Nitrous oxide, chloroform, and ether were the first universally accepted general anesthetics. Methoxy-flurane and enflurane, two potent halogenated agents, were used for many years in North American anesthesia practice. Methoxyflurane was the most potent inhalation agent, but its high solubility and low vapor pressure yielded longer inductions and emergences. Up to 50% of it was metabolized by cytochrome P-450 (CYP) enzymes to free fluoride (F−), oxalic acid, and other nephrotoxic compounds. Prolonged anesthesia with methoxyflurane was as-sociated with a vasopressin-resistant, high-output, renal failure that was most commonly seen when F− levels increased to greater than 50 µmol/L. En-flurane has a nonpungent odor and is nonflammable at clinical concentrations. It depresses myocardial contractility. It also increases the secretion of ce-rebrospinal fluid (CSF) and the resistance to CSF outflow. During deep anesthesia with hypocarbia electroencephalographic changes can progress to a spike-and-wave pattern producing tonic–clonic sei-zures. Because of these concerns, methoxyflurane and enflurane are no longer used.
Five inhalation agents continue to be used in clinical anesthesiology: nitrous oxide, halothane, isoflurane, desflurane, and sevoflurane.
The course of a general anesthetic can be divid-ed into three phases: (1) induction, (2) maintenance, and (3) emergence. Inhalation anesthetics, such as halothane and sevoflurane, are particularly useful in the induction of pediatric patients in whom it may be difficult to start an intravenous line. Although adults are usually induced with intravenous agents, the nonpungency and rapid onset of sevoflurane make inhalation induction practical for them as well. Regardless of the patient’s age, anesthesia is often maintained with inhalation agents. Emergence depends primarily upon redistribution from the brain and pulmonary elimination of these agents.
Because of their unique route of administration, inhalation anesthetics have useful pharmacological properties not shared by other anesthetic agents. For instance, administration via the pulmonary circula-tion allows a more rapid appearance of the drug in arterial blood than intravenous administration.
Although the mechanism of action of inhalation anesthetics is complex, likely involving numerous membrane proteins and ion channels, it is clear that producing their ultimate effect depends on attainment of a therapeutic tissue concentration in the central nervous system (CNS). There are many steps in between the anesthetic vaporizer and the anesthetic’s deposition in the brain (Figure 8–1).