Clorazepate

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Pronunciation: klor-AZ-uh-pait

Chemical Abstracts Service Registry Number: 23887-31-2. (Dipotassium form 57109-90-7)

Formal Names: Tranxene

Type: Depressant (benzodiazepine class). See page 21 Federal Schedule Listing: Schedule IV (DEA no. 2768) USA Availability: Prescription Pregnancy Category: D

Uses. Clorazepate dipotassium is a "prodrug" related to diazepam. A prodrug is a substance that may have little effect itself but that the body metabolizes into another chemical that does have a drug effect. For example, one metabolite of clorazepate dipotassium is desmethyldiazepam, which in turn transforms into oxazepam. Prodrugs are prescribed when direct administration of the desired chemical does not work, such as when the chemical would degrade before it has time to build up in the part of the body where it is needed or when the normal dosage form cannot be given (perhaps a substance that can be absorbed through the skin is needed rather than giving an injection). Although metabolites of clorazepate dipotassium generally create the medical actions, for simplicity this discussion usually refers only to the pro-drug clorazepate dipotassium and calls it a drug.

This long-acting drug's primary medical uses are for anxiety, for convulsions, and as a muscle relaxant. The substance can be taken on a long-term basis for successful control of epilepsy but is described as a "second-line" medication, meaning it is not used unless other drugs have been tried without success. Clorazepate dipotassium's long-term effectiveness against anxiety is unclear. A common short-term use is to reduce nervousness in surgery patients shortly before an operation. The drug is also given to ease withdrawal from Zolpidem and alcohol (including delirium tremens). An injection can quickly calm a bellicose individual.

Weight, age, and gender can affect dosage. A study found that an active metabolite (desmethyldiazepam) from a dose of clorazepate dipotassium lasts almost three times as long in overweight persons compared to normal weight persons, apparently due to accumulation in body fat. Another study noted that the older a male was, the longer the same metabolite from a dose lasted, but that effect was not seen in women.

Although clorazepate dipotassium is used against anxiety, the drug is generally considered unsuitable for depressed or psychotic persons. It has nonetheless been given with success for treating depression (even though sometimes the drug can instead worsen that condition). The drug has helped reduce nightmares caused by other pharmaceuticals and has helped alleviate psychosomatic complaints. It has also been used against tetanus.

Drawbacks. People with severe breathing trouble or acute narrow-angle glaucoma should avoid clorazepate dipotassium. Loosening of the nails has been attributed to the drug in a case report, but that is unusual. Somewhat less surprising is a case report of jaundice, less surprising because many drugs add a burden to the liver. Oral overdose can provoke rage.

The drug routinely makes people sleepy, and users are cautioned against operating dangerous machinery. In experiments the drug increases reaction time and decreases attention. Nonetheless, a laboratory simulation of driving showed no effect on operating a motor vehicle. One authority contends that the substance should not impair driving performance but acknowledges that trouble arises if a driver does not use the drug as medically directed or uses alcohol simultaneously. Other unwanted effects occur less often: peevishness, headache, stomach irritation, dry mouth, rashes, double vision, and unclear speech. Therapeutic advantage sometimes comes from the drowsiness factor, with patients instructed to take the drug at bedtime to help reduce insomnia, a technique that then also allows them to obtain the long-lasting antianxiety effect during daytime hours the next day. In one study people reported more restful sleep, and measurements after they awoke showed little drug impact on performance tests (illustrating the difference a few hours can make on how well someone performs after taking a substance).

Abuse factors. If usage continues for a long time and suddenly stops, a withdrawal syndrome can occur. Withdrawal symptoms can include trouble with sleeping and memory, jitteriness and crankiness, sore muscles, and loose bowels. Those discomforts are similar to what happens in alcohol or barbiturate withdrawal. Researchers suspect the problem may be worsened if a person has taken some other benzodiazepine class drug off and on. The withdrawal problem may be avoided by gradual discontinuation of clorazepate dipotassium. Experiments with dogs and rabbits also show withdrawal symptoms. A canine test demonstrated that abrupt clorazepate dipotassium withdrawal can cause fatal seizures. The kinds of well-documented dependence mentioned above involve relatively brief withdrawal. Reportedly human withdrawal symptoms may continue for months, which is an unusual persistence of dependence. Long-term signs of withdrawal, however, are described as reappearance of anxiety, sometimes accompanied by psychosis and convulsions. Such long-term "withdrawal symptoms" sound much like conditions for which the drug is prescribed, raising a question of whether the victim is experiencing long-term dependence or simply reemergence of conditions formerly controlled by the now-absent drug.

A group of recreational drug abusers was tested to determine their likings, and the group declared clorazepate dipotassium to be less attractive than diazepam or lorazepam.

Drug interactions. Members in a group of recreational drug abusers reported that alcohol boosted clorazepate dipotassium's effect and that the combination made their mood bleaker, but when subjects in another study took that combination they felt happier than alcohol normally made them. Another experiment found that the combination impaired memory, although still another study found that clorazepate alone did not affect memory. In testing how long the desmethyldiazepam metabolite lasts from a clorazepate dipo-tassium dose, conflicting results have come from experiments comparing cigarette smokers to nonsmokers. Opiates, barbiturates, and monoamine oxidase inhibitors (MAOIs) found in some antidepressants may boost actions of clorazepate dipotassium. Clorazepate dipotassium may boost alcohol's effects.

Cancer. Animal studies have failed to find evidence of any cancer-causing potential in clorazepate dipotassium.

Pregnancy. Experiments with pregnant rats and rabbits revealed no impairment of fertility and failed to produce any birth defects attributable to clorazepate dipotassium. One rat study also found no behavioral consequences from prenatal exposure to the drug, but another rat study discovered that offspring walked more slowly than normal and also had some learning difficulty. The drug's potential for creating human birth defects is unknown. A case report associates it with fatal lung collapse in a newborn whose mother had used the drug during pregnancy, and another case report associates the drug with fatal birth defects. "Association" may mean caution is appropriate, but it does not demonstrate cause and effect. Breast-feeding mothers are warned to avoid the drug because its metabolite nordiazepam (which is also a metabolite of diazepam) passes into the milk and into the infant. The metabolite desmethyldiazepam also passes into milk, as does clorazepate dipotas-sium itself.

Additional scientific information may be found in:

Fabre, L.F., and H.P. Putman III. "Depressive Symptoms and Intellectual Functioning in Anxiety Patients Treated with Clorazepate." Journal of Clinical Psychiatry 49 (1988): 189-92.

Fujii, T., et al. "Clorazepate Therapy for Intractable Epilepsy." Brain and Development 9 (1987): 288-91.

Henderson, J.G. "Value of a Single Night-time Dose of Potassium Clorazepate in Anxiety: A Controlled Trial Comparison with Diazepam." Scottish Medical Journal 27 (1982): 292-96.

Moodley, P., S. Golombok, and M. Lader. "Effects of Clorazepate Dipotassium and

Placebo on Psychomotor Skills." Perceptual and Motor Skills 61 (1985): 1121-22. Zung, W.W. "Effect of Clorazepate on Depressed Mood in Anxious Patients." Journal of Clinical Psychiatry 48 (1987): 13-14.

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