Fluorinated Anesthetics
In the early 1930s, progress was made in attempts to fluorinate
hydrocarbons, and many fluorinated compounds became available commercially, primarily
as refrigerants. From a theoretical analysis of hydrocarbon chemistry, it was known
that halogenation of the parent hydrocarbon compound would decrease its flammability.
One early approach to produce a nonflammable anesthetic was to select a flammable
agent and partially fluorinate it. With this in mind, John C. Krantz, Jr., of the
University of Maryland took the flammable anesthetic, vinamar, which is ethyl vinyl
ether, and produced trifluoroethyl vinyl ether,[152]
or fluroxene.
The circumstances surrounding the first anesthetic with fluroxene
illustrate the lure of self-experimentation in research related to the advancement
of anesthetic practice. Max S. Sadove, an anesthesiologist at the University of
Illinois, was a member of the Walter Reed Society, a group of scientists who, following
the example of Walter Reed, allowed themselves to be administered the first dose
of investigational drugs. Sadove, a close acquaintance of Krantz, insisted that
he be given the first fluoride-containing anesthetic, fluroxene, in 1953. Krantz,
who had synthesized the drug, was a pharmacologist with no training in anesthesia.
Krantz advised Sadove that there was danger that the agent might be administered
improperly or might be metabolized to a toxic byproduct. Nevertheless, Sadove was
insistent, and on April 10, 1953, Krantz administered open drop fluoroxene to Sadove,
and recovery was rapid and uneventful.[51]
Fluroxene had marginal success but was eventually withdrawn because
of questions about toxicity and the frequent occurrence of postanesthetic nausea
and vomiting. Charles Suckling, a chemist at Imperial Chemical Industries, synthesized
halothane in 1954 after a theoretical analysis of possible anesthetic halogenated
drugs. The pharmacologic properties of halothane were studied by James Raventos
[153]
(1905–1983), and it was introduced clinically
in 1956 by Michael Johnstone.[154]
Halothane had
definite advantages over ether and cyclopropane because of its more pleasant odor,
higher potency, favorable kinetic characteristics, nonflammability, and low toxicity,
and it gradually replaced the older agents. Halothane was a highly successful drug
and achieved worldwide acceptance, but its unblemished record lasted only a few years
before controversy appeared.
In 1958, a case report described a 39-year-old woman who died
of fulminant hepatic necrosis 11 days after cholecystectomy with halothane anesthesia.
[155]
This was followed in 1963 by nine case reports
of patients who developed hepatic necrosis after halothane anesthesia.[156]
The cases were unique in that hepatic failure often followed minor operations in
which other causes of hepatic failure were not apparent. Eventually, the term halothane
hepatitis became a common clinical diagnosis for patients with postoperative
liver failure, even when halothane was not used as the anesthetic agent. A national
study, formally entitled The National Halothane Study, was established in 1964 and
reported that the incidence of liver failure after halothane anesthesia was no higher
than that reported with other agents.[157]
Nevertheless,
halothane was extensively metabolized in the body, and in some individuals, it seemed
that a toxic metabolite might produce liver necrosis. Other halogenated anesthetics
were also extensively metabolized, and in the case of methoxyflurane, the metabolism
resulted in high levels of fluoride ions. High-output renal failure was an infrequent
but potentially morbid side effect of methoxyflurane[158]
[159]
and thought to be related to the rise of the
fluoride ion concentration after its use.
Beginning in 1960, the pharmaceutical industry launched new efforts
to synthesize the "ideal anesthetic agent." Ross C. Terrell at Ohio Medical Products
synthesized more than 700 potential anesthetic compounds between 1960 and 1980.
During the same period, Edmund I. Eger II (1930-) began a series of studies that
significantly enhanced the rational use of inhalation anesthetics. Eger drew on
the work of Seymore S. Kety[160]
(1915–2000)
and Severinghaus[161]
that had previously demonstrated
that the end-tidal partial pressure of anesthetic gases at steady state was the same
as the brain cerebral partial pressure of those gases. By correlating the end-tidal
(alveolar) concentration with the movement response to supramaximal nociceptive stimulation,
the concept of minimum alveolar concentration (MAC) was born. By definition, MAC
represents the end-tidal concentration for any anesthetic agent at which 50% of patients
move in response to a supramaximal stimulus.[162]
With this standard measure of potency, new agents could be easily introduced to
the anesthesia community. Several further studies by Eger and others on the pharmacokinetics
of inhalation anesthetics and the factors that alter MAC[163]
accelerated an understanding of volatile anesthetic requirements and significantly
enhanced the safe use of these drugs.
Two of the anesthetics developed by Ohio Medical Products, enflurane
and isoflurane, were introduced about 30 years ago[164]
[165]
and have been highly successful and used extensively
since that time. Desflurane was one of the last volatile anesthetics to be synthesized
and required a potentially dangerous explosive method of synthesis. Desflurane had
a high vapor pressure and had the added limitation of requiring more than five times
the quantity of vapor to produce anesthesia compared with isoflurane. Although desflurane
was initially overlooked because of these problems, it was studied thoroughly in
animals[166]
and first used in humans in 1990.[167]
Because of its favorable kinetic properties, it has a more rapid recovery compared
with isoflurane and enflurane.
Sevoflurane was synthesized more than 40 years ago at Travenol
Laboratories. Recovery is rapid with this agent, but because the compound is unstable
in soda lime, it was not introduced until the late 1980s,[168]
[169]
first in Japan and then in the United States.
The decision to introduce the product was, as with desflurane, spurred by the emphasis
on early discharge after anesthesia. Several million anesthetics have been administered
with sevoflurane without apparent complications resulting from the potential by-products
arising from contact with carbon dioxide absorbents. Since the introduction of sevoflurane,
there have been no additional inhalation anesthetics introduced for clinical use.
The inert gas xenon has been under investigation as an anesthetic for several years,
but it is expensive and, like nitrous oxide, requires high concentrations to produce
anesthesia.
