Usage
- Amitriptyline + Chlordiazepoxide is prescribed for moderate to severe depression accompanied by moderate to severe anxiety. It is specifically indicated when anxiety and depression coexist. Symptoms that may improve within the first week include insomnia, feelings of guilt or worthlessness, agitation, psychic and somatic anxiety, suicidal thoughts, and loss of appetite.
- Pharmacological classification: This combination drug falls under two classifications:
- Amitriptyline: Tricyclic antidepressant (TCA)
- Chlordiazepoxide: Benzodiazepine anxiolytic
- Mechanism of Action: Amitriptyline increases the levels of serotonin and norepinephrine, neurotransmitters crucial for mood regulation, in the brain by inhibiting their reuptake. Chlordiazepoxide enhances the effect of GABA, a neurotransmitter that reduces nerve cell activity, leading to a calming effect and anxiety reduction.
Alternate Names
- While there isn’t a distinct international nonproprietary name for the combination, the individual components are recognized as Amitriptyline hydrochloride and Chlordiazepoxide hydrochloride.
- Brand Names: Limbitrol, Limbitrol DS.
How It Works
- Pharmacodynamics: Amitriptyline exerts its antidepressant effect by inhibiting the reuptake of serotonin and norepinephrine, thereby increasing their synaptic concentrations. Chlordiazepoxide enhances the inhibitory effects of GABA by binding to the benzodiazepine site on the GABA-A receptor, leading to increased chloride influx and neuronal hyperpolarization. This results in sedation and anxiolysis.
- Pharmacokinetics: Both drugs are well-absorbed orally. Amitriptyline is extensively metabolized in the liver, primarily by CYP2D6 and CYP2C19, with a half-life of 10-28 hours. Chlordiazepoxide is also metabolized in the liver, forming active metabolites, with a half-life of 5-30 hours. Both drugs and their metabolites are primarily excreted in the urine.
- Mode of Action: Amitriptyline’s primary action is at the presynaptic nerve terminals, where it inhibits the reuptake of serotonin and norepinephrine. Chlordiazepoxide primarily acts at the postsynaptic GABA-A receptor, potentiating the inhibitory action of GABA.
- Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Amitriptyline inhibits the reuptake pumps for serotonin and norepinephrine. Chlordiazepoxide binds to the benzodiazepine site on the GABA-A receptor.
- Elimination pathways: Both drugs are primarily eliminated through hepatic metabolism followed by renal excretion.
Dosage
Standard Dosage
Adults:
- Initial dose: One tablet of either 5 mg chlordiazepoxide / 12.5 mg amitriptyline or 10 mg chlordiazepoxide / 25 mg amitriptyline, three to four times a day.
- Maintenance dose: Can be increased up to a maximum of six tablets per day of either strength, as needed and tolerated. Two tablets daily may be sufficient for some.
- Administration: Oral route.
- Timing: Divided doses, with the larger portion often taken at bedtime. A single bedtime dose may suffice for some.
Children:
- Use and dose must be determined by a doctor. Safety and efficacy have not been established in children.
Special Cases:
- Elderly Patients: Start with the lowest effective dose to minimize risks of ataxia, over-sedation, confusion, and anticholinergic effects.
- Patients with Renal Impairment: Dose adjustment is necessary. Start with a low dose and titrate cautiously, monitoring renal function.
- Patients with Hepatic Dysfunction: Dose adjustment is necessary. Close monitoring of liver function tests is recommended.
- Patients with Comorbid Conditions: Use with caution in patients with cardiovascular disease, seizures, glaucoma, urinary retention, thyroid disorders, or a history of substance abuse. Dose adjustments may be needed based on the specific comorbidity.
Clinical Use Cases
Amitriptyline + Chlordiazepoxide is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations. Benzodiazepines like Midazolam or Lorazepam, and other sedatives and analgesics are preferred in these situations.
Dosage Adjustments
- Dose adjustments should be made based on individual patient response, tolerability, and the presence of renal or hepatic impairment, other comorbid conditions, and drug interactions.
Side Effects
Common Side Effects:
- Drowsiness, dizziness, dry mouth, constipation, blurred vision, nasal congestion, bloating, vivid dreams, tremors, erectile dysfunction, confusion.
Rare but Serious Side Effects:
- Suicidal thoughts or actions, severe allergic reactions (hives, difficulty breathing, swelling), mania, glaucoma, heart rhythm changes, liver damage, serotonin syndrome (when combined with MAOIs), neuroleptic malignant syndrome (NMS).
Long-Term Effects:
- Physical dependence and withdrawal symptoms upon discontinuation, tardive dyskinesia (with long-term amitriptyline use), worsening of glaucoma.
Adverse Drug Reactions (ADR):
- Any signs of serotonin syndrome or NMS, severe allergic reactions, cardiac arrhythmias, significant liver dysfunction, suicidal ideation or behavior.
Contraindications
- Hypersensitivity to tricyclic antidepressants or benzodiazepines.
- Concurrent use or within 14 days of using MAO inhibitors.
- Recent myocardial infarction.
- Glaucoma (especially angle-closure).
Drug Interactions
- MAOIs: Concomitant use is contraindicated due to the risk of serotonin syndrome.
- Alcohol: Increases sedative effects and impairs cognitive function.
- CNS depressants: Additive sedative effects.
- Anticholinergics: Additive anticholinergic effects (dry mouth, constipation, blurred vision, urinary retention).
- CYP2D6 and CYP2C19 inhibitors: Increased amitriptyline levels.
- CYP3A4 inhibitors or inducers: Altered chlordiazepoxide levels.
- Other antidepressants (SSRIs, SNRIs): Increased risk of serotonin syndrome.
- Antihypertensives: May block their effects.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D (chlordiazepoxide) and C (amitriptyline). Not recommended during pregnancy, especially the first trimester, due to the risk of birth defects and neonatal withdrawal symptoms.
- Breastfeeding: The drug passes into breast milk and can cause side effects in the infant. Breastfeeding is not recommended while taking this medication.
Drug Profile Summary
- Mechanism of Action: Amitriptyline inhibits serotonin and norepinephrine reuptake; Chlordiazepoxide enhances GABA activity.
- Side Effects: Drowsiness, dizziness, dry mouth, constipation, blurred vision; rarely, suicidal thoughts, serotonin syndrome, NMS.
- Contraindications: Hypersensitivity, concurrent MAOI use, recent MI.
- Drug Interactions: MAOIs, alcohol, CNS depressants, anticholinergics, CYP inhibitors/inducers, other antidepressants.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Adults: Initial: 1 tablet (5/12.5 mg or 10/25 mg) TID-QID; Max: 6 tablets/day. Elderly: Start low and titrate slowly.
- Monitoring Parameters: Mental status, blood pressure, heart rate, liver function tests, complete blood count.
Popular Combinations
- This combination itself is used clinically. Individual components may be combined with other medications depending on the specific clinical needs. Combining amitriptyline with chlordiazepoxide is done because they target both depression and anxiety.
Precautions
- General Precautions: Screen for allergies, history of seizures, substance abuse, cardiovascular, hepatic, or renal disease, glaucoma, and urinary problems.
- Pregnant Women: Avoid use.
- Breastfeeding Mothers: Avoid use.
- Children & Elderly: Not recommended for children. Elderly: Start with low doses.
- Lifestyle Considerations: Avoid alcohol. Caution with driving or operating machinery.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Amitriptyline + Chlordiazepoxide?
A: Adults: Initially, one tablet (5mg chlordiazepoxide/12.5mg amitriptyline or 10mg/25mg) three to four times daily. The maximum dose is six tablets per day. Elderly patients should start with lower doses. Not recommended for children.
Q2: What are the primary side effects?
A: Common side effects include drowsiness, dizziness, dry mouth, constipation, and blurred vision.
Q3: What are the serious side effects to watch out for?
A: Suicidal thoughts, allergic reactions, mania, changes in heart rhythm, liver damage, and serotonin syndrome are rare but serious side effects.
Q4: Can this medication be used during pregnancy?
A: No, Amitriptyline + Chlordiazepoxide is generally contraindicated during pregnancy due to the risk of fetal harm.
Q5: What are the major drug interactions?
A: Avoid concomitant use with MAOIs. Interactions can also occur with alcohol, CNS depressants, other antidepressants, and certain other medications.
Q6: Can patients drink alcohol while on this medication?
A: Alcohol should be avoided as it can increase the sedative effects and impair cognitive function.
Q7: What should I do if a patient misses a dose?
A: Take the missed dose as soon as remembered, unless it is close to the next scheduled dose. Do not double the dose.
Q8: Is there a risk of dependence with this medication?
A: Yes, long-term use can lead to physical dependence, and withdrawal symptoms may occur upon discontinuation. A gradual tapering of the dose is recommended.
Q9: Who should not take this medication?
A: Patients with hypersensitivity to either component, recent myocardial infarction, or concurrent use of MAOIs should not take this medication.
Q10: What are the key monitoring parameters for patients on this drug?
A: Monitor for changes in mental status, blood pressure, heart rate, and any signs of adverse effects. Periodic blood counts and liver function tests may be advisable.
