Hexobarbital hypnotic activity

The S enantiomer of hexobarbital possesses three- to fourfold greater hypnotic activity than its antipode (4). However, in the elderly population, the clearance of R-hexobarbital, but not that of S-hexobarbital, is substantially reduced (23). Administration of the S enantiomer, therefore, will produce a more predictable clearance than that of the racemate. Also, as the safety profile of the less active enanticaner is unknown, one cannot rule out the possibility of its involvement in the overall toxicity of hexobarbital. For a related barbiturate, pentobarbital, it has been suggested that despite its weaker pharmacological activities, sedation with the R enantiomer is accompanied by symptrans of hyperexcitability (24). 

Hypnotics fall into different categories, including the benzodiazepines (e.g., triazolam, temazepam, clotiaze-pam, nitrazepam), barbiturates (e.g., hexobarbital, pentobarbital), chloral hydrate, and Hi-antihistamines with sedative activity (p. 114). Benzodiazepines act at specific receptors (p. 226). The site and mechanism of action of barbiturates, antihistamines, and chloral hydrate are incompletely understood. 

In a detailed study of a pyrrolo-pyrimidine, BW 58-271 (VI), Norton and Jewett found that the compound was a potent hypnotic agent (three times as active as hexobarbital). It also had local anesthetic and hypotensive activity. Its most unusual effect was sudden suppression of the EEC in conscious cats lasting for several minutes after intravenous injection. 

The kinetics of excretion are a direct consequence of the kinetics of metabolic transformations. The faster a drug is metabolized, the faster its elimination can be expected. In accordance with this assertion, rats given R,S( ), S(+), and R(-)-amphetamine, were found to excrete less (+)-p-hydroxy-amphetamine than its (-)-isomer this may be the basic explanation of the more pronounced pharmacological properties of the dextro-, compared to the levoampheta-mine. For the hypnotic agent hexobarbital, the ehmination half-life in man is about three limes longer for the more active (-l-)-isomer then for the less active ( )-isomer. This was attributed to a difference in hepatic metabolic clearance and not in volumes of distribulion or plasma binding between the enantiomers. " ... 

More than two hundred pharmacologically unrelated compounds, when administered to animals enhance the activity of oxidative microsomal en mes and thus alter the duration and the intensity of drug action. For example, treatment of animals with phenobarbital decreases the hypnotic effect of subsequently administered hexobarbital. the muscle relaxant effect of zoxazolamine. the anticonvulsant activity of diphenylhydantoin, or the anticoagulant effect of bishydnn coumarin. This effect is blocked by co-administration of inhibitors of protein synthesis such as puromycin and actinomydn-D and is thought to result from de novo en me synthesis. Indeed, addition of the foreign compounds to microsomes in vitro does not increase enzyme activity and thus, activation of pre-existing enzyme can be ruled out. 

In the early 19S0 s, a compound was described which, though devoid of significant pharmacologic activity itself, has the ability to markedly prolong the action of many other drugs. For example, when administered shortly before a hypnotic dose of hexobarbital, the compound 2-diethylaminoethyl-2,2-diphenyl-... 

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