Chapter 8

### HISTORY OF DEVELOPMENT

The discovery of inhalation anesthetics has a colorful history and began as early as the late 1700s with nitrous oxide. One initial use was in the treatment of dental pain and was later in combination with oxygen as an anesthetic. Chloroform was discovered in 1831 by an obstetrician, James Simpson, who used it to relieve labor pain for Queen Victoria for her eighth and ninth deliveries in the mid-1800s. Although diethyl ether was discovered in the 1600s, it was not used as an anesthetic until the mid-1800s in the United States, most notably by William Morton at Massachusetts General Hospital in Boston, to successfully anesthetize a patient for a mandibular tumor resection. In search of better anesthetics, development of additional agents continued. Ethyl chloride, an agent used as a topical anesthetic to freeze painful tissue, was later found to render patients unconscious. Additional agents developed during the late 1800s were ethylene and cyclopropane, and during the early 1900s, divinyl ether was developed.

Major drawbacks to these early inhaled agents were they were pungent, flammable, and with selected drugs, associated with substantial hepatoxicity and/or cardiotoxicity, making them less desirable to use. In the 1950s, fluorinated hydrocarbons were introduced as nonflammable alternatives and have remained the mainstay of potent inhaled agents. Since then, numerous fluorinated hydrocarbon compounds have been evaluated, with several introduced into clinical use (enflurane, methoxyflurane, and halothane). Those with the best kinetic profile and minimal toxic side effects remain in use today (isoflurane, sevoflurane, and desflurane).

### MECHANISM OF ACTION AND DRUG EFFECTS

The mechanism of action for potent inhaled agents is not well understood and has been the subject of debate since the agents were discovered to be anesthetics. Unlike intravenous anesthetics, where pharmacologic action is associated with a drug binding to a receptor and triggering an effect, potent inhaled agents do not appear to have specific receptor targets. There are several theories. Researchers have suggested that potent inhaled agents deform lipid membranes such that they alter function of lipid proteins that play a role in neurotransmitter function within synaptic clefts. Inhaled anesthetics may act at multiple sites, making it difficult to pin down their exact mechanism, but it may be best described by physical chemistry (ie, swelling of nerve cell walls) and not chemical bonding between a drug and receptor.1

### PHARMACOKINETICS AND PHARMACODYNAMICS

#### Pharmacokinetics

Important elements of inhaled agent pharmacokinetics are presented in Chapter 2. Inhaled agent kinetics (time course of drug concentration in response to dose) are a function of drug delivery as well as pulmonary ventilation and perfusion. A detailed description of factors that influence inhaled agent pharmacokinetics is presented in Figure 8–1.

###### Figure 8–1

Schematic representation of factors that influence inhalation agent pharmacokinetics. The inspired (inhalation agent delivered is a function of vaporizer setting, fresh gas flow, and circuit ...

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