Chapter INHALED ANESTHETICS 7 Rachel Eshima McKay HISTORY Malignant Hyperthermia Hepatic Effects THE FIRST INHALED ANESTHETICS Renal Effects Nitrous Oxide Diethyl Ether QUESTIONS OF THE DAY Chloroform INHALED ANESTHETICS BETWEEN 1920 AND 1940 FLUORINE CHEMISTRY AND MODERN HISTORY INHALED ANESTHETICS Halothane The discovery of inhaled anesthesia reflects the contri- Methoxyflurane butions of clinicians and scientists in the United States 1 Enflurane and England (Fig. 7.1). The most commonly used inhaled Isoflurane anesthetics in modern anesthesia include volatile liquids Sevoflurane and Desflurane (i.e., halothane, enflurane, isoflurane, desflurane, and sevoflurane) and a single gas (i.e., nitrous oxide) Figs.( MECHANISM OF ACTION 7.2 and 7.3). Halothane, enflurane, and isoflurane are no Measurable Characteristics longer commonly used. Yet, none of these inhaled anes- PHYSICAL PROPERTIES thetics meets all the criteria of an “ideal” inhaled anes- Molecular Structure thetic, and the chemical characteristics differ among the Vapor Pressure and Delivery drugs (Table 7.1). Economic and Environmental Considerations Stability THE FIRST INHALED ANESTHETICS RELATIVE POTENCY OF INHALED Nitrous Oxide ANESTHETICS Nitrous oxide gas was first synthesized in 1772 by PHARMACOKINETICS OF INHALED the English chemist, author, and Unitarian minister ANESTHETICS Joseph Priestley. Twenty-seven years later, Sir Humphry Factors That Determine the Alveolar Partial Davy administered nitrous oxide for dental analgesia. Pressure Although he suspected that nitrous oxide might be used Recovery From Anesthesia to relieve pain for surgery, it was not until it was used Feasibility of Inhaled Anesthetic Use for 42 years later by a 29-year-old dentist named Horace Sedation in the ICU Wells who administered nitrous oxide to himself and EFFECTS ON ORGAN SYSTEMS found that it relieved his pain. Specifically, he noticed Circulatory Effects the hypnotic and analgesic effects of nitrous oxide at a Ventilation Effects public exhibition in Hartford, Connecticut, in 1842. The Central Nervous System Effects next day, Wells himself underwent a dental extraction Neuromuscular Effects by a fellow dentist. Wells felt only minimal pain with the extraction, and he subsequently learned the method of nitrous oxide synthesis to make it available to his own 83 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 20 Sevoflurane Desflurane Isoflurane 15 Methoxyflurane Enflurane Ethyl vinyl ether Halothane Propyl methyl ether Fluroxene 10 Isopropenyl vinyl ether Cyclopropane Trichloroethylene (cumulative listing) Divinyl ether 5 Chloroform Ethylene Ethyl chloride Anesthetics used in clinical practice Ether 0 N2O 1840 1880 1920 1960 2000 Year introduced Fig. 7.1 Anesthetics used in clinical practice. The history of anesthesia began with the introduction of nitrous oxide (N2O), ether, and chloroform. After 1950, all introduced drugs, with the exception of ethyl vinyl ether, have contained fluorine. All anesthetics introduced beginning with halothane have been nonflammable. (From Eger EI.Desflurane (Suprane): A Compendium and Reference. Nutley, NJ: Anaquest; 1993:1­11, used with permission.) F H : : NNO : F CCBr : F CI Halothane : : NNO : F H F : H COCCF Fig. 7.3 Molecular structure of nitrous oxide. Nitrous oxide is a F CI F linear molecule existing in two resonance structures. Dots de­ note nonbonding electrons. Isoflurane F F FCF patients. Two years later, he arranged to demonstrate F painless dental surgery using nitrous oxide administra- H COCCF tion at the Massachusetts General Hospital. Not being completely successful, Wells was discredited as a result H H F of this demonstration. Sevoflurane Diethyl Ether William Morton, a Boston dentist, noticed that diethyl F H F ether, during “ether frolics” in which ether was breathed H COCCF for its inebriating effects, had similar effects as nitrous oxide. Like Wells, Morton applied ether in his dental F F F practice and then demonstrated its anesthetic properties Desflurane at the Massachusetts General Hospital on October 16, 1846 (“ether day”). In contrast to Wells’s debacle, Mor- Fig. 7.2 Molecular structures of potent volatile anesthetics. Ha­ ton’s demonstration was received with great enthusiasm. logenated volatile anesthetics are liquids at room temperature. The results of successful ether anesthetics were soon Among the volatile anesthetics, halothane is an alkane deriva­ published in the Boston Medical and Surgical Journal. tive, whereas all the others are derivatives of methyl ethyl ether. Although Crawford Long administered diethyl ether to a Isoflurane is the chemical isomer of enflurane. patient in 1842, 4 years earlier than Morton, he did not 84 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 7 Inhaled Anesthetics Table 7.1 Comparative Characteristics of Inhaled Anesthetics Characteristic Isoflurane Enflurane Halothane Desflurane Sevoflurane Nitrous Oxide Partition coefficient Blood­gas 1.46 1.9 2.54 0.45 0.65 0.46 Brain­blood 1.6 1.5 1.9 1.3 1.7 1.1 Muscle­blood 2.9 1.7 3.4 2.0 3.1 1.2 Fat­blood 45 36 51 27 48 2.3 MAC (age 30­55 years) 1.15 1.63 0.76 6.0 1.85 104 % of 1 atmosphere II Vapor pressure at 20° C 240 172 244 669 160 (mm Hg) Molecular weight (g) 184.5 184.5 197.4 168 200 44 a a Stable in hydrated CO2 Yes Yes No Yes No Yes absorbent ab b abc Stable in dehydrated CO2 No No No No Yes absorbent Percent metabolized 0­0.2 15­40 0­0.2 5­8 aCompound A. bCarbon monoxide. cSevere exothermic reactions reported. MAC, Minimum alveolar concentration. publicize his work, and Morton therefore has traditionally cyclopropane), whereas others, halogenated entirely with been credited with the discovery of diethyl ether’s capa- chlorine, were toxic (i.e., chloroform, ethyl chloride, and bility to produce anesthesia. trichloroethylene). Chloroform FLUORINE CHEMISTRY AND MODERN James Simpson, an obstetrician from Edinburgh, Scot- INHALED ANESTHETICS land, developed chloroform, which did not share the pro- tracted induction, flammability, and postoperative nausea Techniques of fluorine chemistry, developed from efforts to seen with diethyl ether. Chloroform soon became popu- produce the first atomic weapons, found a fortuitous, socially lar as an inhaled anesthetic in England, although diethyl beneficial purpose in providing a method of synthesizing ether dominated medical practice in North America. modern inhaled anesthetics.2,3 Modern inhaled anesthetics Unfortunately, chloroform was associated with several are halogenated partly or entirely with fluorine (see Fig. 7.2). unexplained intraoperative deaths of otherwise healthy Fluorination provides greater stability and lesser toxicity. patients and numerous cases of hepatotoxicity. Halothane INHALED ANESTHETICS BETWEEN 1920 Halothane was introduced into clinical practice in 1956 AND 1940 and became widely used. It had several advantages compared with the older anesthetics, including non- Between 1920 and 1940, ethylene, cyclopropane, and flammability, a pleasant odor, lesser organ toxicity, and divinyl ether were introduced into use as anesthetics, pharmacokinetic properties allowing a much faster induc- gaining acceptance over the older inhaled anesthet- tion of anesthesia and emergence compared with ether. ics (with the exception of nitrous oxide) by producing Unfortunately after 4 years of commercial use, reports a faster, more pleasant induction of anesthesia and by of fulminant hepatic necrosis after halothane anesthe- allowing faster awakening at the conclusion of surgery. sia began to appear in patients in which other causes of However, each had serious drawbacks. Many were flam- liver damage were not evident. The issue of unpredict- mable (i.e., diethyl ether, divinyl ether, ethylene, and able liver damage stimulated the search for other volatile 85 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Section II PHARMACOLOGY AND PHYSIOLOGY anesthetics. Halothane also sensitizes the myocardium to effects.4 Although inhaled anesthetics have been used to the dysrhythmogenic effects of catecholamines. provide surgical anesthesia for almost 160 years, there is no single, accepted definition of what constitutes the anes- thetic state. For experimental purposes, an operational defi- Methoxyflurane nition of immobility in response to surgical stimulation and Methoxyflurane was first introduced into clinical prac- amnesia for intraoperative events has proved useful. tice in 1960. Within the first decade of its introduction, reports of renal failure with methoxyflurane anesthesia Measurable Characteristics appeared, leading to studies confirming a dose-related nephrotoxicity because of the inorganic fluoride that Measurable and universal characteristics of all inhaled resulted from the metabolism of this anesthetic. anesthetics include production of immobility and amnestic effects. Immobility is measured by the minimum alveolar concentration (MAC) of anesthetic required to