Flurothyl

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]

Flurothyl
Clinical data
Other namesHexafluorodiethyl ether
ATC code
  • None
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.155.160
Chemical and physical data
FormulaC4H4F6O
Molar mass182.064 g·mol−1
3D model (JSmol)
Density1.404 g/cm3 g/cm3
Boiling point62 to 63 °C (144 to 145 °F)
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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]

The main current use of flurothyl is in scientific research for inducing seizures in laboratory animals.[8]

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).[9][10] 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.[11][12] Premedication with pentothal and succinylcholine chloride, as is customary in ECT, was tested and found safe.[13]

Four random assignment treatment studies found the clinical results for flurothyl to be as effective as those of ECT.[14][15][16][17] Flurothyl treatments were administered on the same schedules as ECT. In some patients who had not responded to ECT, flurothyl treatment produced improvement.[18]

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.[17] 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.[19] Oximetric and ECG studies showed comparable heart rate increases with occasional rhythmic irregularities.[15]

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.[20]

An injectable form of flurothyl was formulated.[21] The clinical results were the same as with inhaled flurothyl.[22]

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).[23][24] 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 ‘iso-flurothyl’ (1,1,1,3,3,3-hexafluoro-2-methoxypropane) induces general anesthesia and not convulsions in mice and dogs.[25] Iso-flurothyl 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 iso-flurothyl was provided by electrophysiology studies that showed flurothyl was an antagonist (blocker) of neuronal GABAA receptors and had no effect on neuronal glycine receptors.[26] 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 iso-flurothyl behaved similar to other ether anesthetics in acting as a positive allosteric modulator of GABAA and glycine receptors.[27] There is some evidence that flurothyl may actually possess general anesthetic properties at high concentrations that are masked by the more potent convulsant action.[25]

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See also

References
  1. Rose, L; Watson, A (1967). "Flurothyl (Indoklon). Experience with an inhalational convulsant agent". Anaesthesia. 22 (3): 425–34. doi:10.1111/j.1365-2044.1967.tb02765.x. PMID 4951597.
  2. Karliner, W; Padula, L (1962). "Further clinical studies of hexafluorodiethyl ether convulsive treatments". J. Neuropsychiatry. 3: 159–162.
  3. Speers, L; Neeley, A. H. (1963). "The synthesis, chemical and physical properties of Indoklon". J. Neuropsychiatry. 4: 153–156.
  4. Krantz, J. C. Jr.; Loecher, C. K. (1967). "Anesthesia LXX: effect of inert fluorinated agents on fluroxene and flurothyl". Anesthesia and Analgesia. 46 (3): 271–274. doi:10.1213/00000539-196705000-00001.
  5. Koblin DD, Chortkoff BS, Laster MJ, Eger EI, Halsey MJ, Ionescu P (December 1994). "Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis". Anesthesia and Analgesia. 79 (6): 1043–8. doi:10.1213/00000539-199412000-00004. PMID 7978424.
  6. Koblin DD, Laster MJ, Ionescu P, Gong D, Eger EI, Halsey MJ, Hudlicky T (May 1999). "Polyhalogenated methyl ethyl ethers: solubilities and anesthetic properties". Anesthesia and Analgesia. 88 (5): 1161–7. doi:10.1213/00000539-199905000-00036. PMID 10320188.
  7. Eger EI, Halsey MJ, Harris RA, Koblin DD, Pohorille A, Sewell JC, Sonner JM, Trudell JR (June 1999). "Hypothesis: volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart". Anesthesia and Analgesia. 88 (6): 1395–400. doi:10.1213/00000539-199906000-00036. PMID 10357351.
  8. Hashimoto, Y; Araki, H; Suemaru, K; Gomita, Y (2006). "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. doi:10.1016/j.ejphar.2006.02.036. PMID 16581068.
  9. "A convulsant agent for psychiatric use. Flurothyl (Indoklon)". JAMA: The Journal of the American Medical Association. 196 (1): 29–30. 1966. doi:10.1001/jama.196.1.29. PMID 4379572.
  10. Small, JG; Small, IF; Sharpley, P; Moore, DF (1968). "A double-blind comparative evaluation of flurothyl and ECT". Archives of General Psychiatry. 19 (1): 79–86. doi:10.1001/archpsyc.1968.01740070081012. PMID 5658383.
  11. Esquibel, A.; Krantz, J. C. Jr.; Truitt; et al. "Hexafluorodiethyl ether (Indoklon) – Its use as a convulsant in psychiatric treatment". J. Nerv. Ment. Dis. 1958 (126): 530–534.
  12. Krantz, J. C. Jr.; Esquibel, A.; Truitt, A.; et al. (1958). "Hexafluorodiethyl ether (Indoklon) – an inhalant convulsant: Its use in psychiatric treatment". JAMA. 1958 (166): 1555–1556. doi:10.1001/jama.1958.02990130015004. PMID 13513394.
  13. Karliner, W. Padula (1959). "Indoklon combined with Pentothal and Anectine". Am. J. Psychiatry. 115 (11): 1041–1042. doi:10.1176/ajp.115.11.1041.
  14. Fink, M.; Kahn, R. L.; Karp, E.; et al. (1961). ""Inhalant-induced convulsions " Significance for the theory of the convulsive therapy process". Arch. Gen. Psychiatry. 4 (3): 259–266. doi:10.1001/archpsyc.1961.01710090045006. PMID 13699611.
  15. Kurland, A. A.; Hanlon, T. E.; Esquibel, A. J.; et al. (1959). "A comparative study of hexafluorodiethyl ether (Indoklon) and electroconvulsive therapy". J. Nerv. Ment. Dis. 129: 95–98. doi:10.1097/00005053-195907000-00016. PMID 14412877.
  16. Small, J. G.; Small, I. F.; Sharply, P.; Moore, D. F. (1968). "A double-blind comparative evaluation of flurothyl and ECT". Arch. Gen. Psychiatry. 19: 79–86. doi:10.1001/archpsyc.1968.01740070081012. PMID 5658383.
  17. Laurell, B (1970). "Flurothyl convulsive therapy". Acta Psychiatrica Scandinavica Supplementum. 213: 1–79. PMID 4394881.
  18. Karliner, W.; Padula, L. (1960). "The use of hexafluorodiethyl ether in psychiatric treatment". J. Neuropsychiatry. 2: 67–70. PMID 13751512.
  19. Fink M. Convulsive Therapy: Theory and Practice. New York: Raven Press, 1979
  20. "A convulsant agent for psychiatric use. Flurothyl (Indoklon)". JAMA: The Journal of the American Medical Association. 196 (1): 29–30. 1966. doi:10.1001/jama.196.1.29. PMID 4379572.
  21. Krantz, J. C. Jr.; Manchey, L. L.; Truitt, E. B.; et al. (1959). "The availability of hexafluorodiethyl ether by intravenous injection as a convulsant in psychiatric treatment". J. Nerv. Ment. Dis. 128: 92–94. doi:10.1097/00005053-195907000-00015. PMID 14411701.
  22. Karliner, W (1963). "Clinical experience with intravenous Indoklon: A new convulsant drug". J. Neuropsychiatry. 4: 184–189.
  23. D. D. Koblin, B. S. Chortkoff, M. J. Laster, E. I. 2nd Eger, M. J. Halsey & P. Ionescu (1994). "Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis". Anesthesia and Analgesia. 79 (6): 1043–1048. doi:10.1213/00000539-199412000-00004. PMID 7978424.CS1 maint: multiple names: authors list (link)
  24. Matthew D. Krasowski (2003). "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. doi:10.1016/s1522-8649(03)50031-2. PMC 2701367. PMID 17494361.
  25. D. D. Koblin, E. I. 2nd Eger, B. H. Johnson, P. Collins, R. C. Terrell & L. Speers (1981). "Are convulsant gases also anesthetics?". Anesthesia and Analgesia. 60 (7): 464–470. doi:10.1213/00000539-198107000-00002. PMID 7195661.CS1 maint: multiple names: authors list (link)
  26. M. Wakamori, Y. Ikemoto & N. Akaike (1991). "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): 2014–2021. doi:10.1152/jn.1991.66.6.2014. PMID 1667416.
  27. M. D. Krasowski (2000). "Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels". Neuropharmacology. 39 (7): 1168–1183. doi:10.1016/s0028-3908(99)00221-x. PMC 2846390. PMID 10760360.
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