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Ethinamate

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Ethinamate
Clinical data
Trade namesValmid, Valamin
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • C
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Elimination half-life2.5 hours
Identifiers
  • (1-ethynylcyclohexyl)carbamate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.355 Edit this at Wikidata
Chemical and physical data
FormulaC9H13NO2
Molar mass167.208 g·mol−1
3D model (JSmol)
  • O=C(OC1(C#C)CCCCC1)N
  • InChI=1S/C9H13NO2/c1-2-9(12-8(10)11)6-4-3-5-7-9/h1H,3-7H2,(H2,10,11) checkY
  • Key:GXRZIMHKGDIBEW-UHFFFAOYSA-N checkY
  (verify)

Ethinamate is a short-acting carbamate derivative used as a sedative-hypnotic central nervous system depressant, and medication for short-term treating insomnia. Regular use leads to drug tolerance, however, and it is usually not effective for more than seven days. Prolonged use can lead to dependence.[2] The brand name formulation, Valmid, was produced by Delta Pharmacy, in tablet dosage form, although later with usage generally directed as 500 mg to 1,000 mg at night (1-2 tablets). In contrast to barbiturates, ethinamate has a wide range of toxicity; users have suffered fatal overdose and respiratory depression upon ingesting fifteen grams (15,000 mg); other users have consumed as much as 28 grams (28,000 mg) and survived after awaking from a deep coma.[3]

Ethinamate is an odorless, white powder upon manufacture; in the United States, Canada, and much of Europe. A typical prescription dose was one 500 mg tablet or capsule at bedtime, although some patients would up their dosage to two tablets for a total of 1,000 mg (J. Reynolds, 1989). Reynolds further submits that children are more likely than adults to experience paradoxical effects, and the drug is therefore not indicated, or approved for, use in persons under age 18. The usual prescribed dose (only approved for adults) is 500 milligrams (one tablet) at bedtime, although users may take two tablets (1,000 mg / 1 gram) if necessary.[4]

The active metabolite of ethinamate, 4-hydroxyethinamate is eliminated via urine, averaging around 2.5 hours upon ingestion and metabolization.[2]

Side effect profile and toxicity

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Adverse effects typically relate to CNS depression, such as slow heart rate, shallow breathing, and low blood pressure. Ethinimate is of similar toxicity to any barbiturate, and has been described by Foye (1974) as a "barbiturate-like" agent, although fatality is less likely to occur; rather, loss of consciousness due to respiratory depression and severe hypotension is more likely to leave the patient comatose. Foye (1974) has described ethinamate as "barbiturate-like" with regard to in overall slowing of the central nervous system, and the risk and adverse effects profile are likewise similar (Foye, 1974)[5] Even at therapeutic doses, vomiting, nausea, gastrointestinal upset, and skin rash are fairly common side effects.

Thrombocytopenia purpura and fever have been noted specifically as a hypersensitivity reaction, as well as severe and varied skin rashes. Ethinamate is porphyrinogenic in animals in vivo.

Antidote to toxicity, poisoning, overdose, or hypersensitivity

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Thrombocytopenia purpura and fever have been noted as a hypersensitivity reaction, and it is classified as pregnancy Category C, not recommend for use in pregnant or breastfeeding women for lack of evidence confirming or disproving any teratogenic effect.

In cases of severe overdose or ethinamate poisoning, the primary symptom will be severely low blood pressure (hypotensive crisis), and respiratory depression similar to that seen with barbiturates, potentially capable of inducing a comatose state.[6]

As a remedy to overdose or ethinamate poisoning, activated charcoal may be effective in doses between 25 grams to 100 grams, 25 to 50 g in children under 12, and 1 g/kg in infants less than 1 year old. Respiratory depression similar to that seen with barbiturates would be expected in overdose (Davis et al, 1959).[7] Hypotension is a main symptom of severe overdose or ethinamate poisoning.

Treatment of adverse effects

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Reynolds (1989) asserted that hemodialysis may be of value in treating severe poisoning, while nothing that "severe poisoning" in the context of ethinamate's therapeutic index is not generally lethal, as opposed to barbiturates. In doses up to 1 gram (10,000 mg), patients generally survive, albeit may be comatose for a few days and suffer severe sleep inertia and hangover=like effects upon waking. At 1.5 grams, there have been at least a few patients who have fatally overdosed.[8] In 1958, a patient was reported to have ingested 2.8 grams (28,000 mg) of the substance, and survived, albeit spending 24 hours comatose.[9]

Accessibility and legality

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Globally, ethinamate has mostly been replaced by benzodiazepines, and is no longer available in the Netherlands, Canada,[10] nor in the United States[11] where it remains classified as a schedule IV substance .[12]

Synthesis

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Ethinamate (1-ethynylcyclohexanone carbamate) is synthesized by combining acetylene with cyclohexanone to make 1-ethynylcyclohexanol, and then transforming this into a carbamate by the subsequent reaction with phosgene, and later with ammonia. Some lithium metal or similar is used to make the acetylene react with the cyclohexanone in the first step.[13][14]

References

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  1. ^ Anvisa (31 March 2023). "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 3 August 2023. Retrieved 16 August 2023.
  2. ^ a b "Ethinamate (Valmid, Valamin): Overview". PubChem. Retrieved 2 May 2025.
  3. ^ "Ethinamate, an Overview". JOdrugs.com. Retrieved 2024-04-25.
  4. ^ Reynolds, Jeffrey (13 July 1989). "VALAMIN for sleep onset disorder". Science Journal of Nebraska U. pp. 44–46. {{cite web}}: |access-date= requires |url= (help); Missing or empty |url= (help)
  5. ^ Foye WO: Principles of Medicinal Chemistry, Lea & Febiger, Philadelphia, PA, 1974
  6. ^ Foye, Wilbur (September 16, 1974). "Barbiturate-like" for all intents and purposes: the carbamate ethinamate. Journal Science. p. 4.
  7. ^ (product info, 1989)
  8. ^ Reynolds, James R (2016). "Ethinamate: Overview of Effects". Nebraska University Science Journal. {{cite journal}}: |access-date= requires |url= (help)
  9. ^ Davis RP, Blythe WB, & Newtgon M: The treatment of intoxication with ethynyl-cyclohexyl carbamate (Valmid) by extracorporeal hemodialysis: a case report. Yale J Biol Med 1959; 32:192-196.
  10. ^ 10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
  11. ^ 10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262,
  12. ^ Lowry WT, Garriot JC (1979). "Ethinamate". Forensic Toxicology: Controlled Substances and Dangerous Drugs. Boston, MA: Springer US. p. 215. ISBN 978-1-4684-3444-6.
  13. ^ US 2816910, Pfeiffer H, Junkman K, "Esters of carbamic acid and a method of making same", issued 17 December 1957, assigned to Schering AG 
  14. ^ DE 1021843, Emde H, Grimme W, "Verfahren zur Herstellung des Allophanats des 1-AEthinylcyclohexanols-(1)", issued 2 January 1958, assigned to Rheinpreussen AG 
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