Inhalational Anesthetics

The molecular basis for the anesthetic action of inhalational agents is poorly understood. Although most inhalational anesthetics contain an ether (-O-) link and a halogen (Fig. 35-1), no obvious structure-activity relationships have been defined, suggesting that they do not exert their effects through specific cell-surface receptors, unlike most other therapeutic agents acting on the central nervous system (CNS).

FIGURE 35–1 Chemical structure of inhalational anesthetic agents.

The potency of an inhalational anesthetic is expressed in terms of the minimum alveolar concentration (MAC), which is a concentration that prevents 50% of patients from responding to a painful stimulus, such as a skin incision. MAC is analogous to the median effective dose (ED₅₀) and is used to express the relative potency of gaseous drugs. Meyer and Overton observed that the potencies of anesthetic agents correlate highly with their lipid solubilities, as measured by the oil:gas partition coefficient (Table 35-1; Fig. 35-2). Indeed, this relationship holds not only for agents in clinical use but also for inert gases that are not used clinically, such as xenon and argon. This correlation has given rise to several theories of anesthetic action, none of which has been substantiated.

TABLE 35–1 Characteristics of Inhalational Anesthetic Agents

FIGURE 35–2 The potency of an inhalational anesthetic agent is determined by its lipid solubility, as measured by its oil:gas partition coefficient.

According to the volume expansion theory, molecules of an anesthetic dissolve in the phospholipid bilayer of the neuronal membrane, causing it to expand and impede opening of ion channels necessary for generation and propagation of action potentials. Another hypothesis suggests that anesthetic molecules bind to specific hydrophobic regions of lipoproteins in the neuronal membrane that are part of, or close to, an ion channel. The resulting conformational change in the protein prevents effective operation of the channel. Anesthetics also have been considered to alter the fluidity of membrane lipids, which could also prevent or limit increases in ion conductance.

Alternatively, “nonspecific” effects of anesthetics may occur at specific cell-surface receptors for neurotransmitters or neuromodulators. For example, clinically relevant concentrations of halogenated inhalational anesthetics increase Cl⁻ conductance induced by γ-aminobutyric acid (GABA) in vitro neuronal preparations. Because GABA is the principal inhibitory neurotransmitter in the brain, activation or enhancement of GABA-mediated Cl⁻ conductance would inhibit neuronal activity in the CNS. Similarly, nitrous oxide (N₂O) decreases cation conductance in the ion channel controlled by the N-methyl-D-aspartate (NMDA) glutamate receptor, thereby blocking the actions of the principal excitatory neurotransmitter in the brain, and all inhalational anesthetics inhibit the activity of neuronal nicotinic acetylcholine receptors. Thus, through mechanisms as yet undefined, inhalational anesthetics disrupt the function of ligand-gated ion channels, increasing inhibitory and decreasing excitatory synaptic transmission.

Intravenous Anesthetics

Most IV anesthetic agents contain ring structures (Figure 35-3), have well-documented effects at specific cell-surface receptors, and include benzodiazepines, barbiturates, opioids, and several other compounds.

FIGURE 35–3 Structures of representative intravenous general anesthetic drugs.

The barbiturate anesthetics include thiopental and methohexital, while the benzodiazepine anesthetics include diazepam and midazolam. These agents act at two distinct recognition sites on the GABA_A receptor Cl⁻ channel complex to potentiate GABA-mediated Cl⁻ conductance and neuronal inhibition (see Chapter 31).

Several opioids used for anesthesia include fentanyl and its analogs sufentanil and remifentanil. Although morphine was used for many years, these newer high-potency compounds are gradually replacing it. The depressant action of the opioids on neuronal activity is mediated by the μ opioid receptor and those of mixed-action opioids by μ and κ opioid receptors (see Chapter 36).

Ketamine appears to act by blocking neuronal excitation; it binds to the phencyclidine receptor, a site within the cation channel gated by the NMDA glutamate receptor, and inhibits cation conductance through the channel.

Propofol, the most widely used anesthetic in the United States, appears to facilitate GABA_A receptor-mediated inhibition and inhibits glutamate NMDA receptor-mediated excitation. Etomidate also facilitates GABA_A receptor-mediated neuronal inhibition. In addition, at clinically relevant concentrations in vitro, both drugs block the specific high-affinity neuronal uptake of GABA without affecting its release.

Inhalational Anesthetics

The depth of anesthesia is determined by the concentration of the anesthetic in the brain. Therefore, to produce concentrations adequate for surgery, it is necessary to deliver an appropriate amount of drug to the brain. Unlike most drugs, inhalational anesthetics are administered as gases or vapors. Therefore a specific set of physical principles applies to the delivery of these agents.

In a mixture of gases, the partial pressure of an anesthetic agent is directly proportional to its fractional concentration in the mixture (Dalton’s Law). Thus, as depicted in Figure 35-4, in a mixture of 70% N₂O, 25% O₂, and 5% halothane, which might be used during mask induction of anesthesia, the partial pressures of the component gases are 532, 190, and 38 mm Hg, respectively, at 1 atmosphere (760 mm Hg) of pressure.

FIGURE 35–4 The partial pressure of a gas in a mixture of gases is directly proportional to its concentration.

When a gas is dissolved in the blood or other body tissues, its partial pressure is directly proportional to its concentration but inversely proportional to its solubility in that tissue. The concept of partial pressure is of central importance, because the partial pressure of a gas is the driving force that moves the gas from the anesthetic machine to the lungs, from the lungs to the blood, and from the blood to the brain. At theoretical equilibrium, the partial pressures are equal in all body tissues, alveoli, and the inspired gas mixture. Because solubility varies from tissue to tissue as a consequence of differences in tissue lipophilicity, the concentration of anesthetic must also vary from tissue to tissue if partial pressures are equal throughout the body. The partial pressure (or concentration) of the anesthetic in the inspired gas mixture is the factor controlled most easily by the anesthesiologist. This is accomplished by adjusting the anesthetic machine to optimize partial pressures during induction, maintenance, or both.

The rate of induction of anesthesia by inhalational agents is affected by numerous factors, including those that reduce alveolar ventilation, which represents the product of the rate of respiration and tidal volume less the pulmonary dead space (Table 35-2). Thus if a patient is administered respiratory depressants such as barbiturates or opioid analgesics preoperatively, the rate of respiration or tidal volume decreases, thereby reducing alveolar ventilation in the absence of assisted ventilation. Alveolar dead space is substantial in patients with pulmonary diseases such as emphysema and atelectasis, which result in decreased alveolar ventilation and rate of anesthesia induction.

TABLE 35–2 Factors Affecting the Rate of Induction with an Inhalational Anesthetic

The path followed by an inhalational anesthetic during induction of, and emergence from, anesthesia is diagrammed in Figure 35-5. Induction is facilitated by factors that maintain a high partial pressure of the anesthetic in the inspired gas mixture, alveolar space, and arterial blood to deliver as much of the gas to the brain as quickly as possible. The alveolar membrane poses no barrier to gases, permitting unhindered diffusion in both directions. Therefore, once the anesthetic gas reaches the alveolar space, it obeys the law of mass action and moves down its partial-pressure gradient into arterial blood. At the initiation of anesthetic administration, the partial pressure of the anesthetic in the alveolar space is much higher than that in blood. Thus the partial pressure gradient between the alveolar space and the arteriolar blood is high, and initially the gas moves rapidly into blood. As the partial pressure of the anesthetic agent in blood increases, the gradient between the alveolar space and blood decreases and uptake slows (Fig. 35-6).

FIGURE 35–5 Pathway of an inhalational anesthetic agent during induction of (red arrows) and emergence from (blue arrows) anesthesia. The large arrows indicate the direction of net movement.

FIGURE 35–6 Rate of rise of partial pressure of an inhalational anesthetic agent in arterial blood is determined by its solubility in blood (blood:gas partition coefficient).

Another important factor in the rate of rise of the arterial partial pressure of an anesthetic gas is its solubility in blood. This relationship is expressed as the blood:gas partition coefficient. The higher the solubility is of an anesthetic gas in blood, the more must be dissolved to produce a change in partial pressure (because partial pressure is inversely proportional to solubility). This relationship is illustrated for N₂O and halothane in Figure 35-7.

FIGURE 35–7 The solubility of an inhalational anesthetic in blood determines how rapidly its partial pressure rises in blood and brain with a change in partial pressure in the inspired gas mixture. If the alveolar space and blood were a closed system and N₂O and halothane were allowed to equilibrate between the two, there would be 0.47 parts of N₂O in blood for every 1 part in alveoli, and 2.3 parts of halothane in blood for every 1 part in alveoli. An increase in the partial pressure of N₂O in the inspired gas mixture results in an almost fivefold larger increase in its partial pressure in blood than would a similar increase in the partial pressure of halothane in the inspired gas mixture, driving N₂O into the brain more rapidly.

Nitrous oxide has a blood:gas partition coefficient of 0.47, so relatively little must be dissolved in blood for its partial pressure in blood to rise. This also is true for desflurane and sevoflurane. In contrast, blood serves as a large reservoir for halothane, retaining at equilibrium 2.3 parts for every 1 part in the alveolar space. Induction therefore depends not on dissolving the anesthetic in blood but on raising arterial partial pressure to drive the gas from blood to brain. Therefore the rate of rise of arterial partial pressure and speed of induction are fastest for gases that are least soluble in blood (see Fig. 35-6). The blood:gas partition coefficients of inhalational anesthetics are listed in Table 35-1.

Because cardiac output is the primary determinant of the rate of pulmonary blood flow, it would seem that an increase in cardiac output, and thus an increase in pulmonary blood flow, would accelerate induction of anesthesia. However, the opposite is true. The rate of anesthetic induction decreases with increasing cardiac output. An increased pulmonary blood flow means that the same volume of gas from the alveoli diffuses into a larger volume of blood per unit of time. The initial consequence is a reduced concentration of anesthetic (and partial pressure) in blood. In addition, increases in cardiac output typically increase perfusion of tissues other than brain, such as muscle, thereby increasing the apparent volume of distribution of the anesthetic. In a patient with heart failure, blood loss, or other conditions resulting in decreased cardiac output, the volume of distribution of an anesthetic is reduced, and the rate of induction is increased.

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