Ethinamate

Ethinamate (primarily marketed and sold under the trade names Valmid or Valamin) is a short-acting carbamate derivative and central nervous system depressant drug with sedative-hypnotic properties, commonly prescribed in the latter twentieth century for the short-term treatment of insomnia as an alternative to tranquilizers of the barbiturate chemical class. Regular and prolonged use of ethinamate will result in drug tolerance, and with prolonged use or misuse, psychological or physical dependence; ethinamate rarely effectively promotes sleep onset after seven consecutive days of use.^[3]

The branded product, Valmid, was once United States and United Kingdom; Valamin was a brand in many European, Eurasian, and Asian countries (e.g. Russia). Valmid was manufactured, patented, and marketed by Dista Products Limited, which is now a division of Eli Lilly; it came in the dosage form of a "pill" (tablet) containing 500 mg of ethinamate, which the typical prescribed dose (one pill, or 500nbsp;mg), although in severe cases of insomnia, two pills (1,000 mg) may be prescribed. Unlike barbiturates, ethinamate has a wide range of toxicity, with fatal overdose very (due to respiratory depression) being extremely uncommon. One case of fatal overdose resulted from a user ingesting 15,000 mg (fifteen grams, equivalent to thirty pills/a whole bottle); another user, conversely, consumed upwards of 28,000 mg (28 grams) and went into a deep coma, but ultimately awoke.^[4]

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.^[5] Ethinamate produces the active metabolite, 4-hydroxyethinamate, which is eliminated via urine after an average of 2.5 hours post-ingestion.^[3]

Adverse effects typically relate to CNS depression and manifest as slow heart rate, shallow breathing, and low blood pressure. Ethinimate is toxic in overdose, but is more likely to result in loss of consciousness and a comatose state than it is to result in fatality, according to Foye (1974) who has described ethinamate as "barbiturate-like" in terms of its effects^[6] Even at therapeutic doses, vomiting, nausea, gastrointestinal upset, and skin rash are fairly common side effects.

Hypersensitive reactions often include thrombocytopenia purpura and fever, often alongside severe and varied skin rashes. Ethinamate is porphyrinogenic in animals in vivo, and in humans is classified as pregnancy Category C, meaning it is not recommended for use in pregnant or breastfeeding women due to lack of evidence disproving any teratogenic effect in humans. 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.^[7]

As a remedy to ethinamate poisoning or overdose, 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).^[8] Reynolds (1989) asserted that hemodialysis may be of value in treating severe poisoning, while noting that "severe poisoning" in the context of ethinamate's therapeutic index is not generally lethal. In doses up to 1 gram, patients generally survive, albeit risk a comatose state which can last for several days, typically by 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.^[9] 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.^[10]

Globally, ethinamate has mostly been replaced by benzodiazepines, and is no longer available in the Netherlands, Canada,^[11] nor in the United States^[12] where it remains classified as a schedule IV substance .^[13]

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.^[14][15]