Diazepam

Medication for anxiety, seizures, and muscle spasms

Diazepam
INN
Drug class	Benzodiazepine
Routes of administration	oral, intramuscular, intravenous, rectal, nasal, buccal film
Pregnancy category
Bioavailability	76% (64–97%) oral, 81% (62–98%) rectal
Metabolism	Liver – CYP2B6 (minor route) to desmethyldiazepam, CYP2C19 (major route) to inactive metabolites, CYP3A4 (major route) to temazepam
Elimination half-life
Excretion	Kidney
Legal status	Rx-only
CAS Number	439-14-5
PubChem	3016
DrugBank	DB00829
ChemSpider	2908
KEGG	D00293

Diazepam structure

Diazepam 3D model

Diazepam (Valium) DOJ

5 mg Roche Diazepam

Synthesis of Diazepam

Diazepam is a widely used benzodiazepine medication, primarily prescribed as a sedative, anxiolytic, muscle relaxant, and anticonvulsant for treating acute seizures or status epilepticus. It is available in both oral and intravenous forms, with distinct clinical applications. Oral diazepam is commonly used for managing anxiety disorders, while intravenous diazepam is reserved for emergency anticonvulsant therapy. Although generally well-tolerated, diazepam carries potential risks of dependency and withdrawal and must be used under medical supervision. Rare instances of cholestatic liver injury have been reported with oral use, but intravenous administration is not linked to liver injury.

Mechanism of Action and Pharmacology

Diazepam exerts its effects by enhancing the activity of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS). By binding to GABA_A receptors, diazepam increases GABA-mediated synaptic transmission and induces its sedative, anxiolytic, anticonvulsant, and muscle-relaxing properties.

Anticonvulsant Effects

Diazepam's antiseizure effects are particularly valuable in managing acute seizure activity, such as status epilepticus. Its rapid action and ability to suppress the spread of seizure activity make it a preferred choice for emergency treatment. However, it is less effective for long-term seizure control compared to other benzodiazepines like clobazam, clonazepam, and clorazepate.

Pharmacokinetics

• Absorption: Diazepam is well-absorbed orally, reaching peak plasma concentrations within 1-2 hours.
• Distribution: It is highly lipophilic, allowing rapid penetration of the CNS.
• Metabolism: Metabolized in the liver by cytochrome P450 enzymes, primarily CYP3A4 and CYP2C19, into active metabolites such as desmethyldiazepam.
• Excretion: Excreted mainly via the kidneys in the form of conjugated metabolites.

Clinical Applications and Usage

FDA Approval and Indications

Diazepam was first approved by the Food and Drug Administration (FDA) in 1963 and remains widely used for various medical conditions, including:

• Anxiety disorders
• Acute muscle spasms
• Seizures, including status epilepticus
• Premedication for surgical or diagnostic procedures
• Management of alcohol withdrawal syndrome

Dosage and Administration

• For status epilepticus:
• Intravenous (IV) diazepam at 5-10 mg, repeated every 10-15 minutes if needed, up to a maximum of 30 mg.
• Premedication for anesthesia:
• Intramuscular (IM) diazepam at 10-20 mg.

Adjustments in dosage may be necessary for elderly individuals, patients with liver disease, or those taking other CNS depressants.

Safety and Monitoring

The long-term use of diazepam can lead to tolerance and dependence. Abrupt discontinuation may result in severe withdrawal symptoms, including agitation, tremors, and seizures. Tapering the dose under medical supervision is crucial to minimize withdrawal effects.

Side Effects and Drug Interactions

Side Effects

Common adverse effects of diazepam include:

• Somnolence (drowsiness)
• Confusion
• Dysarthria (difficulty speaking)
• Diplopia (double vision)
• Impaired coordination and coma in cases of overdose

In rare instances, diazepam may cause paradoxical reactions such as increased anxiety, agitation, or hallucinations.

Drug Interactions

Diazepam may interact with other medications, leading to enhanced sedation or altered drug efficacy:

• CNS depressants: Opioids, barbiturates, alcohol, and other benzodiazepines
• Enzyme inducers/inhibitors: Drugs that affect CYP3A4 activity can alter diazepam metabolism.

Patients should inform their healthcare provider of all medications, including over-the-counter and herbal products, to avoid adverse interactions.

Precautions

Diazepam should be used cautiously in:

• Elderly patients: Increased sensitivity to sedative effects
• Pregnant women: Risk of fetal benzodiazepine syndrome
• Individuals with a history of substance abuse: High risk of dependence
• Severe hepatic impairment: Risk of prolonged sedation and toxicity

Therapeutic Role and Limitations

Role in Epilepsy

Diazepam is primarily a short-term solution for acute seizure management. Chronic epilepsy is better managed with other antiepileptic drugs (AEDs) such as valproate, carbamazepine, or lamotrigine.

Psychiatric Applications

Diazepam's anxiolytic properties make it a choice for short-term management of severe anxiety. However, cognitive-behavioral therapy (CBT) is preferred for long-term anxiety management.

Limitations

Despite its effectiveness, diazepam has limitations:

• Dependency risk: Long-term use can lead to benzodiazepine dependence.
• Withdrawal challenges: Abrupt cessation can cause seizures or rebound anxiety.
• Tolerance: Over time, increasing doses may be needed to achieve the same therapeutic effect.

Future Directions

Research into GABAergic pathways and alternative benzodiazepine receptor modulators may pave the way for safer and more effective therapies.

• Dailymed label info on Diazepam
• FDA Diazepam

Medical uses

Pharmacodynamics

Benzodiazipines

• Alprazolam
• Chlordiazepoxide
• Diazepam (Oral)
• Estazolam
• Flurazepam
• Lorazepam
• Midazolam
• Oxazepam
• Quazepam
• Temazepam
• Triazolam

Anticonvulsants Drugs

• Clobazam
• Clonazepam
• Clorazepate
• Diazepam (Intravenous)

Anticonvulsants, and Benzodiazepines]