Clorazepate

Clorazepate (9) is a prodmg of the antiepileptic agent, desmethyldiazepam [1088-11-5] C23H22CIN2O (43) that can also be formed from... 

Clorazepate dIpotassium Cycrimine HCI Diphemanil methyl sulfate Feno profen Medazepam Procyclidine HCI Tamoxifen Tiemonium iodide 4-Bromobenzyl cyanide... 

As with the barbiturates, the most common adverse reaction seen with the use of clonazepam (Klonopin), clorazepate (Tranxene), and diazepam (Valium) is sedation in varying degrees. Additional adverse effects may include anorexia, constipation, or diarrhea. Some adverse reactions are dose dependent, whereas others may diminish in intensity or cause few problems after several weeks of therapy. 

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

Benzodiazepines have a low risk for abuse in anxiety disorder patients without a history of alcohol or other substance abuse. Among the benzodiazepines there may be a spectrum of abuse liability, with drugs that serve as prodrugs for desmethyldiazepam (e.g., clorazepate), slow-onset agents (e.g., oxazepam), and partial agonists (e.g., abecarnil) having the least potential for abuse. However, there is no currently marketed benzodiazepine or related drug that is free of potential for abuse. 

Greenblatt DJ, Shader RI, Harmatz JS, et al Self-rated sedation and plasma concentrations of desmethyldiazepam following single doses of clorazepate. Psychopharmacology (Berl) 66 289-290, 1979... 

Diarrheal conditions may decrease drug absorption as a result of reduced intestinal residence time. The absorption of several drugs was decreased in response to lactose- and saline-induced diarrhea [145]. Digoxin absorption from tablets was impaired in one subject who developed chronic diarrhea as a result of x-ray treatment [146]. Abdominal radiation or the underlying disease has been shown to reduce digoxin and clorazepate absorption [147]. A dosage form that provides rapid drug dissolution (e.g., solution) may partially resolve this problem. 

Diazepam and clorazepate have high lipophilicity and are rapidly absorbed and distributed into the CNS. They have a shorter duration of effect after a single dose than would be predicted on the basis of half-life, as they are rapidly distributed to the periphery. 

Clorazepate, a prodrug, is converted to desmethyldiazepam in the stomach through a pH-dependent process that may be impaired by concurrent antacid use. Several other BZs are also converted to desmethyldiazepam, which has a long half-life and can accumulate, especially in the elderly and those with impaired oxidation. 

Signs and symptoms of BZ withdrawal are similar to those of alcohol withdrawal, including muscle pain, anxiety, restlessness, confusion, irritability, hallucinations, delirium, seizures, and cardiovascular collapse. Withdrawal from short-acting BZs (e.g., oxazepam, lorazepani, alprazolam) has an onset within 12 to 24 hours of the last dose. Diazepam, chlordiazep-oxide, and clorazepate have elimination half-lives (or active metabolites with elimination half-lives) of 24 to greater than 100 hours. So, withdrawal may be delayed for several days after their discontinuation. 

Clorazepate Tranxene Oral Long 15-60 Anxiety disorders, alcohol withdrawal... 

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