indication

For the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety.

pharmacology

Chlordiazepoxide has antianxiety, sedative, appetite-stimulating and weak analgesic actions. The drug seems to block EEG arousal from stimulation in the brain stem reticular formation. The drug has been studied extensively in many species of animals and these studies are suggestive of action on the limbic system of the brain, which recent evidence indicates is involved in emotional responses. Hostile monkeys were made tame by oral drug doses which did not cause sedation. Chlordiazepoxide revealed a "taming" action with the elimination of fear and aggression. The taming effect of chlordiazepoxide was further demonstrated in rats made vicious by lesions in the septal area of the brain. The drug dosage which effectively blocked the vicious reaction was well below the dose which caused sedation in these animals.

mechanism of action

Chlordiazepoxide binds to stereospecific benzodiazepine (BZD) binding sites on GABA (A) receptor complexes at several sites within the central nervous system, including the limbic system and reticular formation. This results in an increased binding of the inhibitory neurotransmitter GABA to the GABA(A) receptor.BZDs, therefore, enhance GABA-mediated chloride influx through GABA receptor channels, causing membrane hyperpolarization. The net neuro-inhibitory effects result in the observed sedative, hypnotic, anxiolytic, and muscle relaxant properties.

toxicity

LD₅₀=537 mg/kg (Orally in rats). Signs of overdose include respiratory depression, muscle weakness, somnolence (general depressed activity).

biotransformation

Hepatic.

half life

24-48 hours

route of elimination

Chlordiazepoxide is excreted in the urine, with 1% to 2% unchanged and 3% to 6% as conjugate.

drug interactions

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

Clozapine: Increased risk of toxicity

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Triprolidine: The CNS depressants, Triprolidine and Chlordiazepoxide, 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 chlordiazepoxide by decreasing its metabolism. Monitor for chlordiazepoxide toxicity if voriconazole is initiated or dose increased.