| 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. |
| Pharmacodynamics |
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 (GABAA)
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. |
| Absorption |
Essentially complete, with a bioavailability of 93%. |
| Volume of distribution |
- 0.8 to 1.0 L/kg [young healthy males]
|
| Protein binding |
98.5% |
| Metabolism |
Hepatic via the Cytochrome P450 enzyme system. The main active
metabolite is desmethyldiazepam, in addition to minor active metabolites
including temazepam and oxazepam. |
| Route of elimination |
Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. |
| Half life |
Biphasic 1-2 days and 2-5 days, active metabolites with long half lives. |
| Clearance |
|
| Toxicity |
Symptoms of overdose include somnolence, confusion, coma, and
diminished reflexes. Respiration, pulse and blood pressure should be
monitored. |
