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Ethinamate

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Ethinamate
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • C
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
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 (Valamin, Valmid) is a short-acting carbamate derivative used as a sedative-hypnotic medication for treating insomnia. Regular use leads to drug tolerance, and it is usually not effective for more than seven days. Prolonged use can lead to dependence.[citation needed] The brand name formulation, Valmid, was produced by Dertra Products, in tablet dosage form, with usage generally directed as 500 mg to 1,000 mg at night (1-2 tablets) (Reynold, 1989). Reynolds (1989) notes that, 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.[2]

Ethinamate is an odorless, white powder upon manufacture and is pressed into tablet dosage form comprising 500 mg of the active ingredient. Prescribed doses were typically one 500 mg tablet at bedtime, although two tablets for a total of 1,000 mg (1 gram) was not uncommon (J. Reynolds, 1989). Reynold further notes that children are more likely than adults to experience paradoxical excitement, and the drug is therefore not indicated 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.[3]

Side effect profile and toxicity

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 efffects profile are likewise similar (Foye, 1974)[4]

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.

In case of poisoning or overdose

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.[5]

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).[6] Hypotension is a main symptom of severe overdose or ethinamate poisoning.

Active metabolite

4-hydroxyethinamate is found in the urine.

Treatment of adverse effects

Hemodialysis may be of some value in the treatment of severe poisoning, according to Reynolds (1989), though Reynolds conceded the therapeutic index of ethinamate relative to barbiturates is vast, and that even in doses of 10,000 mg (1 gram), patients generally survive, albeit with a hangover, sleep inertia, and/or going comatose for a day. 15,000 mg is the threshold at which multiple patients have fatally overdosed (Reynolds, 1989, citing Davis et al, 1959). One patient prior to 1959 was reported to have ingested 28,000 mg and survived, despite briefly entering a comatose state.[7]

Accessibility and legality

Ethinamate has been replaced by other medicines (particularly benzodiazepines), and it is not available in the Netherlands, the United States or Canada.[8]

It is a schedule IV substance in the United States.[9]

Synthesis

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.[10][11]

References

  1. ^ 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.
  2. ^ "Ethinamate, an Overview". JOdrugs.com. Retrieved 2024-04-25.
  3. ^ Reynolds, Jeffrey (July 13, 1989). "VALAMIN for sleep onset disorder". Science Journal of Nebraska U (239): 44–46. {{cite journal}}: |access-date= requires |url= (help)
  4. ^ Foye WO: Principles of Medicinal Chemistry, Lea & Febiger, Philadelphia, PA, 1974
  5. ^ Foye, Wilbur (September 16, 1974). "Barbiturate-like" for all intents and purposes: the carbamate ethinamate. Journal Science. p. 4.
  6. ^ (product info, 1989)
  7. ^ 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.
  8. ^ 10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
  9. ^ 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.
  10. ^ US 2816910, Pfeiffer H, Junkman K, "Esters of carbamic acid and a method of making same", issued 17 December 1957, assigned to Schering AG 
  11. ^ 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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