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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| Pharmacokinetic data | |
| 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 |
| 3D model (JSmol) | |
| 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 name Doriden) is a central nervous system depressant drug, belonging to the piperidine chemical class, unrelated to barbiturates, despite having similar therapeutic efficacy and withdrawal/discontinuation symptoms. Discovered in the early 1950s, tranquilizers produced in the twentieth century, albeit exhibiting barbiturate-like" effects caused by many GABAergics, used for its calming, relaxing, tranquilizing properties, in addition to relieving anxiety and promoting sleep.
History
[edit]Glutethimide was developed Ciba Specialty Chemicals in 1954, and approved for medical use in the United States by the U.S. FDA in 1957, indicated for treating insomnia, and branded Doriden by Ciba, generic trade names that followed Doriden included Elrodorm and Noxyrom.[3] Following the passage of the Controlled Substances Act of 1970 in the U.S., followed by the creation of the U.S. Drug Enforcement Agency (DEA) in 1973, the "[[War on Drugs" began to prioritize the criminalization of combination drugs containing controlled substances.
DEA declared glutethimide to as habit-forming and addicting as barbiturates and other highly-regulated CNS depressants of the imte such as Quaalude and Placidyl. Abrupt cessation of this substance can result in rebound effects similar those found in withdrawal from any GABAergic substance, including ethanol ("alcohol"), barbiturates and benzodiazepines.
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 and uses
[edit]Glutethimide is a CYP2D6 enzyme inducer, enabling the body to convert higher amounts of codeine to morphine, frequently leading to ingstion of glutethimide alongside codeine-containing products, such as (Tylenol No. 3 or No. 4, and widespread misuse, overdose, and fatalities. Colloquially called "hits," "pancakes and syrup," or "Dors and 4s", this combination is highly potent and often lethal due to extreme respiratory depression.[9][10]
In recreational quantities, any form of glutethimide was colloquially called a "Ciba" and all trade names of the medicine were manufactured as a white [tablet (pharmacy)|pill/tablet]] with a score line directed to be taken by mouth, and containing 500mg of the active ingredient. During the 1980s, glutethimide became increasingly harder to access and subject to many restrictions as a CSA-classified Schedule II substance, but market demand for the product constinued to exist amongnortheastern U.S. states and metropolitan centers, leading to the substance'sclandestine "underground" manufacturing and sale, which only increased when methaqualone was fully withdrawan from the U.S. market and lclassifid a Schedule I drug.Gahlinger P (2003). "Methaqualone and Glutethimide". Illegal Drugs: A Complete Guide to Their History, Chemistry, Use, and Abuse. ISBN 9780452285057. OCLC 52269170.</ref>: 203
Clinical 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[clarification needed] that may be a useful alternative to methadone.[11][12] 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]
Legal status
[edit]United States
[edit]Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances.[13] 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,[14] several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.[15][16] 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 as 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
- ^ 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.
- ^ 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.