Diazepam

Usage

Diazepam is prescribed for a variety of medical conditions, including:

• Anxiety disorders: Generalized anxiety disorder, panic disorder, social anxiety disorder.
• Acute alcohol withdrawal: Manages symptoms like agitation, tremors, and delirium tremens.
• Muscle spasms: Relieves skeletal muscle spasms caused by injury, inflammation, or neurological conditions like cerebral palsy.
• Preoperative sedation: Reduces anxiety and tension before surgical procedures.
• Status epilepticus: Controls prolonged or repetitive seizures.
• Sedation in intensive care unit (ICU): Facilitates mechanical ventilation and manages anxiety and agitation.

Pharmacological Classification: Benzodiazepine, Anxiolytic, Sedative-Hypnotic, Anticonvulsant, Skeletal Muscle Relaxant.

Mechanism of Action: Diazepam enhances the effect of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system. It binds to the benzodiazepine site on the GABA_A receptor, increasing the frequency of chloride channel opening. This leads to increased chloride influx into neurons, hyperpolarization, and reduced neuronal excitability.

Alternate Names

• International Nonproprietary Name (INN): Diazepam
• Valium (Commonly used name in some regions)

Brand Names: Valium, Valtoco, Diastat (rectal gel), Diazepam Intensol (concentrated oral solution).

How It Works

Pharmacodynamics: Diazepam’s effects on the body include:

• Sedation and hypnosis: Reduces anxiety, promotes relaxation, and induces sleep.
• Anxiolysis: Decreases feelings of worry and fear.
• Muscle relaxation: Reduces muscle tone and spasticity.
• Anticonvulsant activity: Suppresses seizure activity.
• Anterograde amnesia: Impairs the formation of new memories.

Pharmacokinetics:

• Absorption: Well-absorbed orally. Rapid absorption after intramuscular (IM) or intravenous (IV) administration. Erratic absorption after IM injection.
• Metabolism: Extensively metabolized in the liver, primarily by CYP2C19 and CYP3A4 enzymes, into active metabolites (desmethyldiazepam, oxazepam, temazepam).
• Elimination: Primarily eliminated through the kidneys. Prolonged half-life (20-80 hours), extended in the elderly and patients with hepatic impairment. Active metabolites contribute to the long duration of action.

Mode of Action: Diazepam acts allosterically at the benzodiazepine binding site on the GABA_A receptor complex. This enhances GABA’s inhibitory effects, leading to increased chloride conductance and neuronal hyperpolarization.

Receptor Binding: Binds to the benzodiazepine site on the GABA_A receptor.

Elimination Pathways: Primarily hepatic metabolism followed by renal excretion.

Dosage

Standard Dosage

Adults:

• Oral: 2-10 mg, 2-4 times daily, adjusted according to the indication and severity.
• IM/IV: 2-10 mg (moderate anxiety), 5-10 mg (severe anxiety), repeated every 3-4 hours as needed. Max dose: 30 mg in 8 hours.

Children:

• Dosage based on weight and age (refer to pediatric guidelines). Caution is advised in children under 6 months, especially regarding toxic dose potentials. Generally considered potentially toxic doses in patients under 6 years: greater than 0.5 mg/kg.

Special Cases:

• Elderly Patients: Initiate with lower doses (2-2.5 mg, 1-2 times daily) and titrate cautiously.
• Patients with Renal Impairment: Caution is advised in prolonged administration. Reduce the dose for prolonged use.
• Patients with Hepatic Dysfunction: Reduce dose and monitor closely. Contraindicated in severe hepatic impairment.
• Patients with Comorbid Conditions: Adjust dose based on individual conditions and drug interactions.

Clinical Use Cases

• Intubation: 5-10 mg IV bolus, followed by 5 mg aliquots every minute until adequate sedation is achieved. Use with other agents such as opioids or neuromuscular blockers is left to the attending physician.
• Surgical Procedures: 10 mg IM preoperatively (1-2 hours before surgery), or 5-15 mg IV (5-10 minutes prior to cardioversion). In endoscopic procedures administer slow IV until desired sedation response (up to 20 mg). Reduce narcotic dosing by at least 1/3.
• Mechanical Ventilation: 5-10 mg IV loading dose, followed by 0.03-0.1 mg/kg every 30 minutes to 6 hours, or 1-7 mg every 30 min to 6 hours, depending on titration needs.
• Intensive Care Unit (ICU) Use: 5-10 mg IV/IM, repeated every 5-10 minutes; not to exceed 30 mg, or 0.5 mg/kg rectally. A second rectal dose of 0.25 mg/kg may be given after 10 minutes.
• Emergency Situations (e.g., status epilepticus): 5-10 mg IV initially, repeated every 10-15 minutes up to a maximum of 30 mg. Repeat in 2-4 hours if needed. For pediatric status epilepticus initial dose is 0.2 mg/kg IV (max: 8mg) slowly over 1 minute, then repeat at 0.15 mg/kg up to 10 mg maximum. Can give midazolam IM if no IV access available.

Dosage Adjustments

Adjustments necessary based on renal/hepatic function, comorbidities, concomitant medications, and patient response.

Side Effects

Common Side Effects:

• Drowsiness
• Dizziness
• Fatigue
• Muscle weakness
• Ataxia (loss of coordination)
• Slurred speech
• Confusion

Rare but Serious Side Effects:

• Respiratory depression
• Paradoxical excitement or aggression
• Allergic reactions (rash, itching, swelling)
• Bradycardia
• Hypotension
• Dependence
• Withdrawal symptoms (anxiety, insomnia, seizures)

Long-Term Effects:

• Cognitive impairment
• Dependence
• Withdrawal symptoms

Adverse Drug Reactions (ADR):

• Severe respiratory depression
• Anaphylaxis
• Angioedema
• Stevens-Johnson syndrome

Contraindications

• Hypersensitivity to diazepam or other benzodiazepines
• Severe respiratory insufficiency
• Severe hepatic impairment
• Acute narrow-angle glaucoma
• Myasthenia gravis
• Sleep apnea

Drug Interactions

Diazepam interacts with numerous medications, including:

• CNS depressants: Alcohol, opioids, barbiturates, antihistamines – increased sedation and respiratory depression.
• CYP450 inhibitors: Azole antifungals, macrolide antibiotics, cimetidine – increased diazepam levels and side effects.
• CYP450 inducers: Phenytoin, carbamazepine, rifampin – decreased diazepam levels and efficacy.
• Antacids: May reduce diazepam absorption.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (FDA classification). Avoid use during pregnancy, particularly in the first trimester, due to potential teratogenic risks.
• Breastfeeding: Diazepam is excreted in breast milk. Advise mothers to wait 6-8 hours after a single dose before resuming breastfeeding, especially for preterm infants.

Drug Profile Summary

• Mechanism of Action: Enhances GABAergic neurotransmission.
• Side Effects: Drowsiness, dizziness, ataxia, dependence, respiratory depression.
• Contraindications: Hypersensitivity, respiratory insufficiency, severe hepatic impairment.
• Drug Interactions: CNS depressants, CYP450 inhibitors/inducers.
• Pregnancy & Breastfeeding: Category D; excreted in breast milk.
• Dosage: Varies by indication and patient factors.
• Monitoring Parameters: Respiratory rate, blood pressure, level of sedation.

Popular Combinations

Used in combination with other medications for specific conditions.

Precautions

• Use cautiously in patients with respiratory or hepatic impairment, elderly patients, and individuals with a history of substance abuse.
• Avoid abrupt discontinuation to prevent withdrawal symptoms.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Diazepam?

A: Dosage varies depending on indication, age, and patient-specific factors. Consult dosage guidelines above.

Q2: How should Diazepam be administered?

A: Oral, IM, or IV. IV administration should be slow to minimize risks.

Q3: What are the common side effects of Diazepam?

A: Drowsiness, dizziness, fatigue, muscle weakness, ataxia.

Q4: What are the serious side effects of Diazepam?

A: Respiratory depression, paradoxical excitement, allergic reactions.

Q5: Can Diazepam be used during pregnancy?

A: Generally avoided due to potential teratogenic effects. Consult a specialist.

Q6: What are the drug interactions with Diazepam?

A: Interacts with CNS depressants, CYP450 inhibitors/inducers.

Q7: How is Diazepam metabolized and eliminated?

A: Hepatic metabolism via CYP enzymes, followed by renal excretion.

Q8: What are the signs of Diazepam overdose?

A: Excessive sedation, respiratory depression, coma.

Q9: What are the withdrawal symptoms of Diazepam?

A: Anxiety, insomnia, tremors, seizures. Taper dose gradually upon discontinuation.

Q10: What precautions are necessary when administering Diazepam IV?

A: Slow administration into a large vein is crucial to avoid complications. Monitor for respiratory depression and hypotension. Have resuscitation equipment available.