indication

Used in the treatment of severe anxiety disorders, as a hypnotic in the short-term management of insomnia, as a sedative and premedicant, as an anticonvulsant, and in the management of alcohol withdrawal syndrome.

pharmacology

Diazepam, a benzodiazepine, generates the same active metabolite as chlordiazepoxide and clorazepate. In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function. Injections into animals have produced localized irritation of tissue surrounding injection sites and some thickening of veins after intravenous use.

mechanism of action

Benzodiazepines bind nonspecifically to benzodiazepine receptors which mediate sleep, 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 GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

toxicity

Symptoms of overdose include somnolence, confusion, coma, and diminished reflexes. Respiration, pulse and blood pressure should be monitored.

biotransformation

Hepatic via the Cytochrome P450 enzyme system. The main active metabolite is desmethyldiazepam, in addition to minor active metabolites including temazepam and oxazepam.

absorption

Essentially complete, with a bioavailability of 93%.

half life

Biphasic 1-2 days and 2-5 days, active metabolites with long half lives.

route of elimination

Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates.

drug interactions

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

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

Clarithromycin: The macrolide, clarithromycin, may increase the effect of the benzodiazepine, diazepam.

Clozapine: Increased risk of toxicity

Digoxin: The benzodiazepine, diazepam, may increase the effect of digoxin.

Erythromycin: The macrolide, erythromycin, may increase the effect of the benzodiazepine, diazepam.

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

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

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

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

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

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

Josamycin: The macrolide, josamycin, may increase the effect of the benzodiazepine, diazepam.

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

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

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

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

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

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

Quinupristin: This combination presents an increased risk of toxicity

Rifampin: Rifampin may decrease the effect of the benzodiazepine, diazepam.

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

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

St. John's Wort: St. John's Wort may decrease the effect of the benzodiazepine, diazepam.

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

Ticlopidine: Ticlopidine may decrease the metabolism and clearance of Diazepam. Consider alternate therapy or monitor for adverse/toxic effects of Diazepam if Ticlopidine is initiated, discontinued or dose changed.

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

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