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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 | Extensivehepatic |
| Eliminationhalf-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 names includedDoriden,Elrodorm, andNoxyron) is acentral nervous system (CNS)depressant drug of thepiperidinechemical class, one of many non-barbiturate, "barbiturate-like"GABAergic medications exhibiting generalcalming, relaxing, or "tranquilizing" properties in addition torelieving anxiety andpromoting sleep. As such, "nerve pills" or "sleeping pills" were common vernacular descriptions of these types of medications.
Glutethimide was developedCiba Specialty Chemicals in 1954, andapproved for medical use in theUnited States by the U.S.FDA in 1957. It was indicated for treatinginsomnia, and brandedDoriden by Ciba. Generic trade names that followed includedElrodorm andNoxyron.[3] Following the passage of theControlled 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 ofcombination drugs containingcontrolled substances.
The DEA declared glutethimide to be ashabit-forming andaddicting as barbiturates and other highly-regulatedCNS depressants such asQuaalude andPlacidyl. Abrupt cessation of this substance can result in rebound effects similar to those in withdrawal from anyGABAergic substance, includingalcohol,barbiturates andbenzodiazepines.
The (R) isomer has a fasteronset of action and more potentanticonvulsant activity in animal models than the (S) isomer.[4]
The base catalyzed conjugate addition of 2-phenylbutyronitrile [769-68-6] (1) toethyl 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).
Glutethimide is aCYP2D6 enzyme inducer, enabling the body to convert higher amounts ofcodeine tomorphine, frequently leading to ingestion of glutethimide alongside codeine-containing products, such asTylenol 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 extremerespiratory depression.[9][10]
In recreational quantities, any form of glutethimide was colloquially called a "Ciba" and alltrade names of the medicine were manufactured as a whitepill/tablet with a score line directed to be taken by mouth, and containing 500mg of theactive 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 continued to exist amongnortheastern U.S. states and metropolitan centers, leading to the substance'sclandestine "underground" manufacturing and sale, which only increased whenmethaqualone was fully withdrawn from the U.S. market and classified aSchedule I drug.[11]: 203
Glutethimide's effect on quickening the conversion of codeine to morphine was studied clinically, including some research in the 1970s in various countries. In these studies, it was used under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, particularly as aSubstitutionmittel[clarification needed] that may be a useful alternative tomethadone.[12][13]
Glutethimide was available in the United States until 1993, when production ceased and it was withdrawn from the market. Since 2013, the U.S.DEA has limited annual production to three grams, equivalent to six Doriden tablets, suggesting that current use is limited to small-scale research.[citation needed]
Glutethimide is a Schedule II drug under theConvention on Psychotropic Substances.[14] It was originally a Schedule III drug in the United States under theControlled Substances Act, but in 1991 it was upgraded to Schedule II,[15] several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.[10][16] It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g.
