Halothane

# Overview
Halothane (trademarked as Fluothane) is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane. It is the only inhalational anesthetic containing a bromine atom; several other halogenated anesthesia agents lack the bromine atom and do contain the fluorine and chlorine atoms present in halothane. It is colorless and pleasant-smelling, but unstable in light. It is packaged in dark-colored bottles and contains 0.01% thymol as a stabilizing agent.
It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. Its use in developed countries, however, has been almost entirely superseded by newer inhalational anaesthetic agents such as sevoflurane, isoflurane, and desflurane.

# Anesthetic properties
It is a potent anesthetic with a minimum alveolar concentration of 0.74%. Its blood/gas partition coefficient of 2.4 makes it an agent with moderate induction and recovery time. It is not a good analgesic and its muscle relaxation effect is moderate.

# Availability
It is available as a volatile liquid, at 30, 50, 200, and 250 ml per container.

# Side effects
Repeated exposure to halothane in adults was noted in rare cases to result in severe liver injury. This occurred in about one in 10,000 exposures. The resulting syndrome was referred to as halothane hepatitis, and is thought to result from the metabolism of halothane to trifluoroacetic acid via oxidative reactions in the liver. About 20% of inhaled halothane is metabolized by the liver and these products are excreted in the urine. The hepatitis syndrome had a mortality rate of 30% to 70%. Concern for hepatitis resulted in a dramatic reduction in the use of halothane for adults. It was replaced in the 1980s by enflurane and isoflurane. By 2005, the common volatile anesthetics in use were isoflurane, sevoflurane, and desflurane. Since the risk of halothane hepatitis in children was substantially lower than in adults, halothane continued to be used in pediatrics in the 1990s. However, by 2000, sevoflurane had largely replaced the use of halothane in children.
Halothane sensitises the heart to catecholamines, so it is liable to cause cardiac arrhythmias, occasionally fatal, particularly if hypercapnia has been allowed to develop.  This seems to be especially problematic in dental anaesthesia.
Like all the potent inhalational anaesthetic agents, it is a potent trigger for malignant hyperthermia.  Similarly, it relaxes uterine smooth muscle and this may increase blood loss during delivery or termination of pregnancy.

# Pharmacology
Halothane activates GABAA and glycine receptors. It also acts as an NMDA receptor antagonist, inhibits nACh and voltage-gated sodium channels, and activates 5-HT3 and twin-pore K+ channels. It does not affect the AMPA or kainate receptors.

# Chemical and physical properties
Chemically, halothane is an alkyl halide (not an ether like many other anesthetics). The structure has one stereocenter, so (R)- and (S)-optical isomers occur.

# Synthesis
The commercial synthesis of halothane starts from trichloroethylene, which is reacted with hydrogen fluoride in the presence of antimony trichloride at 130C to form 2-chloro-1,1,1-trifluoroethane. This is then reacted with bromine at 450C to produce halothane.
File:Halothane synth.png

# Related substances
Attempts to find anesthetics with less metabolism led to halogenated ethers such as enflurane and isoflurane. The incidence of hepatic reactions with these agents is lower. The exact degree of hepatotoxic potential of enflurane is debated, although it is minimally metabolized. Isoflurane is essentially not metabolized and reports of associated liver injury are quite rare. Small amounts of trifluoroacetic acid can be formed from both halothane and isoflurane metabolism and possibly accounts for cross sensitization of patients between these agents.
The main advantage of the more modern agents is lower blood solubility, resulting in faster induction of and recovery from anaesthesia.

# History
This halogenated hydrocarbon was first synthesized by C. W. Suckling of Imperial Chemical Industries in 1951 and was first used clinically by M. Johnstone in Manchester in 1956. Halothane became popular as a nonflammable general anasthetic replacing other volatile anesthetics such as diethyl ether and cyclopropane. Use of the anesthetic was phased out during the 1980s and 1990s as newer anesthetic agents became popular.  Halothane retains some use in veterinary surgery and in the Third World because of its lower cost.
Halothane was given to many millions of adult and pediatric patients worldwide from its introduction in 1956 through the 1980s. Its properties include cardiac depression at high levels, cardiac sensitization to catecholamines such as norepinephrine, and potent bronchial relaxation. Its lack of airway irritation made it a common inhalation induction agent in pediatric anesthesia. Due to its cardiac depressive effect, it was contraindicated in patients with cardiac failure. Halothane was also contraindicated in patients susceptible to cardiac arrhythmias, or in situations related to high catecholamine levels such as pheochromocytoma.