Tranquilizers chlordiazepoxide

Valium (diazepam) is a widely prescribed tranquilizer. Chlordiazepoxide is a closely related compound. Phenobarbital (also see the model) is used to control epileptic seizures and as a sedative for insomnia and relief of anxiety. 

In 1960, the sedative, muscle-relaxing and anticonvulsant properties of 7-chloro-tV-methyl-5-phenyl-3//-l, 4-benzodiazcpin-2-amine 4-oxide ( chlordiazepoxide ) led to its introduction into clinical use as the active ingredient of the tranquilizer Librium . 

Some of the benzodiazepine group of tranquillizers and hypnotics, for example, chlordiazepoxide and nitrazepam, have been shown to be phototoxic [221],... 

A series of tranquilizers, drugs that relieve anxiety and nervous tension without impairing consciousness, have a benzene ring fused to a seven-membered ring containing two nitrogens. As a group they are called benzodiazepines. The two most successful are diazepam (Valium ) and chlordiazepoxide (Librium ) introduced in 1964 and 1960, respectively. Flurazepam (Dalmane ), first used in 1970, is a hypnotic. 

Oxazepam is similar to chlordiazepoxide in terms of pharmacological properties however, it has a somewhat less harsh effect, is less toxic, and exhibits a less expressed myorelax-ant effect. It is often tolerated better by patients than other tranquilizers. It is used in neurosis, conditions of anxiety, fear, stress, trouble falhng asleep, and psychovegatative disorders. The most common synonyms are nozepam and tazepam. 

Benzodiazepines are primarily used in medicine as tranquilizers. However, they also have been snccessfully used for epilepsy in controlling long-lasting convnlsions. The most widely nsed is diazepam (5.1.2) and chlordiazepoxide (5.1.22). The synthesis of these was described in Chapter 5. 

Only in the case of chlordiazepoxide can one speak in terms of goal-directed development here the intention was to find tranquillizing compounds in a new and patentable class of substances. In no case, however, was there a biochemical hypothesis concerning the illness or symptoms to be treated that would have led to the rational synthesis and development of appropriate pharmaceuticals. 

OFFICIAL NAMES Minor tranquilizers (sedative-hyp-notics/anxiolytics)/Benzodiazepines Alprazolam (Xanax) chlordiazepoxide (Librium, Novopoxide) clonazepam (Klonopin) clorazepate (Azene, Tranxene) diazepam (Valium) estazolam (ProSom) flunitrazepam (Rohypnol/illegal in the United States) flurazepam (Dalmane) halazepam (Paxipam) lorazepam (Ativan) midazolam (Versed) oxazepam (Serax) prazepam (Centrax) quazepam (Doral) temazepam (Restoril) triazolam (Halcion)... 

Most of the minor tranquilizers in the BZD exhibit similar clinical effects they differ primarily in their duration of action and in the dosage required to achieve the same effect. The BZDs are classified as short- (triazolam [Halcion]), intermediate- (alprazolam [Xanax] and lorazepam [Ativan]), and long-acting (chlordiazepoxide [Librium] and diazepam [Valium]). Of the various BZDs available in the United States in 2002, those primarily prescribed as anxiolytics and hypnotics include the intermediate- and long-acting variety. 

The most popular minor tranquilizers appeared in the 1960s =— a family of drugs called benzodiazepines. Some of the most famous are chlordiazepoxide (Lihrium), diazepam (Valium), flu-razepam (Dalmane), triazolam (Halcion), alprazolam (Xanax), and lorazepam (Ativan). The manufacturer of Librium and Valium, once a small company selling vitamins and antacids, is now one of the most powerful pharmaceutical corporations in the world. 

It turned out that the nearly discarded substance had a novel structure, 5, a chlordiazepoxide. It was developed further and became known under the trade name Librium , which was the first antianxiety agent. Librium became the lead compound for the development of many other compounds with related structures. The best known is the diazepam Vh/ium , 6, a tranquilizer used to treat anxiety, muscle spasm, and symptoms of epilepsy. Today, about 40 diazepines are in the market. Nearly forgotten on the laboratory shelf, Librium and Valium became blockbuster drugs that fueled the growth of the Roche company. (Drugs are called blockbusters when sales are much higher than US 1 billion per year.)... 

A family of CNS depressants that has gained wide acceptance and use in the medical community is the benzodiazepines. These drugs, also called the minor tranquilizers, have been developed over the past 30 years, starting with chlordiazepoxide (Librium ),... 

Clinically important, potentially hazardous interactions with alcohol, anticholinergics, barbiturates, benzodiazepines, butabarbital, chloral hydrate, chlordiazepoxide, chlorpromazine, clonazepam, clorazepate, diazepam, ethchlorvynol, fluphenazine, flurazepam, hypnotics, lorazepam, MAO inhibitors, mephobarbital, mesoridazine, midazolam, narcotics, oxazepam, pentobarbital, phenobarbital, phenothiazines, phenylbutazone, primidone, prochlorperazine, promethazine, quazepam, secobarbital, sedatives, temazepam, thioridazine, tranquilizers, trifluoperazine, zolpidem... 

Several of the most-used benzodiazepine tranquillizers seem to act as the metabolic product, nordazepam (3.47), which has the full therapeutic action of the starting materials, and acts faster. Thus diazepam (12.95) ( Valium ) loses 1-Me, chlordiazepoxide ( Librium ) loses 4-0 and hydrolyses 2-MeNH- to=0, whereas clorazepate ( Tranxene ) loses 4-CO2, and in each case nordazepam is the product. While the latter is available for prescribing, clinical experience with the pro-drugs is greater moreover they have very different pharmacokinetics, diazepam being absorbed quickly and chlordiazepoxide slowly from the gastrointestinal tract. See further Section 12.7 Garattini, Mussini and Randall (1973), Nicholson a/. (1976), and Hollister (1978). 

The second major class of depressants is the benzodiazepines. The familiar tranquilizers Librium (chlordiazepoxide) and Valium (diazepam) are members of this group. Both the barbiturates and the benzodiazepines... 

Benzodiazepines, therapeutically used as tranquillizers, hypnotics, anticonvulsants, and centrally acting muscle relaxants, rank among the most frequently prescribed drugs. In 1960, the first benzodiazepine, chlordiazepoxide, was introduced. To date, more than 50 benzodiazepines have been marketed in over 100 different preparations. They appear mainly as capsules and tablets, however, some are marketed in other forms such injectable solutions or powders. Benzodiazepines were introduced to replace barbiturates and methaqualone as tranquillizers, hypnotics, anticonvulsants, and muscle relaxants. Currently there are 33 benzodiazepines on the control list all of which appear as tablets or capsules, though some also appear as vials or powders for preparation of injection (Figure 7). 

Po and Irwin (1979) used TLC to separate numerous tricyclic neuroleptic tranquilizers. Samples were dissolved in ethyl acetate, and the mobile phase consisted of mixtures of different n-alcohols with water. Circular development in a Camag U chamber was used, and spots were detected by fluorescence quenching. The /Jp values of some of the better known drugs developed in methanol-water (90 10) were amitriptyline, 0.17 clopenthixol, 0.40 doxepin, 0.42 nortriptyline, 0.37 and promazine, 0.14. Shirke et al. (1994) determined amitriptyline and chlordiazepoxide in combined dosage forms using ethyl acetate-methanol-dieth-ylamine (9.5 0.5 0.05) mobile phase and scanning at 245 nm. 

Benzodiazepine-derivative tranquilizers are widely prescribed in the United States. Chlordiazepoxide (Librium) is a commonly prescribed antianxiety (tran-... 

TLC methods for the separation of various benzodiazepine tranquilizers have been reported. Thus, Okumura and Nagaoka (1979) separated various benzodiazepines in methanol-water (2 1 or 3 1), and spots were detected by fluorescence quenching. Tranquilizers and their metabolites have been chromatographed on Whatman HP-KF plates (Whatman Technical Series, Volume 2). Samples prepared in methanol were separated in the mobile phase ethyl acetate-methanol (95 5) spots were detected by fluorescence quenching under 254-nm ultraviolet (UV) light the compounds along with their values were n-desmethycheordiazepoxide, 0.11 chlordiazepoxide, 0.21 demoxepam, 0.38 oxazepam, 0.45 and diazepam, 0.60. 

Doxepin, (21) previously studied as an antidepressant, proved effective as a tranquilizer in a double blind comparison with chlordiazepoxide ... 

Chlordiazepoxide, tranquilizer. Rat. Phenyl ring hydroxylation followed by demethylation (M), and deamination N-oxlde reduction. Metabolites free or conj. Urinary recovery, 30% of dose. 

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