Non-barbiturate sedatives

Non-barbiturate sedatives like chloral hydrate, paraldehyde and glutethimide may be used. 

Methyprylon. Interestingly, the two piperidinediones viz., glutethimide and methyprylon and the quinazolone viz., methaqualone, are of vital importance within the context of non-barbiturate sedatives and hypnotics. However, glutethimide and methyl prylon possess a striking resem-blanee to barbiturates as given below ... 

Compounds which have been reported to induce microsomal enzymes include barbiturates and non-barbiturate sedatives, antihistaminics. analgesics, anti-inflammatory compounds, halogenated hydrocarbon insecticides, certain carcinogenic polycyclic hydrocarbons, and most recently, aromatic constituents of certain conifer woods. Based on differences in their profile of biologic effects, most of these agents can be placed into one of three general groups (1) the phenobarbital type, (2) the polycyclic hydrocarbon type and (3) anabolic steroids. 

Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, paraldehyde and urethane. It was not until the early years of this century that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. 

Etomidate, a non-barbiturate anesthetic, is considered to be safe, especially in patients with hemodynamic instability. The most common complications of using etomidate are venous sequelae, pain on injection (1), and involuntary muscle movements (SED-11, 211) (2). 

Chloral hydrate, paraldehyde, meprobamate and glutethimide cause sedation, but are neither benzodiazepines or barbiturates. Chloral hydrate is used most often for the sedation of children. It is reduced in the body to trichloroethanol, a potent ethanol. Like ethyl alcohol, the side effects of chloral hydrate include mucosal irritation, light-headedness, malaise and ataxia. Paraldehyde, meprobamate and glutethimide are seldom used and their mechanism of action is unknown. The non-barbiturate/non-benzodiazepine sedatives are not listed in a table. 

Fig. 3.1 Thalidomide was developed as a non-addictive sedative as an alternative to barbiturates. Following its administration to pregnant women, it was found that the babies were bom with truncated limbs (phocomeUa). At the time this was perceived as a classic case of the pharmacological activity residing in one enantiomer (R-) and the undesirable toxicological effect residing in the other enantiomer. The simation is now known to be much more complex than this (see text and reference cited therein).

The importance of producing pharmaceuticals in enantiomerically pure forms was brought to the public s attention with the thalidomide (Formula 4.2) tragedy in the early 1960s. Thalidomide, as a racemic mixture, was originally produced in 1953 as a sedative and a non-addictive alternative to barbiturates. It was later found that it alleviated many of the unpleasant symptoms of early pregnancy but by 1961 its use had been linked with an increase in the number of severe birth deformities and it was withdrawn. It... 

Barbiturate drugs like pentobarbital (Nembutal ), secobarbital (Seconal ), amobarbital (Amytal ), and phenobarbital are extremely potent sedatives that induce sleep, mostly non-REM sleep. However, barbiturates actually decrease the amount of REM sleep a person gets. Thus, if a person took a barbiturate as a sleep aid nightly for a week, the total amount of REM sleep would be significantly less than if he or she was not taking the drug. Then, when the person stopped taking the barbiturate, he or she would experience a severe REM... 

Since the synthesis of diethyl barbiturate, literally hundreds of barbiturates, and more recently nonbarbiturate sedatives, have been prepared. Most have been abandoned as not of sufficient merit to use clinically. About a dozen barbiturates are still used and half as many nonbarbiturate sedatives are described in the New and Non-Official Drugs or the United States Pharmacopeia (Figure 2). Most of these are used to some extent clinically. There is very little merit in retaining for use any more than these, since they represent the best agents for use in medicine. 

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