CLORAZEPATE DIPOTASSIUM

Chemistry - A benzodiazepine anxiolytic, sedative-hypnotic and anticonvulsant, clorazepatedipotassium occurs as a light yellow, fine powder that is very soluble in water and slightly solublein alcohol.

Storage, Stability, Compatibility

Capsules and tablets should be stored in tight, light resistantcontainers at room temperature. Clorazepate dipotassium is unstable in the presence of water. It hasbeen recommended to keep the dessicant packets in with the original container of the capsules andtablets and to consider adding a dessicant packet to the prescription vial when dispensing largequantities of tablets or capsules to the client.

Pharmacology - CLORAZEPATE DIPOTASSIUM

The subcortical levels (primarily limbic, thalamic, and hypothalamic) of the CNSare depressed by clorazepate and other benzodiazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant and anticonvulsant effects seen. The exact mechanism of action isunknown, but postulated mechanisms include: antagonism of serotonin, increased release of and/orfacilitation of gamma-aminobutyric acid (GABA) activity and diminished release or turnover ofacetylcholine in the CNS. Benzodiazepine specific receptors have been located in the mammalianbrain, kidney, liver, lung and heart. In all species studied, receptors are lacking in the white matter.

Uses, Indications

Clorazepate has been used in dogs both as an adjunctive anticonvulsant(usually in conjunction with phenobarbital) and in the treatment of behavior disorders, primarilythose that are anxiety or phobia-related. In dogs, clorazepate has been reported to be less prone todeveloping tolerance to its anticonvulsant effects than is clonazepam.

Pharmacokinetics - CLORAZEPATE DIPOTASSIUM

Clorazepate is one of the most rapidly absorbed oral benzodiazepines and, therefore, has a rapid onset of action. Peak serum levels generally occur within 1-2 hours.
Clorazepate's distribution characteristics are not well described. Clorazepate is metabolized todesmethyldiazepam and other metabolites. Desmethyldiazepam is active and has a very long halflife (in humans up to 100 hours). In dogs, the sustained release preparation apparently offers nopharmacokinetic advantage over the non-sustained preparations (Brown and Forrester 1989).

Contraindications, Precautions, Reproductive Safety

Clorazepate is contraindicated in patients who are hypersensitive to it or other benzodiazepines, have significant liver dysfunction or have acute narrow angle glaucoma. Benzodiazepines have been reported to exacerbate myasthenia gravis.
Safe use during pregnancy has not been established; teratogenic effects of similar benzodiazepineshave been noted in rabbits and rats. It is not known if the drug enters maternal milk, howeverdesmethyldiazepam (an active metabolite of clorazepate) and several other benzodiazepines havebeen documented to enter maternal milk.

Adverse Effects, Warnings

In dogs, the most likely adverse effects seen include sedation andataxia. These effects apparently occur infrequently, are mild and usually transient. Many otheradverse effects are potentially possible; see the clonazepam monograph for more information.
Use with caution in dogs displaying fear-induced aggression, as they actually provoke dogs toattack.

Overdosage, Acute Toxicity

When used alone, clorazepate overdoses are generally limited tosignificant CNS depression (confusion, coma, decreased reflexes, etc). Treatment of significant oraloverdoses consists of standard protocols for removing and/or binding the drug in the gut andsupportive systemic measures. The use of analeptic agents (CNS stimulants such as caffeine, amphetamines, etc) are generally not recommended.

Drug Interactions

If administered with other CNS depressant agents (barbiturates, narcotics, anesthetics, etc.) additive effects may occur. If used with phenytoin, increased serumphenytoin levels and decreased clorazepate levels may occur.
Rifampin may induce hepatic microsomal enzymes and decrease the pharmacologic effects ofbenzodiazepines. Cimetidine or Erythromycin has been reported to decrease the metabolism ofbenzodiazepines.
Antacids do not affect the degree of absorption of clorazepate, but may decrease the rate ofconversion of clorazepate to desmethyldiazepam (active metabolite). It is unlikely this interaction isof clinical significance.Laboratory Considerations - Benzodiazepines may decrease the thyroidal uptake of I123 or I131. Clorazepate may increase serum alkaline phosphatase and serum cholesterol levels; clinicalsignificance is unclear.