Glutethimide
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| Pronunciation | /ɡluːˈtɛθɪˌmaɪd/ gloo-TE-thi-MYDE |
| Trade names | Doriden, Elrodorm, Noxyron, others |
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| Dependence liability | Moderate - high |
| Routes of administration | By mouth |
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| Bioavailability | Variable (Tmax = 1–6 hours)[2] |
| Protein binding | ~50% |
| Metabolism | Extensive hepatic |
| Elimination half-life | 8–12 hours |
| Excretion | Renal |
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| ECHA InfoCard | 100.000.921 |
| Chemical and physical data | |
| Formula | C13H15NO2 |
| Molar mass | 217.268 g·mol−1 |
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| Melting point | 84 °C (183 °F) |
| Solubility in water | 999 mg/L (30 °C/86 °F) mg/mL (20 °C) |
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Glutethimide (brand names included Doriden, Elrodorm, and Noxyrom) is a central nervous system (CNS) depressant drug of the piperidine chemical class, one of many non-barbiturate, "barbiturate-like" GABAergic medications exhibiting general calming, relaxing, or "tranquilizing" properties in addition to relieving anxiety and promoting sleep. As such, "nerve pills" or "sleeping pills" were common vernacular descriptions of these types of medications
Glutethimide was developed and released by Ciba Specialty Chemicals in 1954, and was approved by the Food and Drug Administration (FDA) for use in the United States in 1957 for treating insomnia, under the brand name Doriden.[3] Generic formulations were eventually marketed beginning in the early 1970s, following the signing of the Controlled Substances Act, which marked the start of the American War on Drugs. Initially considered a preferable and safer prescription drug alternative to barbiturate salts, by the 1970s, glutethimide was recognized as having a similar abuse potential, being as habit-forming and addicting as barbiturates and similar contemporary non-barbiturate CNS depressants commonly in use at the time, such as methaqualone, ethchlorvynol, meprobamate, and ethinamate. Abrupt cessation of this substance can result in rebound effects similar those found in alcohol withdrawal, as well from barbiturates and benzoediazpines, given their similar mechanism of action with regard to GABA..
In recreational quantities, any form of glutethimide was colloquially called a "Ciba" and all trade names of the medicine were manufactured as a pill/tablet directed to be taken by mouth. Each branded tablet was scored and white in color, and contained 500 mg of the active ingredient, which was prescribed to be used 1-2 times daily. Glutethimide was available in the United States until 1993, when production ceased and it was withdrawn from the market. Since 2013, the U.S. Drug Enforcement Administration has limited annual production to three grams, equivalent to six Doriden tablets, suggesting current use is limited to small-scale research.[citation needed]
The substance was discontinued in Hungary in 2006.
Chemical Compoition and Synthesis
[edit]The (R) isomer has a faster onset of actionand more potent anticonvulsant activity in animal models than the (S) isomer.[4]
The base catalyzed conjugate addition of 2-phenylbutyronitrile [769-68-6] (1) to ethyl acrylate (2) gives ethyl 4-cyano-4-phenylhexanoate, CID:139890735 (3). Alkaline hydrolysis of the nitrile group into an amide group, and subsequent acidic cyclization of the product affords the desired glutethimide (4).
Mechanism of Action
[edit]Glutethimide is a CYP2D6 enzyme inducer, enabling the body to convert higher amounts of codeine to morphine, frequently leading to s users ingesting the substance with Tylenol 4 (codeine/acetaminophen).
Uses and Usage
[edit]Prescription Use
[edit]Doriden was commonly prescribed as a sleeping pull until the 1970s, when prescriptions gradually began to decline. Following long-term use, abrupt withdrawal of glutethimide was found to produce rebound effects resembling those of barbiturate withdrawal; anecdotally, patients consistently taking stable doses of the drug long-term have reported symptoms including delirium, hallucinosis, convulsions, and fever.[9]
Recreational misuse
[edit]Glutethimide was often combined with products containing codeine, which metabolizes upon ingestion into morphine.colloquially called "hits," "pancakes and syrup," and most frequently "Dors and 4s", a highly potent and often lethal combination, resulting in fatal respiratory depression.[10][11]
The drug became increasingly harder to access in the 1970s, increasing demand for glutethimide in such urban centers as Boston, Philadelphia, Pittsburgh, New York City, Baltimore, and Newark, New Jersey, leading to small-scale clandestine synthesis of glutethimide beginning in 1984, when methaqualone was fully withdrawan from the U.S. market and nearly impossible to access.[12]: 203
Clinical Use and Research
[edit]Glutethimide's effect on quickening the conversion of codeine to morphine was studied clinically, including some research in the 1970s in various countries of using it under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, particularly as a Substitutionmittel that may be a useful alternative to methadone.[13][14]
Discontinuation
[edit]Commercial production of glutethimide was discontinued in the U.S. in 1993, followed by several Eastern European countries in 2006, notably Hungary. Analysis of confiscated glutethimide seems to invariably show the drug or the results of attempted synthesis, as opposed to being "laced" with similar depressants.[12]
Legal status
[edit]United States
[edit]Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances.[15] It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II,[16] several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.[17][18] It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g.
See also
[edit]- Aminoglutethimide, close relative to this substance
- Piperidione
- Methyprylon, sometimes spelled methyprylone and branded Noludar and Dimeran
- Pyrithyldione
References
[edit]- ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
- ^ Barceloux DG (2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. Hoboken, N.J.: John Wiley & Sons, Inc. pp. 492–493. ISBN 978-0-471-72760-6. OCLC 814224300.
- ^ a b US patent 2673205, Hoffmann K, Tagmann E, "3-Disubstituted Dioxopiperidines and the Manufacture thereof", issued 23 March 1954, assigned to CIBA
- ^ Houlihan WJ, Bennett GB (January 1977). "Anti-Anxiety Agents, Anticonvulsants and Sedative-Hypnotics". Annual Reports in Medicinal Chemistry. 12. Academic Press: 10–19. doi:10.1016/S0065-7743(08)61540-7.
- ^ Tagmann E, Sury E, Hoffmann K (1952). "Über Alkylenimin-Derivate. 2. Mitteilung". Helvetica Chimica Acta. 35 (5): 1541–1548. doi:10.1002/hlca.19520350516.
- ^ Salmon-Legagneur F, Neveu C (January 1952). "Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques". Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences. 234 (10): 1060–2.
- ^ Salmon-Legagneur F, Neveu C (1953). "Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques". Bull. Soc. Chim. France: 70.
- ^ DE patent 950193, Hoffmann K Tagmann E, "Verfahren zur Herstellung neuer Dioxopiperidine", issued 4 October 1956, assigned to CIBA
- ^ Cookson JC (September 1995). "Rebound exacerbation of anxiety during prolonged tranquilizer ingestion". Journal of the Royal Society of Medicine. 88 (9): 544. PMC 1295346. PMID 7562864.
- ^ Shamoian CA (1975). "Codeine and glutethimide. Euphoretic, addicting combination". New York State Journal of Medicine. 75 (1): 97–99. PMID 1053824.
- ^ Havier RG, Lin R (April 1985). "Deaths as a result of a combination of codeine and glutethimide". Journal of Forensic Sciences. 30 (2): 563–6. doi:10.1520/JFS11840J. PMID 3998703. S2CID 45780806.
- ^ a b Gahlinger P (2003). "Methaqualone and Glutethimide". Illegal Drugs: A Complete Guide to Their History, Chemistry, Use, and Abuse. ISBN 9780452285057. OCLC 52269170.
- ^ Popa D, Loghin F, Imre S, Curea E (August 2003). "The study of codeine-gluthetimide pharmacokinetic interaction in rats". Journal of Pharmaceutical and Biomedical Analysis. 32 (4–5): 867–77. doi:10.1016/s0731-7085(03)00189-4. PMID 12899973.
- ^ Khajawall AM, Sramek JJ, Simpson GM (August 1982). "'Loads' alert". The Western Journal of Medicine. 137 (2): 166–8. PMC 1274052. PMID 7135952.
- ^ "List of psychotropic substances under international control" (PDF). International Narcotics Control Board. Archived from the original (PDF) on 2012-08-31.
- ^ "Section 1308.12 Schedules of Controlled Substances". Title 21 Code of Federal Regulations. Drug Enforcement Administration. Archived from the original on 2015-08-04. Retrieved 2011-10-07.
- ^ Havier RG, Lin R (April 1985). "Deaths as a result of a combination of codeine and glutethimide". Journal of Forensic Sciences. 30 (2): 563–6. doi:10.1520/JFS11840J. PMID 3998703. S2CID 45780806.
- ^ Feuer E, French J (February 1984). "Descriptive epidemiology of mortality in New Jersey due to combinations of codeine and glutethimide". American Journal of Epidemiology. 119 (2): 202–7. doi:10.1093/oxfordjournals.aje.a113738. PMID 6695899.