Diazepam

Diazepam is a long-acting benzodiazepine classified as an anxiolytic, sedative-hypnotic, anticonvulsant, and muscle relaxant. It is widely used for both acute and chronic conditions, including anxiety disorders, alcohol withdrawal, seizures, muscle spasms, and premedication before procedures. Due to its CNS depressant properties and high potential for dependence, its use is restricted to short-term management in most indications. Diazepam acts by potentiating the effect of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system.

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Pharmacological Classification

• Therapeutic Class: Anxiolytic, Anticonvulsant, Hypnotic, Muscle Relaxant

• Pharmacological Class: Benzodiazepine

• ATC Code: N05BA01

• Legal Status: Controlled Substance (Schedule IV in the U.S., Class C in the UK), Prescription Only (Rx)

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Mechanism of Action

Diazepam exerts its pharmacological actions by binding to the benzodiazepine site on the GABA_A receptor complex in the brain. This enhances the binding affinity of GABA to its receptor, thereby increasing chloride ion influx into neurons. The result is hyperpolarization of neuronal membranes, which leads to:

• CNS depression

• Reduction in neuronal excitability

• Sedation and anxiolysis

• Muscle relaxation

• Anticonvulsant effects

Diazepam has a rapid onset and a long half-life (up to 48 hours), which is further extended by its active metabolites such as desmethyldiazepam.

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Therapeutic Indications

Psychiatric and Neurological

• Acute anxiety and panic attacks

• Generalized anxiety disorder (short-term use)

• Status epilepticus

• Epilepsy adjunctive therapy

• Pre-operative sedation or procedural anxiety relief

Musculoskeletal and Spasticity

• Muscle spasms (e.g., tetanus, spinal cord injury)

• Spasticity from cerebral palsy, multiple sclerosis, or stroke

Substance Use Disorders

• Alcohol withdrawal syndrome, including delirium tremens

• Drug-induced convulsions or agitation

Emergency and ICU Use

• Sedation during mechanical ventilation

• Management of severe agitation

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Formulations and Routes of Administration

• Oral tablets: 2 mg, 5 mg, 10 mg

• Oral solution: e.g., 2 mg/5 mL

• Rectal gel: 2.5 mg, 5 mg, 10 mg (e.g., for seizures)

• Intramuscular or intravenous injection: 5 mg/mL ampoules

• Intranasal spray (approved in some countries for acute repetitive seizures)

Brand Names include: Valium®, Stesolid®, Diastat®, Apo-Diazepam, among others

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Dosing Guidelines

Anxiety (Short-Term)

• Adult oral dose: 2–10 mg two to four times daily

• Initiate with lowest dose and titrate based on response

• Use limited to 2–4 weeks due to dependence risk

Alcohol Withdrawal

• 10 mg orally every 6–8 hours initially, tapering over 3–7 days

• May also be administered IV or IM in inpatient settings

Status Epilepticus

• IV 5–10 mg slowly every 10–15 minutes; max dose 30 mg

• May require repeated dosing or transition to long-acting anticonvulsants

Muscle Spasms

• 5–10 mg orally three to four times daily

Children (Seizure Management)

• Rectal gel (Diastat) dosed by weight and age

• Used in community or home settings for seizure clusters

Always adjust dosage based on renal and hepatic function, age, and concomitant medications.

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Contraindications

• Known hypersensitivity to diazepam or benzodiazepines

• Severe respiratory insufficiency (e.g., COPD, sleep apnea)

• Myasthenia gravis

• Severe hepatic insufficiency

• Acute narrow-angle glaucoma

• Sleep apnea syndrome

• Use in infants <6 months (except under specialist care)

• Porphyria (due to potential enzyme induction)

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Precautions and Warnings

• Tolerance and Dependence: Risk increases with prolonged use or high doses

• Withdrawal Syndrome: Rebound anxiety, insomnia, seizures—taper slowly

• Paradoxical Reactions: Increased anxiety, aggression, hallucinations (more likely in elderly)

• Respiratory Depression: Enhanced risk with opioids, alcohol, or other CNS depressants

• Hepatic Impairment: Metabolism may be slowed—use caution or avoid

• Elderly: More sensitive to sedative effects—risk of falls and cognitive impairment

• Pregnancy: Avoid unless benefit outweighs risk—associated with floppy infant syndrome and neonatal withdrawal

• Driving and Machinery Use: Causes drowsiness and impaired coordination

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Adverse Effects

Common (1–10%)

• Drowsiness

• Fatigue

• Muscle weakness

• Dizziness

• Confusion

• Ataxia

• Blurred vision

Less Common to Rare (<1%)

• Anterograde amnesia

• Slurred speech

• Hypotension

• Respiratory depression

• Jaundice (rare)

• Skin rash

• Paradoxical excitement or aggression

• Depression

• Dependency and abuse

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Drug Interactions

Increased CNS Depression

• Opioids (e.g., morphine, oxycodone) → respiratory depression

• Alcohol → synergistic sedative effect

• Antipsychotics, antidepressants, antihistamines → additive drowsiness

• Barbiturates → enhanced sedative effect

Pharmacokinetic Interactions

• CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) → increased diazepam levels

• CYP3A4 inducers (e.g., rifampin, carbamazepine) → reduced effectiveness

• Antacids may delay absorption (minimal clinical effect)

Other Considerations

• May potentiate effects of muscle relaxants

• Avoid with clozapine due to enhanced risk of hypotension and respiratory suppression

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Use in Special Populations

Pregnancy

• Category D (US FDA)

• Crosses placenta; chronic use may result in neonatal abstinence syndrome

• Use only if benefits outweigh risks (e.g., status epilepticus in pregnancy)

Breastfeeding

• Small amounts excreted in breast milk

• May cause drowsiness, feeding difficulties in infants

• Use cautiously or avoid if long-term therapy needed

Elderly

• Lower starting doses recommended

• High sensitivity to CNS effects—risk of falls, confusion, delirium

Renal Impairment

• No major dose adjustment required, but caution still advised

Hepatic Impairment

• Use with extreme caution due to risk of accumulation

• Consider alternatives (e.g., lorazepam which bypasses hepatic oxidation)

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Comparison with Other Benzodiazepines (Without Tables)

Diazepam vs. Lorazepam

• Diazepam has faster onset but longer half-life

• Lorazepam is more suitable in liver impairment due to non-hepatic metabolism

• Diazepam preferred for muscle spasm and alcohol withdrawal

• Lorazepam favored in status epilepticus in hospitals due to more predictable IM absorption

Diazepam vs. Clonazepam

• Both are long-acting

• Clonazepam used more in seizure disorders or panic attacks

• Diazepam used in acute seizures and muscle relaxation

Diazepam vs. Alprazolam

• Alprazolam is shorter-acting, used primarily for panic and anxiety

• Diazepam has more muscle-relaxant properties

• Alprazolam has higher potential for addiction and withdrawal symptoms

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Toxicity and Overdose

Symptoms

• Drowsiness, confusion

• Hypotonia

• Slurred speech

• Respiratory depression

• Coma (rarely fatal unless combined with alcohol or opioids)

Management

• Supportive care (airway protection, ventilation)

• Flumazenil: Specific benzodiazepine receptor antagonist; used cautiously due to seizure risk, especially in chronic users or co-ingestion of proconvulsants

• Activated charcoal if recent ingestion

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Patient Counseling Points

• Take exactly as prescribed; do not exceed dose or duration

• Avoid alcohol and CNS depressants

• Do not suddenly stop—withdrawal can be dangerous

• Drowsiness and dizziness are common—caution while driving

• Store securely to prevent misuse

• Report symptoms of memory loss, mood changes, difficulty breathing

• Do not share medication—it is habit-forming and legally restricted