Continuing Education Activity
Chlordiazepoxide is a long-acting benzodiazepine and is an FDA approved medication for adults with mild-moderate to severe anxiety, preoperative anxiety, and alcohol withdrawal. It is also FDA approved for pediatric patients greater than six years old for anxiety. It ranks among the safer of the effective psychopharmacologic benzodiazepine compounds. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring of chlordiazepoxide so providers can direct patient therapy, where indicated, as part of the interprofessional team.
- Outline the symptoms of chlordiazepoxide toxicity.
- Identify the indications for chlordiazepoxide medication therapy.
- Review the mechanism of action of chlordiazepoxide.
- Describe how the interprofessional healthcare team can improve the outcome of chlordiazepoxide usage.
Chlordiazepoxide is a long-acting benzodiazepine and is an FDA approved medication for adults with mild-moderate to severe anxiety disorder, preoperative apprehension and anxiety, and withdrawal symptoms of acute alcohol use disorder. It is also FDA approved for pediatric patients greater than six years old for anxiety. Off-label, it can be used in the treatment of catatonia. It was synthesized and developed in 1956 and approved for use in 1960. It is among the least harmful of the effective psychopharmacological benzodiazepine composites. Like other medications in the benzodiazepine class, it serves as an augmenting agent for antipsychotics, mood stabilizers, SSRI, and SNRI to treat psychotic disorder, bipolar disorder, and anxiety disorders. Clinicians should not combine chlordiazepoxide with other benzodiazepines.
Mechanism of Action
Chlordiazepoxide has anti-anxiety, sedative, appetite-stimulating, and weak analgesic actions. It binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex and enhances GABA's inhibitory effects. Also, it increases chloride conductance through GABA-regulated channels. Moreover, its therapeutic benefits in anxiety disorder come from the inhibition of neuronal activity in amygdala-centered fear circuits. Additionally, it blocks EEG arousal from stimulation of the brain stem reticular formation. It is common to see some immediate relief of anxiety symptoms with first dosing, but several weeks with daily dosing are needed to see the maximal therapeutic benefit. It is metabolized by the liver microsomal pathway, first by hepatic oxidation, then by glucuronidation. The elimination half-life of this medication is 24 to 48 hours, and its excretion is via the urine.
Chlordiazepoxide is available as a capsule with three different strengths: 5, 10, and 25 mg for oral dosing, and as an injectable with a concentration of 100 mg/5 ml. It is usually in the form of a gelatin capsule, and storage should be at 68 F to 77 F (20 C to 25 C). For pediatric patients over six years old and geriatric patients, the recommendation is to use the lowest effective dose. Moreover, for pediatric patients, injectable forms are not recommended, and there is no data on the long-term effects of this medication in this age group.
Treatment of mild to moderate anxiety:
- Oral: 15 to 40 mg/day in 3 to 4 doses
Treatment of severe anxiety:
- Oral: 60 to 100 mg/day in 3 to 4 doses
Treatment of acute to severe anxiety:
- Injectable: initially 50 to 100 mg, then 25 to 50 mg 3 to 4 times/day if necessary
Treatment of alcohol withdrawal:
- Oral: initially 50 to 100 mg, then repeat after 2 hours as needed until agitation or withdrawals are controlled and can increase up to 300 mg/day
Treatment of preoperative apprehension and anxiety:
- Oral: 5 to 10 mg/day 3 to 4 doses preceding surgery
- Injectable: 50 to 100 mg IM 1 hour before surgery
Treatment of renal impairment, hepatic impairment:
- Oral: initially 10 to 20 mg/day in 2 to 4 doses then increase as needed
- Injectable: 25 to 50 mg
Treatment for geriatric patients or with existing debilitating disease:
Discontinuation of this medication because of side effects is rare, but some common adverse effects can occur, particularly in the elderly and debilitated. Most of the side effects associated with these medications are preventable by correct dose adjustment. Common side effects include fatigue, sedation, depression, dizziness, ataxia, slurred speech, weakness, confusion, forgetfulness, nervousness, hyperexcitability, and pain at the injection site. Some of the rare side effects include mania, weight gain, hallucination, hypotension, skin eruptions, menstrual irregularity, dry mouth, and hyper-salivation. Life-threatening side 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.
There is an absolute contraindication in patients with known hypersensitivity to chlordiazepoxide, other benzodiazepines or its components, and the patient who has angle-closure glaucoma. Strong drug interactions exist with the use of another CNS depressant or opioid medications. Respiratory depression, increased sedation, coma, and death can occur if taking these two 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. 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. Likewise, it may diminish mental alertness in children.
Chlordiazepoxide is a schedule IV controlled drug. There is a reported risk of dependence with long term use. Even though there is no established cause-effect relationship, patients on anticoagulation should require monitoring for possible blood coagulation. Patients with porphyria also need monitoring because of possible porphyria exacerbation. Per clinical data, there have been reports of paradoxical reactions such as acute rage, stimulation, and excitement in psychiatric and hyperactive aggressive pediatric patients on chlordiazepoxide therapy.
In cases of chlordiazepoxide overdose or toxicity, the patient may present with confusion, diminished reflexes, comatose, or somnolent. Interventions include securing the airway and providing adequate intravenous fluid resuscitation. Patient respiration, blood pressure, and pulse must have regular monitoring. 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 competitive inhibition of the alpha-beta subunit GABA binding site to insert 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.
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, it has been widely used all around the world, in and out of the hospital. Because of its serious side effects, all healthcare professionals involved in prescribing, administering, and distributing this drug must educate patients on how to use the drug. 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 side 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.
After the clinician makes the therapeutic decision to prescribe chlordiazepoxide, the other interprofessional healthcare team members must also have involvement in the therapy regimen. Nursing can counsel the patient, answer questions, monitor for signs of adverse effects, and verify patient compliance. The pharmacist should verify 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 need to have a clear communication channel to the prescriber. This type of interprofessional teamwork ensures the optimal therapeutic benefit and minimal adverse events from chlordiazepoxide therapy, leading to better patient outcomes. [Level 5]