide). Since most of our commonly used inhalational agents have low to intermediate solubilities, this effect is therefore of a moderate significance.

Theories of Inhalational Anesthetic Action

The mechanism of action of the inhalational anesthetics remains incompletely understood. Anesthetic effects have been demonstrated at the levels of the spinal cord, brain stem, and cerebral cortex.

Theories explaining the mechanism of action of inhalational anesthetics include:

The Meyer-Overton Rule : It has been observed that the potencies of inhalational agents correlate with their lipid solubilities. Extrapolating from this observation, it has been theorized that inhalational anesthetics act by dissolving at hydrophobic sites, formerly assumed to be in the lipid bilayers of cell membranes, but currently thought to be in the relatively hydrophobic regions of one or more proteins.
GABA enhancement : Many inhaled anesthetic agents enhance activity of the gamma-aminobutyric acid (GABA) system, which is also enhanced by intravenous anesthetic agents such as benzodiazepines, propofol, and etomidate. It has been observed that the potencies of inhalational agents correlate with their potentiation of the GABA system, leading to the theory that GABA enhancement may be a key element of inhalational anesthetic activity.
Other receptors systems: Inhalational anesthetic agents have been shown to interact to varying degrees with a wide variety of cellular receptors, including NMDA and acetylcholine receptors.

Depth of Anesthesia and MAC

The minimum alveolar concentration (MAC) is a commonly used method for describing the dose of inhalational anesthetics. MAC, as used by anesthesiologists, is a specialized example of an ED₅₀, where a MAC of 1 is the alveolar concentration of a drug at which movement in response to a surgical incision will be absent in 50 % of subjects. By referring to the MAC of a volatile agent being delivered, one can normalize the different potencies of the various agents when comparing them. In addition, MAC values for inhalational agents are additive (a patient receiving 0.5 MAC of one agent and 0.4 MAC of another has a total anesthetic dose of 0.9 MAC), allowing estimation of anesthetic depth in patients receiving more than one agent concurrently (usually a volatile anesthetic and nitrous oxide).

Multiples of the MAC for inhalational anesthetics can be used to describe differing depths of anesthesia, although MAC multiples are not linear because the dose–response curves for different agents do not parallel. Nevertheless, some useful dose levels are:

0.3–0.4 MAC is associated with awakening from anesthesia in the absence of other agents (referred to as MAC-awake).
1.3 MAC is known to prevent movement in 95 % of patients in response to a surgical incision (making 1.3 MAC an inhalational anesthetic analog to an ED95 dose used for intravenous agents).
1.5 MAC typically blocks the adrenergic response to the surgical stimulus.

Please note that the MAC values cited above for inhalational anesthetics are values for normal adults. Table 5.2 lists MAC values for commonly used inhalational agents.

Table 5.2

Minimum alveolar concentration (MAC) values