Chlordiazepoxide - Drug Monograph

Introduction

Chlordiazepoxide is a benzodiazepine derivative that was the first drug of its class to be synthesized and marketed. It is primarily used for its anxiolytic, sedative, hypnotic, and muscle relaxant properties. As a Schedule IV controlled substance, chlordiazepoxide has significant abuse potential and requires careful clinical management.

Mechanism of Action

Chlordiazepoxide potentiates the effects of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. It binds to specific sites on the GABA-A receptor complex, enhancing GABA-mediated chloride ion channel opening. This results in increased neuronal membrane hyperpolarization and reduced neuronal excitability throughout the CNS.

Indications

• Management of anxiety disorders
• Short-term relief of anxiety symptoms
• Alcohol withdrawal syndrome
• Preoperative apprehension and anxiety
• Adjunct therapy for skeletal muscle spasm

Dosage and Administration

• Anxiety: 5-25 mg orally 3-4 times daily
• Alcohol withdrawal: 50-100 mg IM or IV initially, then repeated as needed
• Preoperative anxiety: 5-10 mg IM 1-2 hours before surgery

• Initial dose: 5 mg orally 2-4 times daily

Pharmacokinetics

• Absorption: Well absorbed from GI tract, peak plasma concentrations in 1-4 hours
• Distribution: Highly protein-bound (96-98%), crosses blood-brain barrier and placenta
• Metabolism: Extensive hepatic metabolism via demethylation and hydroxylation
• Elimination: Half-life of 5-30 hours (active metabolites have longer half-lives)
• Excretion: Primarily renal (urine) as metabolites

Contraindications

• Hypersensitivity to benzodiazepines
• Acute narrow-angle glaucoma
• Severe respiratory depression
• Severe hepatic impairment
• Myasthenia gravis
• Sleep apnea syndrome
• Pregnancy (first trimester)

Warnings and Precautions

• Risk of dependence and withdrawal symptoms
• Potential for abuse and misuse
• Paradoxical reactions may occur
• Impaired cognitive and motor performance
• Respiratory depression risk, especially with CNS depressants
• Elderly patients at increased risk of falls and cognitive impairment
• Not recommended during pregnancy (FDA Pregnancy Category D)

Drug Interactions

• CNS depressants: Enhanced sedation with alcohol, opioids, barbiturates
• Enzyme inhibitors: Cimetidine, disulfiram may increase levels
• Enzyme inducers: Rifampin, carbamazepine may decrease efficacy
• Oral contraceptives: May increase chlordiazepoxide levels
• Probenecid: May delay elimination

Adverse Effects

• Drowsiness, fatigue
• Ataxia, dizziness
• Confusion
• Memory impairment

• Respiratory depression
• Dependence and withdrawal syndrome
• Paradoxical excitement or aggression
• Blood dyscrasias (rare)
• Hepatic dysfunction (rare)

Monitoring Parameters

• Therapeutic response and symptom control
• Signs of excessive sedation or CNS depression
• Respiratory function, especially in compromised patients
• Liver function tests with long-term use
• Signs of dependence or misuse
• Cognitive and psychomotor function
• Fall risk assessment in elderly patients

Patient Education

• Take exactly as prescribed; do not increase dose without consultation
• Avoid alcohol and other CNS depressants
• Do not abruptly discontinue medication
• May cause drowsiness - avoid driving or operating machinery
• Use caution with activities requiring mental alertness
• Report any signs of worsening anxiety, depression, or suicidal thoughts
• Inform all healthcare providers about chlordiazepoxide use
• Store securely to prevent misuse by others

References

1. FDA Prescribing Information: Librium (chlordiazepoxide) 2. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14th Edition 3. American Psychiatric Association. (2010). Practice Guideline for the Treatment of Patients with Acute Stress Disorder and Posttraumatic Stress Disorder 4. Lexicomp Online, Chlordiazepoxide Monograph 5. Micromedex Solutions: Chlordiazepoxide Drug Information 6. Schatzberg AF, Nemeroff CB. The American Psychiatric Association Publishing Textbook of Psychopharmacology, 5th Edition 7. World Health Organization. (2019). WHO Model List of Essential Medicines