Clorazepate dependence

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. 

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. 

The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration. 

The drugs in Schedule IV have a relatively low abuse potential and risk for psychological or physical dependence relative to those listed in Schedule in and include such drugs as barbital, phenobarbital, methylphe-nobarbital, chloral betaine (Beta Chlor), chloral hydrate, ethchlorvynol (Placidyl), ethinamate (Valmid), meprobamate (Equanil, Miltown), paraldehyde, methohexital, fenfluramine, diethyipropion, phentermine, chlor-diazepoxide (Librium), diazepam (Valium), oxazepam (Serax), clorazepate (Tranxene), flurazepam (Dalmane), clonazepam (Clonopin), prazepam (Verstran), lorazepam (Ativan), mebutamate, and dextropropoxyphene (Dar-von). 

A 31-year-old man developed priapism after taking zuclopenthixol 30 mg/day for 8 days, the dose having been increased to 75 mg the day before, while he was still taking oral carbamazepine 600 mg/day and clora-zepate dipotassium 30 mg/day. He had a history of perinatal anoxic encephalopathy with severe motor sequelae and dyslalia, alcohol dependence, and a personality disorder. On the day before the priapism occurred, he had been physically restrained and given an extra dose of intramuscular clorazepate dipotassium 50 mg. When priapism occurred, all drugs except clorazepate were withdrawn and about 6 hours later the corpora cavernosa were washed and infused with noradrenaline in glucose (8 doses of 40 pg), after which the priapism resolved. 

Benzodiazepine (BZ) intoxication is manifested as slurred speech, poor coordination, swaying, drowsiness, hypotension, nystagmus, and confusion. Signs and symptoms of BZ withdrawal are similar to those of alcohol withdrawal, including muscle pain, anxiety, restlessness, confusion, irritability, haJlucinations, delirium, seizures, and cardiovascular collapse. Withdrawal from short-acting BZs (e.g., oxazepam, lorazepam, 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. Sedative-hypnotic dependence is summarized in Table 73-2. 

Clorazepate is a prodrug and possesses no anxiolytic effects until metabolism to DMDZ. Before absorption, clorazepate is metabolized rapidly in the stomach through a pH-dependent process under acidic conditions. 

As well as the opioids cocaine and cannabis, polytoxicomane drug abusers also consume bromazepam, diazepam and flunitrazepam in high doses, and fatalities among drug abusers and substitution patients can often be blamed on the consumption of these substances, often in combination with alcohol [48]. Patients who suffer low-dose dependence, in addition to consuming the three above-named substances, also consume therapeutic amounts of dipotassium clorazepate, flurazepam, lorezepam, nitrazepam or oxazepam, sometimes also in combination with amphetamines or antihistamines. 

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