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.
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.
The active metabolite of ethinamate, 4-hydroxyethinamate is eliminated via urine, averaging around 2.5 hours upon ingestion and metabolization.
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 effects profile are likewise similar (Foye, 1974)
[Foye WO: Principles of Medicinal Chemistry, Lea & Febiger, Philadelphia, PA, 1974] 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 Porphyria in animals in vivo.
Antidote to toxicity, poisoning, overdose, or hypersensitivity
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.
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).[(product info, 1989)] Hypotension is a main symptom of severe overdose or ethinamate poisoning.
Treatment of adverse effects
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.
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.
[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.]
Accessibility and legality
Globally, ethinamate has mostly been replaced by
, and is no longer available in the
Netherlands,
Canada,
[10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.] nor in the
United States[10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262,] where it remains classified as a schedule IV substance .
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.
