chlordiazepoxide
benzodiazepine· Brands: Librium, RisolidIMIVPO
Mechanism of action
Chlordiazepoxide enhances the inhibitory effect of gamma-aminobutyric acid (GABA) at GABA-A receptors, increasing chloride ion influx and causing neuronal hyperpolarisation, resulting in central nervous system depression.
Pharmacokinetics
Chlordiazepoxide is well absorbed after oral administration and is extensively metabolised in the liver to active metabolites, including desmethylchlordiazepoxide and oxazepam. The parent drug has a long half-life, and active metabolites prolong the effective duration of action. Excretion is mainly via the kidneys.
Indications & dosing
Anxiety
Usual initial dose; adjust according to response. In elderly, a lower dose may be appropriate.
- adult · PO: 5–10 mg Three times daily · Usual initial dose; adjust according to response. In elderly, a lower dose may be appropriate.
Acute alcohol withdrawal
Initial dose, may be repeated as needed; reduce gradually. Monitor for sedation and respiratory depression.
- adult · PO: 20–30 mg Every 2-4 hours PRN · Initial dose, may be repeated as needed; reduce gradually. Monitor for sedation and respiratory depression.
Pre-operative anxiety
Administered before surgery to reduce anxiety. Consider patient's respiratory status and concurrent medications.
- adult · PO: 20–30 mg 1-2 hours pre-op · Administered before surgery to reduce anxiety. Consider patient's respiratory status and concurrent medications.
Contraindications & precautions
- Hypersensitivity to benzodiazepines · Cross-sensitivity may occur among benzodiazepines.
- Severe respiratory insufficiency · Risk of respiratory depression is increased.
- Severe hepatic impairment · Metabolism is impaired, leading to accumulation and increased toxicity.
- Acute narrow-angle glaucoma · Benzodiazepines do not typically increase intraocular pressure (they generally reduce it); the caution in narrow-angle glaucoma is largely historical.
- Myasthenia gravis · Muscle weakness may be exacerbated. Avoid unless benefits clearly outweigh risks.
- Avoid abrupt discontinuation; taper the dose slowly to prevent withdrawal seizures and rebound anxiety.
- Use caution in patients with renal or hepatic impairment, and consider dose reduction in hepatic impairment.
- Use caution in elderly or debilitated patients; lower doses are often required due to increased sensitivity.
- Avoid concurrent use of alcohol and other CNS depressants because of additive sedative and respiratory depressant effects.
- Caution in patients with a history of drug or alcohol dependence, as the risk of abuse and dependence is increased.
Adverse effects
- Drowsiness and sedation
- Ataxia
- Dizziness
- Confusion, especially in elderly
- Respiratory depressionserious
- Paradoxical aggression or agitationserious
- Dependence and withdrawal reactionsserious
Renal & hepatic adjustment
- eGFR 30–60: No dose adjustment usually required, but use with caution as active metabolites may accumulate.
- eGFR 0–30: Consider dose reduction. Use with caution; monitor for excessive sedation and respiratory depression.
- Hepatic impairment (mild): Use with caution; consider dose reduction.
- Hepatic impairment (moderate): Use with caution; reduce dose and monitor closely.
- Hepatic impairment (severe): Avoid, as metabolism is impaired and risk of encephalopathy and excessive sedation. (avoid)
Monitoring, pregnancy & toxicity
- Respiratory rate · Assess for respiratory depression, especially if concurrent opioids or other CNS depressants.
- Level of sedation · Monitor for excessive drowsiness or ataxia; adjust dose accordingly.
- Blood pressure and heart rate · Monitor vital signs, especially during alcohol withdrawal treatment.
- Signs of dependence and withdrawal · Observe for tolerance, dependence, and withdrawal symptoms on dose reduction or discontinuation.
- Paradoxical reactions · Monitor for agitation, aggression, or excitement, particularly in the elderly.
- Liver function tests · Monitor hepatic function, especially with long-term use or pre-existing liver disease.
- Pregnancy: Avoid use in pregnancy, especially during the first trimester. Use only if clearly necessary, and if used near delivery, monitor the neonate for respiratory depression and withdrawal symptoms.
- Toxicity: CNS depression: drowsiness, confusion, ataxia, slurred speech, and respiratory depression. · Supportive care: maintain airway, breathing, and circulation. Consider flumazenil in severe cases, but weigh against risk of precipitating seizures. Monitor for co-ingestants.
- Toxicity: Paradoxical agitation: in some patients, especially the elderly, benzodiazepines may cause paradoxical excitement. · Reassure and manage in a calm environment; treat symptomatically if needed.
- Toxicity: Withdrawal: abrupt cessation after long-term use may precipitate withdrawal symptoms including anxiety, tremor, seizures, and confusion. · Gradual dose reduction or short-term use of a long-acting benzodiazepine if withdrawal occurs.
Antidotes & reversal
- Flumazenil · Long-acting benzodiazepine; flumazenil risk of seizures/withdrawal.
Clinical notes
Chlordiazepoxide is used for short-term management of anxiety and alcohol withdrawal. Because of its long half-life it may accumulate, especially in the elderly or in hepatic impairment. Tolerance and dependence can occur; withdrawal should be gradual. It should be used with caution, avoiding alcohol and other CNS depressants.
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BNF; local formulary