Introduction

Inhalational anesthetics (IAs) are a group of medications utilized, almost exclusively, for the induction and maintenance of anesthesia during surgery. The demonstration of ether anesthesia in 1846 marked the beginning of the use of IAs in clinical practice. Today, modern IAs are used widely, mainly due to their reliability, minimal interindividual variation of the desired pharmacological effect, and the ease of continuous monitoring during anesthesia. Interestingly, the exact mechanism of action of modern IAs is not completely understood. However, recent developments in basic neuropharmacology have elucidated a probable mechanism of action. IAs display unique pharmacokinetics due to the fact that they are gases and are delivered directly to the lungs via the anesthesia machine. Consequently, the interactions of IAs with the body (pharmacokinetics) are very different in comparison to other anesthetics that are administered intravenously. IAs have proven to be instrumental in the modern practice of anesthesia. However, they are not without unwanted adverse effects, some of which can be life-threatening. A deep understanding of these potent drugs and their effects on patients is indispensable for the practice of anesthesiology. This chapter will briefly review the history of IAs and describe the pharmacology of these drugs, including potential complications.

History

Diethyl ether has been known for centuries. However, in 1842, Crawford Williamson began experimenting with the administration of the drug as an anesthetic for small surgeries. This event initiated a course of events that paved the way to the use of volatile gases to provide anesthesia [Reference Whalen, Bacon and Smith1]. In October 16, 1846, William Thomas Green Morton demonstrated the use of inhaled ether to an audience at the Massachusetts General Hospital in Boston on what is now known as “ether day” [Reference Chaturvedi and Gogna2]. Although he is not credited as the first person to utilize an IA, his demonstration received worldwide attention and revolutionized the practice of medicine. Nitrous oxide was discovered in 1772 by Joseph Priestley, and in 1844, the first demonstration of its medical use was performed during dental extractions [Reference Lew, McKay and Maze3]. This makes nitrous oxide the oldest IA currently in use.

Modern fluorinated hydrocarbon anesthetics are very simple chemical compounds with an interesting historical origin. Their development was facilitated by the ultrasecret Manhattan Project, which was commissioned to develop nuclear weapons during the Second World War. Prior to this effort, there was little interest in the chemistry of such compounds. However, during the late 1930s, a sudden and intense interest in fluorine chemistry emerged as fluorine was recognized as a valuable adjuvant in the process of uranium enrichment. Enriched uranium is a critical constituent of atomic weapons. Shortly after, it was recognized that fluorinated hydrocarbons had anesthetic properties [Reference Holmes4]. However, it was not until 1956 that Raventos discovered halothane, the first fluorinated anesthetic of clinical utility. The development of the modern fluorinated hydrocarbon anesthetics currently in use (desflurane, isoflurane, and sevoflurane) was the result of extensive research and experimentation with the objective of improving the characteristics of earlier-generation anesthetics [Reference Terrell5].

Pharmacology

All IAs are gases with different chemical structures, but similar clinical effects. Chemically, they comprise halogenated hydrocarbons, ethers, alkanes, noble gases, aromatic molecules, and alcohols [Reference Lynch6]. Modern anesthetics in current use include the fluorinated hydrocarbons desflurane (CF2 H-O-CFH-CF3), isoflurane (CF2 H-O-CCIH-CF3), and sevoflurane (CFH2-O-CH[CF3]2) [Reference Eger7], and the inorganic gas nitrous oxide (N₂O). Other anesthetics such as halothane and enflurane are still used in some developing countries. Interestingly, a resurgence of ether has also been proposed [Reference Chang, Goldstein, Agarwal and Swan8]. However, the use of these older anesthetics is generally disfavored due to their side effect profile. This chapter will only discuss the modern halogenated anesthetics and nitrous oxide.

Pharmacodynamics

General anesthesia can be defined as a reversible state of drug-induced unconsciousness, amnesia, analgesia, and immobility in response to a surgical stimulus [Reference Brown, Pavone and Naranjo9]. The exact mechanism by which IAs can induce and maintain general anesthesia has not yet been fully elucidated and remains one of the biggest mysteries of neuropharmacology. However, recent developments have given some insight into the likely pathways of unconsciousness caused by these drugs.

A unique property of IAs is that they exert the same biological effects in all living organisms, including animals, plants, and even prokaryotes [Reference Kelz and Mashour10]. This means that all organisms, complex or unicellular, can be reversibly anesthetized [Reference Lynch6]. The extent to which these drugs affect the entirety of earth’s biodiversity supports a target molecule or group of molecules that are fundamental to life, and therefore universally preserved throughout the evolution of species. These target molecules have remained elusive; however, it is known that anesthetics affect vital intracellular processes, including mitochondrial energy pathways, cytoskeletal structure, and ion channel function. An important clinical consequence of the homogeneity of effects of IAs is that there is very little interspecies difference in response among all different genotypes. This means that there is a strong and predictable correlation between IA concentration and observed effects in most humans. This property, combined with the ability to continuously monitor their end-tidal concentrations, is what makes them very reliable drugs for maintenance of anesthesia during surgery.

At the beginning of the twentieth century, Meyer and Overton independently discovered the correlation between lipid solubility and anesthetic potency. This led to the Meyer–Overton “lipoid” hypothesis [Reference Krasowski11], which formulates that IAs exert their effects by changing the lipid solubility of neuronal cellular membranes. This change in solubility leads to a nonspecific effect that alters the activity of molecules embedded in the membrane. Among those molecules are ion channels that can change the membrane potential, and thus the likelihood of neuronal depolarization. However, newer evidence has shown that IAs interact directly with protein targets [Reference Kelz and Mashour10], including direct inhibition of luciferase and other proteins that affect modulatory mechanisms linked to neurotransmitter receptors, neuronal ion channels, and the cytoskeleton. A group of potassium channels (TREK-1) were recently discovered that are strongly activated by IAs. The importance of these channels in the mechanisms of general anesthesia is evidenced by knockout TREK-1 animals that exhibit anesthetic resistance. Recently, a novel mechanism of TREK-1 activation via disruption of phospholipase D2 and disruption of lipid–protein domains, known as “lipid rafts” [Reference Sezgin, Levental, Mayor and Eggeling12], has been demonstrated [Reference Pavel, Petersen, Wang, Lerner and Hansen13]. This would represent a direct effect of IAs on membrane lipids and membrane proteins that then exert effects on ion channels – perhaps explaining Meyer and Overton’s results from the last century.

Pharmacokinetics

One of the most important pharmacokinetic characteristics of IAs is the blood/gas partition coefficient. This coefficient describes how the particles of each gas will distribute between the alveoli and the blood after equilibrium has been achieved. It affects the anesthetic uptake, and therefore its onset of action, as well as its clearance. Age, body mass index, gender, and hemoglobin do not appear to have any effect on the blood/gas coefficient [Reference Esper, Wehner, Meinecke and Rueffert14]. The water/gas partition coefficient of isoflurane is 0.59, sevoflurane 0.37, and desflurane 0.27 [Reference Esper, Wehner, Meinecke and Rueffert14]. The higher the partition coefficient, the higher the solubility and potency of the IA. Higher solubility correlates inversely with onset of anesthesia; therefore, the more soluble an IA is, the slower its onset [Reference Vallejo and Zakowski15]. The partition coefficients between the gas and blood, and blood and brain (the target organ) are known and shown in Table 5.1. Notice that isoflurane is the most soluble of the halogenated hydrocarbon anesthetics, and therefore the most potent. This correlates with its comparatively low minimum alveolar concentration (MAC). Inversely, it also has the slowest onset of action.

Clearance of IAs occurs almost exclusively via the lungs, since liver metabolism of available modern IAs is minimal [Reference Kharasch16]. Consequently, the most important factor in the clearance of IAs is ventilation, and there is a direct correlation between rate of clearance and ventilation. Theoretically, the lower the blood/gas partition coefficient of an anesthetic, the faster it should be cleared. However, this assumption is not supported by clinical evidence [Reference Stevanovic, Rossaint and Fritz17]. The duration of administration of an IA also correlates directly with the rate of clearance [Reference Carpenter, Eger, Johnson, Unadkat and Sheiner18]. An increase in the alveolar concentration of an IA can occur when it is used concomitantly with a gas with a high uptake rate (nitrous oxide). This phenomenon is known as the second gas effect. Conversely, during emergence, nitrous oxide is quickly removed from the circulation and it increases the clearance of other gases [Reference Peyton, Chao, Weinberg, Robinson and Thompson19]. Oxygen is one of such gases, and therefore, emergence of nitrous oxide anesthesia can be complicated by hypoxemia. Consequently, administration of 100% inhaled oxygen is recommended after the administration of nitrous oxide anesthesia.

Adverse Reactions

Like all drugs, IAs have the potential to cause adverse reactions, including life-threatening complications. This underscores the importance of an in-depth understanding of the pharmacology of these drugs by anesthesiologists. Some adverse effects are common to all modern IAs. All IAs cause postoperative nausea and vomiting, albeit to a different extent. Similarly, all modern fluorinated hydrocarbon anesthetics cause hypotension by decreasing vascular tone. It is important to appreciate that although volatile anesthetics are associated with adverse reactions, they remain very important agents for maintenance of anesthesia. Perhaps the most important reason that IAs remain the most common drugs utilized for this objective is the ability to continuously monitor their exhaled concentration. Consequently, they are considered protective against the very important complication of intraoperative awareness. When total intravenous anesthesia is used as an alternative to IAs, patients are at a tenfold increase risk of this complication [Reference Zhang, Xu and Ma25].

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