For chemical reasons that are easily rationalized, few aldehydes are valuable hypnotic drugs. The aldehyde in use, chloral (as the hydrate), is thought to act principally through a metabolite, trichloroethanol. Acetaldehyde is used as the cyclic trimer derivative, paraldehyde, which could also be grouped as a cyclic polyether.
Chloral Hydrate, USP. Chloral hydrate, trichloroac-etaldehyde monohydrate, CCl3CH(OH)2 (Noctec), is an aldehyde hydrate stable enough to be isolated. The relative stability of this gem-diol is largely a result of an unfavorable dipole-dipole repulsion between the trichloromethyl carbon and the carbonyl carbon present in the parent carbonyl compound.20
Chloral hydrate is unstable in alkaline solutions, undergoing the last step of the haloform reaction to yield chloroform and formate ion. In hydroalcoholic solutions, it forms the hemiacetal with ethanol. Whether or not this compound is the basis for the notorious and potentially lethal effect of
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Figure 12.4 • Reaction and metabolism of chloral.
the combination of ethanol and chloral hydrate (the "Mickey Finn") is controversial. Synergism between two different CNS depressants also could be involved. Additionally, ethanol, by increasing the concentration of nicotinamide adenine dinucleotide (NADH), enhances the reduction of chloral to the more active metabolite trichloroethanol, and chloral can inhibit the metabolism of alcohol because it inhibits alcohol dehydrogenase. Chloral hydrate is a weak acid because its CCl3 group is very strong electron withdrawing. A 10% aqueous solution of chloral hydrate has pH 3.5 to 4.4, which makes it irritating to mucous membranes in the stomach. As a result, GI upset commonly occurs for the drug if undiluted or taken on an empty stomach. Chloral hydrate as a capsule, syrup, or suppository is currently available. Although it is suggested that chloral hydrate per se may act as a hypnotic,21 chloral hydrate is very quickly converted to trichloroethanol, which is generally assumed to account for almost all of the hypnotic effect. The trichloroethanol is metabolized by oxidation to chloral and then to the inactive metabolite, trichloracetic acid (see Fig. 12.4), which is also extensively metabolized to acylglu-curonides via conjugation with glucuronic acid. It appears to have potent barbiturate-like binding to GABAa receptors. Although an old drug, it still finds use as a sedative in non-operating room procedures for the pediatric patient.
Paraldehyde, USP. Paraldehyde, 2,4,6-trimethyl-s-trioxane, paracetaldehyde, is recognizable as the cyclic trimer of acetaldehyde. It is a liquid with a strong characteristic odor detectable in the expired air and an unpleasant taste. These properties limit its use almost exclusively to an institutional setting (e.g., in the treatment of delirium tremens). In the past, when containers were opened and air admitted and then reclosed and allowed to stand, fatalities occurred because of oxidation of paraldehyde to glacial acetic acid.
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