indication

For the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Also used as adjunctive therapy in the management of partial seizures and for the symptomatic relief of acute alcohol withdrawal.

pharmacology

Clorazepate is a member of the group of drugs called benzodiazepines. Pharmacologically, clorazepate has the characteristics of the benzodiazepines. It has depressant effects on the central nervous system. The primary metabolite, nordiazepam, quickly appears in the blood stream. Studies in healthy men have shown that clorazenate has depressant effects on the central nervous system. Since orally administered clorazepate dipotassium is rapidly decarboxylated to form nordiazepam, there is essentially no circulating parent drug.

mechanism of action

Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA_A) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

toxicity

Oral LD₅₀ in rats is 1320 mg/kg. In monkeys, oral LD₅₀ exceed 1600 mg/kg. Symptoms of overdose include confusion, coma, impaired coordination, sleepiness, and slowed reaction time.

biotransformation

The drug is metabolized in the liver and excreted primarily in the urine. The primary metabolite, nordiazepam, is further metabolized by hydroxylation. The major urinary metabolite is conjugated oxazepam (3-hydroxynordiazepam), and smaller amounts of conjugated p-hydroxynordiazepam and nordiazepam are also found in the urine.

absorption

Rapidly absorbed following oral administration (bioavailability is 91%).

half life

The serum half-life is about 2 days. Nordiazepam, the primary metabolite, quickly appears in the blood and is eliminated from the plasma with an apparent half-life of about 40 to 50 hours.

route of elimination

The drug is metabolized in the liver and excreted primarily in the urine.

drug interactions

Amprenavir: Amprenavir may increase the effect and toxicity of the benzodiazepine, clorazepate.

Cimetidine: Cimetidine may increase the effect of the benzodiazepine, clorazepate.

Clozapine: Increased risk of toxicity

Ethotoin: Ethotoin may increase the metabolism of clorazepate via CYP3A4.

Fluconazole: Fluconazole may increase the effect of the benzodiazepine, clorazepate.

Fosamprenavir: Fosamprenavir may increase the effect and toxicity of the benzodiazepine, clorazepate.

Fosphenytoin: Fosphenytoin may increase the metabolism of clorazepate via CYP3A4.

Indinavir: The protease inhibitor, indinavir, may increase the effect of the benzodiazepine, clorazepate.

Itraconazole: Itraconazole may increase the effect of the benzodiazepine, clorazepate.

Kava: Kava may increase the effect of the benzodiazepine, clorazepate.

Ketoconazole: Ketoconazole may increase the effect of the benzodiazepine, clorazepate.

Mephenytoin: Mephenytoin may increase the metabolism of clorazepate via CYP3A4.

Nelfinavir: The protease inhibitor, nelfinavir, may increase the effect of the benzodiazepine, clorazepate.

Omeprazole: Omeprazole may increase the effect of the benzodiazepine, clorazepate.

Phenytoin: Phenytoin may increase the metabolism of clorazepate via CYP3A4.

Ritonavir: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, clorazepate.

Saquinavir: The protease inhibitor, saquinavir, may increase the effect of the benzodiazepine, clorazepate.

Telithromycin: Telithromycin may reduce clearance of Clorazepate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Clorazepate if Telithromycin is initiated, discontinued or dose changed.

Tipranavir: Tipranavir may decrease the metabolism and clearance of Clorazepate. Consider alternate therapy or monitor for Clorazepate toxic effects if Tipranavir is initiated or dose increased.

Triprolidine: The CNS depressants, Triprolidine and Clorazepate, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Voriconazole: Voriconazole may increase the serum concentration of clorazepate by decreasing its metabolism. Monitor for clorazepate toxicity if voriconazole is initiated or dose increased.