Depressants Chlordiazepoxide

Figure 19.4 The activity spectrum of the benzodiazepines. Motor impairment and CNS depression increases with drug dose. (Based on data for chlordiazepoxide (Sternbach, Randall and Gustafson 1964))...

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. 

Anxiety For the management of anxiety disorders or for the short-term relief of the symptoms of anxiety (anxiety associated with depression is also responsive) (alprazolam immediate-release and intensol, clorazepate, chlordiazepoxide, diazepam, lorazepam, oxazepam) for the management of anxiety, tension, agitation, and irritability in older patients (oxazepam). 

The CNS depressants include barbiturates, nonbarbiturate sedatives, and the benzodiazepines. As the medical use of barbiturates decreased, primarily because of their high addiction liability and the danger of acute lethality, the use of the benzodiazepine anxiolytics increased. The most commonly abused barbiturates are secobarbital, pentobarbital, and amobarbital. Pheno-barbital is not generally abused, because of its slow onset of action. The most commonly abused anxiolytics include diazepam, chlordiazepoxide, midazolam, lo-razepam, and flurazepam. These drugs are readily attainable from illicit sources. 

Kahn RJ, McNair DM, Lipman RS, et al. Imipramine and chlordiazepoxide in depressive and anxiety disorders 2. Efficacy in anxious outpatients. Arch Gen Psychiatry 1986 43 79-85. 

Benzodiazepines exert central depressant effects on spinal reflexes, in part mediated by the brainstem reticular system.3 For example, chlordiazepoxide depresses the duration of electrical after-discharge in the limbic system. Most benzodiazepines elevate the seizure threshold and therefore may be used as anticonvulsant medications. Diazepam, clonazepam, and clorazepate may be prescribed for this therapeutic purpose. 

The treatment of patients during a delirium tremens episode includes the intravenous administration of another CNS depressant (usually diazepam) during the acute phase, followed by the oral administration of chlordiazepoxide or oxazepam. In addition, other medications and dietary management may become essential. 

The coat state assessment is a fast and simple qualitative method of assessing mouse depression-like states through observation of the condition of an animal s fur. In rodents, coat state tends to decline with increased depression, similar to depressed patients who frequently exhibit poor hygiene (29-31). Antidepressants have been shown to improve the coat condition of mice while reducing depression-like symptoms (29-31). For example, the reduction of corticotropin-releasing factor (CRF) has been associated with improved coat state (and is implicated in depression) (32). Of importance here, antidepressants (e.g., imipramine) and anxiolytics (e.g., chlordiazepoxide) have been shown to interact with corticotropin-releasing factor (33) (see Note 7). 

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. 

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. 

Central nervous system depressants include the barbiturates, such as phenobarbital, and the antianxiety drugs, including diazepam (VaUum), chlordiazepoxide Odbrium), oxazepam (Serax), flurazepam hydrochloride (Dalmane), and lorazepam (Ativan). The benzodiazepines, including diazepam, occasionally cause mydriasis, presumably because of their anticholinergic side effects. 

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 ),... 

Amitriptyline blocks reuptake of serotonin and norepinephrine in CNS. Chlordiazepoxide potentiates effects of GABA in CNS. The combination is indicated in the treatment of moderate to severe depression associated with moderate to severe anxiety. 

As with chlordiazepoxide, the dosage of diazepam should be lower in the elderly (initial dose, about half the usual), not only because of the pharmacokinetic differences but also because accumulation of the parent drug and active metabolites is more likely to lead to confusion and muscle weakness in the elderly. Furthermore, the elderly seem to be more sensitive to the depressant effects of diazepam than are younger patients. 

Occasional Confusion amnesia disinhibition paradoxical excitement depression dizziness witiidrawal symptoms, including convulsions, on abrupt discontinuance (witiidrawal may be especially difficult with alprazolam) rebound insomnia or excitement Rare Hypotension blood dyscrasias jaundice allergic reactions paradoxical rage reactions stuttering with alprazolam BUPROPION, Anxiety agitation insomnia tremor anorexia BUSPIRONE, Dizziness headache nausea paresthesias diarrhea CHLORDIAZEPOXIDE, see Benzodiazepines CHLORPROMAZINE, see Phenothiazines, aliphatic CHLORPROTHIXENE, similar to Phenothiazines CLOMIPRAMINE, see Tricyclic antidepressants CLORAZEPATE, see Benzodiazepines CLOZAPINE... 

Perhaps the most common drugs based on 7-membered rings are the benzodiazepines. Different benzodiazepines have been used for the treatment of seizures, insomnia, depression, or anxiety. Examples of benzodiazepines include alprazolam (XANAX, Pfizer, Inc.), chlordiazepoxide (LIBRIUM, Hoffman-LaRoche, Inc.), diazepam (VALIUM, Roche Laboratories), and lorazepam (ATIVAN, Biovail Pharmaceuticals, Inc.). 

As with depression, those who are battling or have battled cancer sometimes report feelings of anxiousness that may also respond to medications. Benzodiazepines (BZs) are one class of drugs used in the treatment of anxiety and insomnia. Unlike antidepressants, they work almost immediately. The drugs include lorazepam (Ativan), alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), chlordiazepoxide (Librium) and triazolam (Halcion). Some people do become dependent upon BZs, but the drugs are generally safe... 

Boston Collaborative Drug Surveillance Program. Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. N EnglJMed( 973) 288, 277-80. 

A patient with depression responded well when given phenelzine 15 mg and chlordiazepoxide 10 mg three times a day, but 4 to 5 months later developed choreiform movements of moderate severity, and slight dysarthria. These symptoms subsided when both drugs were withdrawn. ... 

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