Chlordiazepoxide

Mechanism of Action

Chlordiazepoxide has anti-anxiety, sedative, appetite-stimulating, and myorelaxant actions. The medication binds to benzodiazepine receptors at the gamma-aminobutyric acid type A (GABA-A) ligand-gated chloride channel complex and enhances GABA's inhibitory effects. Chlordiazepoxide increases the frequency of chloride opening through GABA-regulated channels.[5] The therapeutic benefits of anxiety disorder occur from the inhibition of neuronal activity in amygdala-centered fear circuits.[6][7] Additionally, it blocks electroencephalogram (EEG) arousal of the reticular formation.[8] Observing some immediate relief of anxiety symptoms with the first dosing is common, but several weeks with regular dosing are needed to see the maximal therapeutic benefit.

Pharmacokinetics

Absorption: The peak plasma concentrations for long-acting chlordiazepoxide are attained in several hours.

Distribution: Benzodiazepines exhibit widespread distribution throughout the body, preferring accumulation in lipid-rich regions, including the central nervous system (CNS). The plasma protein binding of chlordiazepoxide is high, approximately 96%.[9]

Metabolism: Chlordiazepoxide is metabolized by the liver microsomal pathway, first by hepatic oxidation and then glucuronidation.[10]

Elimination: The elimination half-life of this medication is 24 to 48 hours, and its excretion is via urine.[11][12]

Administration

Available Dosage Forms and Strengths

Chlordiazepoxide is available as a capsule with 3 different strengths—5 mg, 10 mg, and 25 mg—for oral dosing and as an injectable with a concentration of 100 mg/5 mL. Typically available in gelatin capsule form, it is advised to store chlordiazepoxide between 68 °F and 77°F (20 °C to 25 °C). The recommended approach is to administer the lowest effective dose, especially for pediatric patients aged 6 and older and geriatric patients. Injectable forms are not recommended for pediatric patients, and no data exist on their long-term effects.

Adult Dosage

Treatment of mild-to-moderate anxiety: For the management of mild-to-moderate anxiety, the recommended oral dosage ranges from 15 to 40 mg/d, administered in 3 to 4 doses.

Treatment of severe anxiety: For the treatment of severe anxiety, the oral dosage is typically prescribed in the range of 60 to 100 mg/d, distributed across 3 to 4 doses.

Treatment of acute-to-severe anxiety: For the management of acute-to-severe anxiety using injectable chlordiazepoxide, the recommended initial dosage is 50 to 100 mg/d, followed by 25 to 50 mg/d administered 3 to 4 times if needed.

Treatment of alcohol withdrawal: For the treatment of alcohol withdrawal, the recommended oral dosage involves an initial administration of 50 to 100 mg/d, with the option to repeat after 2 hours as necessary until agitation or withdrawal symptoms are controlled. The dosage can be increased up to a maximum of 300 mg/d.

Treatment of preoperative apprehension and anxiety: For preoperative apprehension and anxiety, the oral dosage is 5 to 10 mg/d, administered in 3 to 4 doses preceding surgery. Alternatively, an injectable form may be used with 50 to 100 mg administered intramuscularly (IM) 1 hour before surgery.

Specific Patient Populations

Hepatic impairment: The manufacturer's labeling does not include dosage adjustments; however, caution should be exercised when using chlordiazepoxide due to its hepatic metabolism.[10]

Renal impairment: In patients with renal impairment, chlordiazepoxide is typically initiated orally at 10 to 20 mg daily, divided into 2 to 4 doses. Subsequent adjustments may be made based on individual responses and requirements. An initial dose of 25 to 50 mg is recommended for injectable forms.

Pregnancy considerations: A risk of congenital malformations is associated with the administration of benzodiazepines, including chlordiazepoxide, during the first trimester of pregnancy. As the requirement for administering chlordiazepoxide is rarely urgent, it is advisable to refrain from their use during this crucial period. Healthcare professionals should be vigilant of the potential pregnancy status of women of childbearing potential at the initiation of therapy. Patients are advised that if they become pregnant during treatment or are planning pregnancy, it is recommended to discuss with their healthcare providers the appropriateness of discontinuing the drug.

Breastfeeding considerations: A lack of available information precludes recommendations on chlordiazepoxide use during breastfeeding. Due to the potential accumulation of the drug and its metabolites in the breastfed infant, opting for an alternative medication is advisable, particularly when nursing a newborn or preterm infant. In cases where chlordiazepoxide is utilized, it is recommended to closely monitor the infant for signs such as sedation, poor feeding, and inadequate weight gain.[13]

Pediatric patients: Due to the diverse response of pediatric patients to CNS-acting drugs, initiating therapy with chlordiazepoxide is recommended at the lowest effective dose and adjusting it as needed. Considering the limited clinical experience in pediatric patients aged 6 or younger, the use of chlordiazepoxide in this age group is not advisable. The suggested starting dosage for chlordiazepoxide is 5 mg, administered 2 to 4 times daily, with a potential increase to 10 mg, 2 to 3 times in specific pediatric cases.

Older patients: The FDA-approved label recommends 5 mg of chlordiazepoxide, administered 2 to 4 times daily. As per the guidelines by the American Geriatric Society Beers Criteria, chlordiazepoxide is considered a potentially inappropriate medication for older adults due to its heightened sensitivity to benzodiazepines. Older patients are at an increased risk of experiencing cognitive impairment, falls, and fractures. However, the cautious use of chlordiazepoxide may be considered justifiable in some instances, including the management of seizure disorders, alcohol withdrawal, and periprocedural sedation.[14]

Adverse Effects

Discontinuation of chlordiazepoxide due to adverse effects is uncommon. However, older and debilitated patients may experience certain common adverse effects. Most adverse effects associated with these medications are preventable by correct dosage adjustments. Common adverse effects include fatigue, sedation, depression, dizziness, ataxia, slurred speech, weakness, confusion, forgetfulness, nervousness, hyperexcitability, and pain at the injection site. Some of the rare adverse effects include mania, weight gain, hallucination, hypotension, skin eruptions, menstrual irregularity, dry mouth, and hypersalivation. Life-threatening adverse effects are blood dyscrasias, renal dysfunction, hepatic dysfunction, and respiratory depression, particularly when taken with CNS depressants in overdose. Hyperactive pediatric patients require monitoring for the paradoxical effect.[15][16] Acute withdrawal of chlordiazepoxide can be associated with catatonia.[17] Chlordiazepoxide-associated delirium in alcohol withdrawal has been reported.[18] Benzodiazepines also increase the risk of angle closure glaucoma.[19]

Drug-Drug Interactions

Strong drug interactions exist with the use of other CNS depressants or opioid medications. Respiratory depression, increased sedation, coma, and death can occur if taking these 2 drugs simultaneously. If it is necessary to use an opioid and chlordiazepoxide together, using the lowest possible dose with the shortest duration would help decrease the likelihood of respiratory depression. Clinicians should use this medication cautiously in people with pulmonary disease.[20][21]

Kratom has partial opioid agonist effects and is frequently subject to misuse. When kratom is used concurrently with benzodiazepines such as chlordiazepoxide, it elevates the risk of severe CNS depression. Consequently, it is recommended to avoid this combination.[27][26]

Contraindications

 Box Warnings

• The simultaneous use of benzodiazepines and opioids can lead to profound sedation, respiratory depression, coma, and, in severe cases, fatalities. Prescribe these medications concomitantly only when alternative treatments are insufficient. Limit doses and treatment durations to the minimum necessary. Monitor for sedation and respiratory depression.

• The use of benzodiazepines, including chlordiazepoxide, exposes individuals to the risk of misuse, abuse, and potential addiction, resulting in overdose or death. Benzodiazepine abuse and misuse often involve concurrent alcohol and illicit substances, contributing to a higher incidence of severe adverse outcomes. Before prescribing chlordiazepoxide and throughout treatment, evaluate each patient's susceptibility to abuse, misuse, and addiction.

• Prolonged use of benzodiazepines, including chlordiazepoxide, may lead to clinically significant physical dependence. The likelihood of dependence and withdrawal symptoms rises with extended treatment duration and higher daily doses. Abrupt cessation or rapid dose reduction of chlordiazepoxide following prolonged use can precipitate severe withdrawal reactions, posing a potential threat to life. To mitigate the risk of withdrawal reactions, employ a gradual taper when discontinuing chlordiazepoxide or adjusting the dosage.

• An increased risk of suicidal ideation exists in a patient with major depressive disorder. It is not recommended for a pregnant patient or planning to get pregnant due to the potential risk of congenital anomalies, especially during the first trimester. Chlordiazepoxide may reduce the mental and physical abilities needed for the performance of some tasks, including driving a vehicle or operating heavy machinery. Similarly, it may diminish mental alertness in children.[22]

Warnings and Precautions

Chlordiazepoxide is contraindicated with known hypersensitivity to chlordiazepoxide, other benzodiazepines, or its excipients.[23]

Monitoring

Chlordiazepoxide is a schedule IV controlled drug. A reported risk of dependence exists with long-term use.[24] Though no established cause-effect relationship exists, patients on anticoagulation should require monitoring for prothrombin time/international normalized ratio (PT/INR). Patients with porphyria also need monitoring because of possible porphyria exacerbation. Per clinical data, reports document paradoxical reactions such as acute rage, stimulation, and excitement in psychiatric and hyperactive pediatric patients on chlordiazepoxide therapy.[25] Prescribers and pharmacists must monitor treatment, provide patient education, and be vigilant in prescribing benzodiazepines such as chlordiazepoxide. The Prescription Drug Monitoring Program is capable of detecting potential misuse of chlordiazepoxide.[41]

Toxicity

Signs and Symptoms of Overdose

In cases of chlordiazepoxide overdose or toxicity, the patient may present with confusion, diminished reflexes, coma, or somnolence. Interventions include securing the airway and providing adequate intravenous fluid resuscitation. Patient respiration, blood pressure, and pulse require regular monitoring.

Management of Overdose

Flumazenil, a specific benzodiazepine receptor antagonist used for a partial or complete reversal of the sedative property of benzodiazepines, is an option for treatment. Flumazenil works by competitively inhibiting the alpha-beta subunit GABA-binding site to exert its effect. After the administration of flumazenil, clinicians should monitor the patient for the risk of seizure associated with this medication, especially in patients with chronic benzodiazepine use.[26]

Enhancing Healthcare Team Outcomes

Chlordiazepoxide, a prototype for the benzodiazepine compounds, has been in use since its development in 1960. Like other medications in this group, the use is worldwide, in and out of the hospital. Because of serious adverse effects, all healthcare professionals involved in prescribing, administering, and distributing this drug must educate patients on best-use practices. Patients should be informed about addiction potential, suicidal ideation in depression, respiratory depression, fetus malformation during pregnancy, sedation, fatigue, dizziness, ataxia, slurred speech, weakness, confusion, forgetfulness, nervousness, and hyperexcitability. Patients should be informed about life-threatening adverse effects if combined with opiates, alcohol, and other CNS-depressant medications. Furthermore, patients should understand the need to refrain from driving a car or operating heavy machinery.[27][28]

In a study, numerous investigations were identified that evaluated targeted pharmacist interventions for deprescribing benzodiazepines in older adults, with a limited emphasis on opioids. The EMPOWER brochure, directed at patients, emerged as a prevalent targeted intervention, complemented by electronic pharmacist communications, pharmacist-led deprescribing services, and multimodal interventions. Pharmacists, acknowledged as accessible and trusted healthcare professionals, are well-positioned for deprescribing. The outpatient focus on deprescribing opioids may be influenced by increased scrutiny in long-term care settings, emphasizing the importance of longitudinal care continuity. Despite inherent limitations in rapid reviews, this study provides valuable insights into targeted pharmacist interventions for deprescribing in older adults, underscoring the pivotal role of pharmacists in facilitating safe and effective deprescribing practices.[29]

After the clinician makes the therapeutic decision to prescribe chlordiazepoxide, the other interprofessional healthcare team members must also be involved in the therapy regimen. Nurses can counsel the patient, answer questions, monitor for signs of adverse effects, and verify patient compliance. The pharmacist should verify that the dosing is appropriate for the condition, check the medication profile for drug interactions, and be available to counsel the patient. Both pharmacy and nursing must have a clear communication channel to the prescriber. Psychiatrists should be consulted for severe anxiety disorders. An addiction medicine specialist should be consulted in chlordiazepoxide for acute alcohol withdrawal. Toxicologists and critical care clinicians should be consulted for overdose. This type of interprofessional teamwork, including specialists, pharmacists, and nurses, ensures the optimal therapeutic benefit and minimal adverse events from chlordiazepoxide therapy, leading to better patient outcomes.