Flurothyl Explained

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 family, related to inhaled anaesthetic agents such as diethyl ether, but having the opposite effects, acting as a stimulant and convulsant.[1] 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.[2] [3] [4]

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.[5] [6] [7]

Currently, the main uses of flurothyl are:

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, as an alternative to electroconvulsive therapy (ECT).[10] [11] 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.[12] [13] Premedication with pentothal and succinylcholine chloride, as is customary in ECT, was tested and found safe.[14]

Four random assignment treatment studies found the clinical results for flurothyl to be as effective as those of ECT.[15] [16] [17] [18] Flurothyl treatments were administered on the same schedules as ECT. In some patients who had not responded to ECT, flurothyl treatment produced improvement.[19]

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.[20] 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.[21]

An injectable form of flurothyl was formulated.[22] The clinical results were the same as with inhaled flurothyl.[23]

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).[24] [25] A variety of halogenated ethers (e.g., isoflurane, sevoflurane) 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 (1,1,1,3,3,3-hexafluoro-2-methoxypropane) induces general anesthesia and not convulsions in mice and dogs.[26] Isoflurothyl differs from the widely used inhalational anesthetic sevoflurane by only a single fluorine 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 GABAA receptors and had no effect on neuronal glycine receptors.[27] This receptor selectivity resembles that of the well-characterized GABAA receptor antagonist picrotoxin. Studies using recombinant GABAA 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 GABAA and glycine receptors.[28] There is some evidence that flurothyl may actually possess general anesthetic properties at high concentrations that are masked by the more potent convulsant action.[26]

See also

Notes and References

  1. Rose L, Watson A . Flurothyl (Indoklon). Experience with an inhalational convulsant agent . Anaesthesia . 22 . 3 . 425–34 . July 1967 . 4951597 . 10.1111/j.1365-2044.1967.tb02765.x . 5714209 . free .
  2. Karliner W, Padula LJ . Further clinical studies of hexafluorodiethyl ether convulsive treatments . Journal of Neuropsychiatry . 3 . 159–62 . 1962 . 14453985 .
  3. Speers L, Neeley AH . The synthesis, chemical and physical properties of Indoklon . Journal of Neuropsychiatry . 4 . 153–6 . February 1963 . 13989984 .
  4. Krantz JC, Loecher CK . Anesthesia LXX: effect of inert fluorinated agents on fluroxene and flurothyl . Anesthesia and Analgesia . 46 . 3 . 271–4 . 1967 . 4381591 . 10.1213/00000539-196705000-00001 . 36367759 .
  5. Koblin DD, Chortkoff BS, Laster MJ, Eger EI, Halsey MJ, Ionescu P . Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis . Anesthesia and Analgesia . 79 . 6 . 1043–8 . December 1994 . 7978424 . 10.1213/00000539-199412000-00004 . free .
  6. Koblin DD, Laster MJ, Ionescu P, Gong D, Eger EI, Halsey MJ, Hudlicky T . Polyhalogenated methyl ethyl ethers: solubilities and anesthetic properties . Anesthesia and Analgesia . 88 . 5 . 1161–7 . May 1999 . 10320188 . 10.1213/00000539-199905000-00036 . free .
  7. Eger EI, Halsey MJ, Harris RA, Koblin DD, Pohorille A, Sewell JC, Sonner JM, Trudell JR . 6 . Hypothesis: volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart . Anesthesia and Analgesia . 88 . 6 . 1395–400 . June 1999 . 10357351 . 10.1213/00000539-199906000-00036 . free .
  8. Hashimoto Y, Araki H, Suemaru K, Gomita Y . Effects of drugs acting on the GABA-benzodiazepine receptor complex on flurothyl-induced seizures in Mongolian gerbils . European Journal of Pharmacology . 536 . 3 . 241–7 . May 2006 . 16581068 . 10.1016/j.ejphar.2006.02.036 .
  9. (76) Jiang, L. L.; Yan, C.; Yao, Y. X.; Cai, W.; Huang, J. Q.; Zhang, Q. Inhibiting Solvent Cointercalation in a Graphite Anode by a Localized High-Concentration Electrolyte in Fast-Charging Batteries. Angew. Chem., Int. Ed. 2021, 60, 3402−3406.
  10. A convulsant agent for psychiatric use. Flurothyl (Indoklon) . JAMA . 196 . 1 . 29–30 . April 1966 . 4379572 . 10.1001/jama.196.1.29 .
  11. Small JG, Small IF, Sharpley P, Moore DF . A double-blind comparative evaluation of flurothyl and ECT . Archives of General Psychiatry . 19 . 1 . 79–86 . July 1968 . 5658383 . 10.1001/archpsyc.1968.01740070081012 .
  12. Esquibel AJ, Krantz JC, Truitt EB, Ling AS, Kurland AA . Hexafluorodiethyl ether (indoklon): its use as a convulsant in psychiatric treatment . The Journal of Nervous and Mental Disease . 126 . 6 . 530–4 . June 1958 . 10.1097/00005053-195806000-00004 . 13564231 . 2650010 .
  13. Krantz JC, Esquibel A, Truitt EB, Ling AS, Kurland AA . Hexafluorodiethyl ether (indoklon); an inhalant convulsant; its use in psychiatric treatment . Journal of the American Medical Association . 166 . 13 . 1555–62 . March 1958 . 13513394 . 10.1001/jama.1958.02990130015004 .
  14. Karliner WJ, Padina LJ . 1959 . Indoklon combined with Pentothal and Anectine . Am. J. Psychiatry . 115 . 11. 1041–1042 . 10.1176/ajp.115.11.1041.
  15. Fink M, Kahn RL, Karp E, Pollack M, Green MA, Alan B, Efkowits HJ . Inhalant-induced convulsions. Significance for the theory of the convulsive therapy process . Archives of General Psychiatry . 4 . 3 . 259–66 . March 1961 . 13699611 . 10.1001/archpsyc.1961.01710090045006 .
  16. Kurland AA, Hanlon TE, Esquibel AJ, Krantz JC, Sheets CS . A comparative study of hexafluorodiethyl ether (indoklon) and electroconvulsive therapy . The Journal of Nervous and Mental Disease . 129 . 95–8 . July 1959 . 14412877 . 10.1097/00005053-195907000-00016 .
  17. Small JG, Small IF, Sharpley P, Moore DF . A double-blind comparative evaluation of flurothyl and ECT . Archives of General Psychiatry . 19 . 1 . 79–86 . July 1968 . 5658383 . 10.1001/archpsyc.1968.01740070081012 .
  18. Laurell B . Flurothyl convulsive therapy . Acta Psychiatrica Scandinavica. Supplementum . 213 . 1–79 . 1970 . 4394881 .
  19. Karliner W, Padula LJ . The use of hexafluorodiethyl ether in psychiatric treatment . Journal of Neuropsychiatry . 2 . 67–70 . 1960 . 13751512 .
  20. Book: Fink M . Convulsive Therapy: Theory and Practice. . New York . Raven Press . 1979 .
  21. A convulsant agent for psychiatric use. Flurothyl (Indoklon) . JAMA . 196 . 1 . 29–30 . April 1966 . 4379572 . 10.1001/jama.196.1.29 .
  22. Krantz JC, Manchey LL, Truitt EB, Ling AS, Kurland AA . The availability of hexafluorodiethyl ether by intravenous injection as a convulsant in psychiatric treatment . The Journal of Nervous and Mental Disease . 129 . 92–4 . July 1959 . 14411701 . 10.1097/00005053-195907000-00015 .
  23. Karliner W . Clinical experiences with intravenous Indoklon: a new convulsant drug . Journal of Neuropsychiatry . 4 . 184–9 . February 1963 . 13962526 .
  24. Koblin DD, Chortkoff BS, Laster MJ, Eger EI, Halsey MJ, Ionescu P . Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis . Anesthesia and Analgesia . 79 . 6 . 1043–8 . December 1994 . 7978424 . 10.1213/00000539-199412000-00004 . free .
  25. Krasowski MD . Contradicting a unitary theory of general anesthetic action: a history of three compounds from 1901 to 2001 . Bulletin of Anesthesia History . 21 . 3 . 1, 4-8, 21 passim . July 2003 . 17494361 . 2701367 . 10.1016/s1522-8649(03)50031-2 .
  26. Koblin DD, Eger EI, Johnson BH, Collins P, Terrell RC, Speers L . Are convulsant gases also anesthetics? . Anesthesia and Analgesia . 60 . 7 . 464–70 . July 1981 . 7195661 . 10.1213/00000539-198107000-00002 . free .
  27. Wakamori M, Ikemoto Y, Akaike N . Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses in dissociated CNS neurons of the rat . Journal of Neurophysiology . 66 . 6 . 2014–21 . December 1991 . 1667416 . 10.1152/jn.1991.66.6.2014 .
  28. Krasowski MD . Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels . Neuropharmacology . 39 . 7 . 1168–83 . April 2000 . 10760360 . 2846390 . 10.1016/s0028-3908(99)00221-x .

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