Chlordiazepoxide properties

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 . 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

It was conclusively shown that deoxychlordiazepoxide (393) had none of the phototoxic properties of the parent drug, at least in the rat [225]. Chlordiazepoxide, demethylchlordiazepoxide, demoxepam and diazepam-4-oxide were all phototoxic to a bacterial cell preparation. There was a close relationship between the phototoxicities of the A-oxides and the toxicity in the dark of their oxaziridines. The reduced forms of the four compounds were not phototoxic [ 228 ]. Kinetic studies demonstrated that the oxaziridine (390) covalently bonds to plasma proteins. The half-life of the oxaziridine in the presence of high concentrations of protein was about 30 min. It therefore has time not only to bind to biomolecules in the skin surface, but also to attack internal organs. This was put forward as the explanation of previously observed kidney and liver damage in the rat [229]. 

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. 

The benzodiazepines constitute the most commonly used group of anxiolytics and sedative-hypnotics. Since the first member of this group, chlordiazepoxide, was introduced, many congeners have been marketed. Most of these drugs possess anxiolytic, sedative-hypnotic, and anticonvulsant properties. Thus, the clinical indications for specific benzodiazepines are not absolute, and their uses overlaps considerably. 

B. Chlordiazepoxide, through its metabolites, has a relatively long biological half-life. It will prevent many of the severe symptoms of acute alcohol withdrawal. Buspirone is not a sedative and will not suppress alcohol withdrawal. The other agents have sedative properties and could potentially suppress alcohol withdrawal but each has a much shorter biological half-life than chlordiazepoxide. 

Amitriptyline (Elavil), chlordiazepoxide-amitriptyline (Limbitrol), and perphenazine-amitriptyline (Triavil) Because of its strong anticholinergic and sedation properties, amitriptyline is rarely the antidepressant of choice for elderly patients. High... 

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. 

This fivefold clinical activity is possessed, to a greater or lesser extent, by all benzodiazepines in current clinical use. The properties of benzodiazepines make them ideally useful for managing anxiety (e.g. diazepam, chlordiazepoxide, lorazepam) insomnia (e.g. diazepam, temazepam, nitrazepam, loprazolam, flurazepam, lormetazepam) epilepsy (e.g. clobazam, diazepam, lorazepam) sports injuries where muscle relaxation is required (e.g. diazepam) and as premedications prior to surgery (e.g. midazolam, lorazepam). The benzodiazepines have a number of other uses, including management of alcohol withdrawal syndrome (chlordiazepoxide, diazepam) and restless legs (clonazepam). Short... 

The introduction of chlordiazepoxide (Librium) into clinical medicine in 1961 ushered in the era of benzodiazepines. Most of the benzodiazepines that have reached the marketplace were selected for their effectiveness as antianxiety agents, not for their ability to depress CNS function. However, all benzodiazepines possess sedative-hypnotic properties to varying degrees these properties are extensively exploited clinically, especially to facilitate sleep and ease anxiety. Mainly because of their remarkably low capacity to lead to fatal suppression of key CNS functions, the benzodiazepines have displaced barbiturates as sedative-hypnotic agents. 

The antianxiety effects of chlordiazepoxide (165) were described in 1960 and this compound was followed by diazepam (135). These two drugs have captured 75% of the market for sedatives in the USA. Other benzodiazepines used as antianxiety agents include oxazepam (166 R = H), a metabolite of diazepam that is better tolerated, lorazepam (166 R = Cl) and potassium clorazepate (167). Prazepam is the iV-cyclopropylmethyl analogue of diazepam. The benzodiazepines have other therapeutic applications, many being used for inducing sleep, diazepam and nitrazepam are anticonvulsants and flurazepam (168) is both an antianxiety agent and a potent hypnotic. Thieno- and pyrazolo-1,4-diazepinones isosteric with diazepam have similar pharmacological properties (B-81 Ml 10604). 

The benzodiazepines are a group of chemically related drugs, the best-known members of which are chlordiazepoxide (Librium ) and diazepam (Valium ). There are many others with variations in properties, particularly onset of effects and duration of action. The most recognized effects of the benzodiazepines are centrally mediated and include sedation, hypnosis, decrease in anxiety, muscle relaxation and anticonvulsant effects. 

According to the chemical structure, the anxiolytic agents used in allopathic medicine may be divided into three classes carbamate of propanodiol and related compounds, BZDs and several others compounds. The most effective are the BDZs Chlordiazepoxide, Fig. (3), which was commercialized in 1960 as a therapeutic innovation for the treatment of anxiety. As from the identification of its property, dozens of new BDZs derivates were commercialized, including diazepam. Fig. (3), one of the medicines most prescribed worldwide. 

Currie reported that 7-chloro-2-methylamino-5-phenyl-3//-benzo-l,4 diazepine-4-oxide hydrochloride (methaminodiazepoxide hydrochloride, chlordiazepoxide hydrochloride. Librium), possesses oedema inhibitory, anti-inflammatory and analgesic effects in rats similar to those of compounds such as amidopyrine and phenylbutazone. In view of these results, the compound was subjected to clinical trial in rheumatoid arthritis and was found to have neither antirheumatic nor analgesic properties in doses up to 200 mg daily. 

Chlordiazepoxide turned out to have rather remarkable pharmacological properties and tremendous potential as a pharmacotherapeutic product, but it possessed a number of unacceptable physical chemical properties. In an effort to enhance its pharmaceutical elegance, structural modifications of chlordiazepoxide were undertaken that eventually led to the synthesis of diazepam in 1 959. In contrast to the maxim that basic groups impart biological... 

Flurazepam is administered orally as the dihydrochloride salt. It is rapidly N-dealkylated to give the 2 -fluoro derivative of N-desmethyIdiazepam, and it subsequently follows the same metabolic pathways as chlordiazepoxide and diazepam (Fig. 22.18). The half-life of flurazepam is fairly long ( 7 hours) consequently, it has the same potential as chlordiazepoxide and diazepam to produce cumulative clinical effects and side effects (e.g., excessive sedation) and residual pharmacological activity, even after discontinuation. Chlorazepate is yet another benzodiazepine that is rapidly metabolized (3-decarboxylation) to N-desmethyIdiazepam and so shares similar clinical and pharmacokinetic properties to chlordiazepoxide and diazepam. 

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