Diazepam (Valium®)
Diazepam
Diastat® | Dizac™ | Valium®
Classification:
Anesthetics
» Benzodiazepines
Musculoskeletal Agents
» Skeletal Muscle Relaxants
Neurological Agents
» Anticonvulsants
» Benzodiazepines
Psychotropic Agents
» Anxiolytics, Sedatives, and Hypnotics
» Benzodiazepines
Toxicology Agents
» Substance Abuse Agents
» Withdrawal agents
NOTE: In April 2006 the FDA reported a potential hazard caused by cracks in the applicator tips of Diastat® AcuDial (diazepam rectal gel) delivery systems. The manufacturer believes that it has identified the source of the defects, but its new version of this product will not reach the market until June or July 2006. Until then, current syringes will continue to be sold because there are no other available treatments for this condition that can be administered at home. Instruct patients and caregivers to inspect product before preparation and administration (diazepam-administration/">see Administration section).
NOTE: Diazepam is a schedule C-IV controlled substance.
Description: Diazepam (Valium) is a long-acting oral and parenteral benzodiazepine. Diazepam is similar to chlordiazepoxide and clorazepate in that all three generate the same active metabolite. Diazepam is used orally for the short-term management of anxiety disorders and acute alcohol withdrawal and as a skeletal muscle relaxant. Parenterally, it is indicated as an antianxiety agent, sedative, amnestic, anticonvulsant, skeletal muscle relaxant, anesthetic adjunct, and as a treatment for alcohol withdrawal. In addition to treating status epilepticus, diazepam has recently been shown effective in preventing recurrence of febrile seizures. Although diazepam has been the benzodiazepine of choice for status epilepticus, recent evidence indicates that lorazepam may be more beneficial because it provides longer control of seizures and produces less cardiorespiratory depression. Diazepam was originally approved by the FDA in November 1963. A rectal gel formulation of diazepam (Diastat® ) was approved for the treatment of acute repetitive seizures on July 31, 1997 and is designed for in-home use. On September 16, 2005, the FDA approved Diastat® AcuDial™, a diazepam rectal gel delivery system for at-home use that enables immediate treatment of seizures by a non-medically trained caregiver. Diazepam is a schedule IV controlled substance.
Mechanism of Action: Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.
Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2 which ultimately enhances the effects of GABA. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance 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.
The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal following stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono- and polysynaptic pathways. Benzodiazepine can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus. Benzodiazepines alleviate insomnia by decreasing the latency to sleep and increasing sleep continuity and total sleep time through their effects on GABA.
Benzodiazepines may also have other actions. For example, diazepam has been shown to counteract the cardiovascular toxicity of chloroquine. It is thought that diazepam increases the urinary clearance of chloroquine by improving electrocardiographic and hemodynamic function.
Pharmacokinetics: Diazepam is administered orally, rectally, and parenterally. Diazepam is the most rapidly absorbed benzodiazepine following an oral dose; however, absorption following an IM injection is slow and erratic. Diazepam administered rectally is well absorbed with an absolute bioavailability of about 90% relative to Valium® injection. Anticonvulsant, skeletal muscle relaxant, and anxiolytic effects are usually evident after the first dose. The onset of action after an IV dose is 1 - 5 minutes. The duration for some clinical effects (e.g., sedation, anticonvulsant activity) is much shorter than would be expected considering the very long half-life for both diazepam and its metabolite, desmethyldiazepam.
Diazepam is widely distributed, with CSF levels similar to plasma levels. This benzodiazepine crosses the placenta and distributes into breast milk (diazepam-valium-contraindications-precautions/">see Contraindications). The disparity between elimination half-life and duration of action for some conditions may be partially explained by rapid shifts in distribution of diazepam out of the CNS. Although diazepam is 99% protein-bound, interactions based on protein binding are not clinically significant. Metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4). Diazepam is extensively metabolized to one major active metabolite desmethyldiazepam and two minor active metabolites temazepam (3-hydroxydiazepam) and oxazepam (3-hydroxy-N-diazepam), with half-lives of 30 - 100 hours, 9.5 - 12 hours, and 5 - 15 hours, respectively. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam. Oxazepam and temazepam plasma concentrations are usually undetectable. The half-life of diazepam is 30 - 60 hours. These metabolites are subsequently glucuronidated and excreted in the urine.
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References
. Rosman NP, Colton T, Labazzo J et al. A controlled trial of diazepam administered during febrile illness to prevent recurrence of febrile seizures. N Engl J Med 1993;329:79 - 84.
. Riou B, Barriot P, Rimailho A et al. Treatment of severe chloroquine poisoning. N Engl J Med 1988;318:1 - 6.
[ Revised 10/19/2006 3:14:00 PM ]
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