Flurothyl (Indoklon) (IUPAC names: 1,1,1-trifluoro-2-(2,2,2-trifluoroethoxy)ethane or bis(2,2,2-trifluoroethyl) ether) is a volatile liquid drug from the

halogenated ether A halogenated ether is a subcategory of a larger group of chemicals known as ethers. An ether is an organic chemical that contains an ether group—an oxygen atom connected to two (substituted) alkyl groups. A good example of an ether is t ...

family, related to

inhaled anaesthetic agent An inhalational anesthetic is a chemical compound possessing general anesthetic properties that can be delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vapori ...

s such as diethyl ether, but having the opposite effects, acting as a

stimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...

and convulsant. A clear and stable liquid, it has a mild ethereal odor whose vapors are non-flammable. It is excreted from the body by the lungs in an unchanged state. Several compounds related to the halogenated ether anesthetics have similar convulsant effects rather than producing sedation, and this has been helpful in studying the mechanism of action of these drugs. The main current use of flurothyl is in scientific research for inducing seizures in laboratory animals.

Research into psychiatric treatment

Flurothyl was at one time studied in psychiatric medicine for shock therapy, in a similar manner to other convulsant drugs such as

pentetrazol Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country ...

, as an alternative to electroconvulsive therapy (ECT). This use has now been discontinued. In 1953, the Maryland pharmacologist J. C. Krantz experimented with flurothyl to induce seizures in psychiatric patients as an alternative to ECT. Flurothyl was injected into a plastic container in a tight fitting face mask. The patient inhaled a mixture of vapor and air, and expired air was forced into a charcoal adsorbent via a one-way valve. Oxygen was administered simultaneously. Flurothyl inhalations were first conducted without sedation or muscle paralysis. Premedication with pentothal and succinylcholine chloride, as is customary in ECT, was tested and found safe. Four random assignment treatment studies found the clinical results for flurothyl to be as effective as those of ECT. Flurothyl treatments were administered on the same schedules as ECT. In some patients who had not responded to ECT, flurothyl treatment produced improvement. The flurothyl treated patients showed less amnesia and confusion during the course of treatment with better patient acceptance. A detailed study comparing flurothyl and ECT in patients with severe endogenous depression, reported the degree of anterograde amnesia to be similar, but the degree of retrograde amnesia was much lower after flurothyl. Psychological tests showed memory impairments at the fourth week of treatment, and memory improvement two weeks after the last treatment, with no measurable differences between the treatments. Equal degrees of EEG slow wave increases were recorded in flurothyl and electrical induced seizures. Oximetric and ECG studies showed comparable heart rate increases with occasional rhythmic irregularities. Flurothyl induced seizures were deemed clinically equal to electrical seizures with lesser effects on cognition and memory. An editorial in the Journal of the American Medical Association in 1966 encouraged its use. An injectable form of flurothyl was formulated. The clinical results were the same as with inhaled flurothyl.

Mechanism of Action

The convulsant properties of flurothyl pose a challenge to unifying theories of general anesthetics such as the Meyer-Overton hypothesis (see Theories of general anaesthetic action). A variety of halogenated ethers (e.g.,

isoflurane Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia rather than isoflurane, due to airway irritation w ...

sevoflurane Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desfluran ...

) and diethyl ether itself are general anesthetics, and flurothyl is a substituted diethyl ether. Even more strikingly, a structural isomer of flurothyl known as

isoflurothyl Isoflurothyl is a fluorinated ether related to the inhalational convulsant flurothyl. It is the structural isomer of flurothyl. Unlike flurothyl, however, isoflurothyl is a general anesthetic. See also *Convulsant *Flurothyl *Sevoflurane Sevof ...

(1,1,1,3,3,3-hexafluoro-2-methoxypropane) induces general anesthesia and not convulsions in mice and dogs. Isoflurothyl differs from the widely used inhalational anesthetic

by only a single

fluorine Fluorine is a chemical element with the symbol F and atomic number 9. It is the lightest halogen and exists at standard conditions as a highly toxic, pale yellow diatomic gas. As the most electronegative reactive element, it is extremely reacti ...

atom (sevoflurane has an additional fluorine on the methyl group). A molecular explanation for the difference between flurothyl and isoflurothyl was provided by electrophysiology studies that showed flurothyl was an antagonist (blocker) of neuronal GABA_A receptors and had no effect on neuronal glycine receptors. This receptor selectivity resembles that of the well-characterized GABA_A receptor antagonist picrotoxin. Studies using recombinant GABA_A and glycine receptors confirmed this activity profile and further showed that isoflurothyl behaved similar to other ether anesthetics in acting as a positive allosteric modulator of GABA_A and glycine receptors. There is some evidence that flurothyl may actually possess general anesthetic properties at high concentrations that are masked by the more potent convulsant action.

References

{{Convulsants Antidepressants Convulsants Ethers GABAA receptor negative allosteric modulators Organofluorides Stimulants