Chlordiazepoxide + Amitriptyline

Debilitated patients: Use the lowest effective dose.

Patients receiving opioids: Use the lowest effective dose for the shortest possible duration. Monitor closely for sedation and respiratory depression.

Pharmacogenomics:

Amitriptyline

TCAs are classified as tertiary or secondary amines based on their similar yet distinct chemical structures. Amitriptyline, a tertiary amine, is primarily metabolised by CYP2C19 isoenzyme via demethylation into the secondary amine, nortriptyline (active metabolite). Both amitriptyline and nortriptyline are metabolised by CYP2D6 isoenzyme into less active hydroxy metabolites. CYP2C19 and CYP2D6 genes are highly polymorphic. Genetic variation in CYP2C19 which alters the ratio of parent drug to metabolites, or in CYP2D6 which affects drug clearance, may predispose patients to treatment failure or adverse effects.

CYP2D6 isoenzyme activity is reduced in approx 7-10% of Caucasians who are classified as CYP2D6 poor metabolisers. Reliable data on the prevalence of reduced CYP2D6 isoenzyme activity among Asians, Africans, and other populations are not yet available. Genetic testing may be considered prior to treatment initiation to help optimise efficacy and minimise the risk of adverse reactions.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2016:

CYP2D6

Phenotype and Genotype	Implications	Recommendations
CYP2D6 ultrarapid metaboliser (activity score of >2) Patients carrying duplications of functional alleles e.g. (*1/*1)xN, (*1/*2)xN, (*2/*2)xN (where xN represents the number of CYP2D6 gene copies)	Increased TCA metabolism to less active metabolites as compared to normal metabolisers. Lower plasma levels of the active metabolite may increase the possibility of treatment failure.	Avoid the use of TCA and consider an alternative drug not metabolised by CYP2D6. If TCA use is warranted, consider adjusting to a higher target dose compared to normal metabolisers. Use therapeutic drug monitoring to guide dose adjustments.
CYP2D6 intermediate metaboliser (activity score of 0.5 or 1) Patients carrying 1 decreased function and 1 non-functional allele e.g. *4/*41, *5/*9, *4/*10 CPIC update as of October 2019: Phenotype assignment for activity score of 1 has been changed from CYP2D6 normal metaboliser to CYP2D6 intermediate metaboliser.	Decreased TCA metabolism to less active metabolites as compared to normal metabolisers. Higher plasma levels of the active metabolite may increase the risk of adverse effects.	Consider a 25% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.
CYP2D6 poor metaboliser (activity score of 0) Patients carrying only non-functional alleles e.g. *4/*4, (*4/*4)xN, *3/*4, *5/*5, *5/*6	Significantly decreased TCA metabolism to less active metabolites as compared to normal metabolisers. Higher plasma levels of the active metabolite may increase the risk of adverse effects.	Avoid the use of TCA and consider an alternative drug not metabolised by CYP2D6. If TCA use is warranted, consider a 50% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.

CYP2C19

Phenotype and Genotype	Implications	Recommendations
CYP2C19 ultrarapid metaboliser Patients carrying 2 increased function alleles e.g. *17/*17	Increased tertiary amine metabolism as compared to normal metabolisers. Enhanced conversion of tertiary amines to secondary amines may affect treatment response or adverse effects.	Avoid the use of amitriptyline and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If amitriptyline use is necessary, utilise therapeutic drug monitoring to guide dose adjustments.
CYP2C19 rapid metaboliser Patients carrying 1 normal function allele and 1 increased function allele e.g. *1/*17	Increased tertiary amine metabolism as compared to normal metabolisers. Enhanced conversion of tertiary amines to secondary amines may affect treatment response or adverse effects.	Avoid the use of amitriptyline and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If amitriptyline use is necessary, utilise therapeutic drug monitoring to guide dose adjustments.
CYP2C19 intermediate metaboliser Patients carrying 1 normal function allele and 1 non-functional allele or 1 non-functional allele and 1 increased function allele e.g. *1/*2, *1/*3, *2/*17	Decreased tertiary amine metabolism as compared to normal metabolisers.	Initiate treatment with the recommended dose.
CYP2C19 poor metaboliser Patients carrying 2 non-functional alleles e.g. *2/*2, *2/*3, *3/*3	Significantly decreased tertiary amine metabolism as compared to normal metabolisers. Decreased conversion of tertiary amines to secondary amines may affect treatment response or adverse effects.	Avoid the use of amitriptyline and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If amitriptyline use is necessary, consider a 50% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.

Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of August 2019:

Phenotype	Description	Recommendations
CYP2D6 ultrarapid metaboliser	Enhanced conversion of amitriptyline into nortriptyline (active metabolite) and to inactive or less active metabolites. May increase the risk of therapeutic failure and cardiotoxicity.	Use 1.4 times the standard dose. Obtain amitriptyline and Z-10-hydroxy metabolites plasma concentrations and monitor the therapeutic or adverse effects. Avoid amitriptyline if a dose increase is not desired due to cardiotoxic hydroxy metabolite. Other antidepressant drugs that are not metabolised (or to a lesser extent) by CYP2D6 include citalopram and sertraline.
CYP2D6 intermediate metaboliser	Increased plasma concentration of amitriptyline (to a lesser extent) and nortriptyline (active metabolite), which may increase the risk of adverse effects.	Use 75% of the standard dose. Obtain amitriptyline plasma concentrations and monitor the therapeutic or adverse effects to determine the maintenance dose.
CYP2D6 poor metaboliser	Increased plasma concentration of amitriptyline (to a lesser extent) and nortriptyline (active metabolite), which may increase the risk of adverse effects.	Use 70% of the standard dose. Obtain amitriptyline plasma concentrations and monitor the therapeutic or adverse effects to determine the maintenance dose.

Dosage or treatment recommendations may vary among countries. Refer to local guidelines for the appropriate clinical recommendations.

Acute recovery period following MI. Concomitant use with MAOIs or within 14 days of discontinuing MAOIs.

Patient with history of CV disease (e.g. stroke, tachycardia, conduction abnormalities), depression (particularly if with suicidal risk), myasthenia gravis, porphyria, respiratory disease (including sleep apnoea and COPD), diabetes mellitus, hyperthyroidism, history or at risk of seizures (including those with head trauma, brain damage, alcoholism); decreased gastrointestinal motility, paralytic ileus, benign prostatic hyperplasia, urinary retention, xerostomia, angle-closure glaucoma, increased IOP, visual problems; risk factors for orthostatic hypotension (e.g. hypovolaemia, cerebrovascular or CV disease); at risk of falls. Patients undergoing electroconvulsive therapy or surgery (discontinue treatment several days before elective surgery). Debilitated patients. Avoid abrupt withdrawal. CYP2D6 ultrarapid, intermediate, and poor metabolisers. CYP2C19 ultrarapid, rapid, intermediate, and poor metabolisers. Renal and hepatic impairment. Elderly. Pregnancy and lactation. Concomitant use with opioids should be reserved for patients for whom alternative treatment options are inadequate.

Significant: Physical or psychological dependence, withdrawal reactions (prolonged use or high doses), tolerance; suicidal thoughts and behaviour; may precipitate mania or hypomania (particularly in patients with bipolar disorder); CNS depression; SIADH and hyponatraemia; anticholinergic effects (e.g. blurred vision, constipation, xerostomia, urinary retention), angle-closure glaucoma; bone fractures; orthostatic hypotension; altered blood glucose regulation; may lower seizure threshold; anterograde amnesia, paradoxical reactions (including hyperactive or aggressive behaviour), sleep-related activities (e.g. making phone calls, sleep-driving, cooking, and eating food while asleep). Rarely, bone marrow suppression.
Blood and lymphatic system disorders: Rarely, granulocytopenia.
Cardiac disorders: Tachycardia, palpitations, MI, arrhythmias, heart block.
Gastrointestinal disorders: Bloating, nausea, vomiting, diarrhoea, black tongue.
General disorders and administration site conditions: Fatigue, weakness, restlessness, lethargy.
Hepatobiliary disorders: Rarely, jaundice, hepatic dysfunction.
Metabolism and nutrition disorders: Anorexia.
Nervous system disorders: Drowsiness, dizziness, headache, tremor, incoordination, ataxia, numbness.
Psychiatric disorders: Euphoria, confusion, apprehension, poor concentration, delusions, hallucinations, hypomania.
Reproductive system and breast disorders: Impotence, decreased libido.
Respiratory, thoracic and mediastinal disorders: Nasal congestion.
Skin and subcutaneous tissue disorders: Rash, urticaria, photosensitivity, angioedema.
Vascular disorders: Hypotension, hypertension, syncope, stroke.
Potentially Fatal: Increased risks of abuse, misuse, and addiction; serotonin syndrome.

This drug may impair physical or mental abilities, if affected, do not drive or operate machinery.

Screen patients for risk of abuse, misuse, and addiction and suicidal ideation before treatment initiation and during therapy. Evaluate mental status, social functioning, mania, anxiety, panic attacks, or other unusual changes in behaviour. Monitor respiratory status, heart rate, blood pressure, ECG (in older adults and patients with preexisting cardiac disease), blood glucose; periodic liver and renal function tests, and CBC (prolonged use); serum sodium (as clinically indicated in at-risk populations), weight, and BMI. Assess for signs and symptoms of serotonin syndrome.

Symptoms: Chlordiazepoxide: Drowsiness, confusion, hypnotic state, lethargy, dysarthria, diminished reflexes, ataxia, hypotonia, respiratory depression, and coma. Rarely, disinhibitory or paradoxical reactions (including restlessness, excitement, talkativeness, agitation, irritability, impulsivity, and violent behaviour). Amitriptyline: Disturbed concentration, vomiting, transient visual hallucinations, dilated pupils, hyperactive reflexes, stupor, muscle rigidity, hypothermia, hyperpyrexia, cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma.

Management: Symptomatic and supportive treatment. Initiate IV fluids administration and maintain an adequate airway. Obtain ECG and initiate cardiac monitoring. Flumazenil may be given for the complete or partial reversal of the sedative effects of benzodiazepine overdose.

Amitriptyline: May increase serum concentrations with topiramate. May reduce the antihypertensive effects of guanethidine. May increase serum concentration with CYP2D6 inhibitors such as quinidine, cimetidine, and CYP2D6 substrates, including phenothiazines, type 1c antiarrhythmics (e.g. flecainide, propafenone).
Potentially Fatal: Increased risk of serotonin syndrome with MAOIs (including linezolid and IV methylthioninium chloride) and other serotonergic agents (e.g. buspirone, lithium, tramadol, triptans, tryptophan, SSRIs, SNRIs, other TCAs).
Chlordiazepoxide: Concomitant use with opioids may result in profound sedation, respiratory depression, and coma.

May enhance the CNS depressant effect of alcohol. May increase the risk of serotonin syndrome and reduce plasma concentrations with St. John's wort.

Description:
Mechanism of Action: Chlordiazepoxide is a long-acting benzodiazepine. It binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron in different sites within the CNS. It enhances the inhibitory effect of GABA by increasing the permeability of the neuronal membrane to chloride ions, thus resulting in hyperpolarisation and stabilisation.
Amitriptyline is a dibenzocycloheptadiene tricyclic antidepressant. Its exact mechanism of action is unknown, but it appears to inhibit the reuptake of serotonin and/or norepinephrine through the presynaptic neuronal membrane pump, leading to an increase in synaptic concentrations of these neurotransmitters in the CNS.
Pharmacokinetics:
Absorption: Chlordiazepoxide: Almost completely absorbed. Time to peak plasma concentration: 0.5-2 hours.
Amitriptyline: Readily absorbed from the gastrointestinal tract. Bioavailability: Approx 43-46%. Time to peak plasma concentration: Approx 2-5 hours.
Distribution: Crosses the placenta and enters breast milk.
Chlordiazepoxide: Passes into CSF. Volume of distribution: 3.3 L/kg. Plasma protein binding: Approx 96%.
Amitriptyline: Widely distributed throughout the body. Volume of distribution: Approx 18-22 L/kg. Plasma protein binding: >90%.
Metabolism: Chlordiazepoxide: Extensively metabolised in the liver into desmethylchlordiazepoxide, desmethyldiazepam (active and long-acting metabolite), and demoxepam.
Amitriptyline: Metabolised in the liver by CYP3A4, CYP2C19, and CYP2D6 via demethylation into nortriptyline (primary active metabolite); undergoes extensive first-pass metabolism.
Excretion: Chlordiazepoxide: Via urine (1-2% as unchanged drug; 3-6% as metabolite). Elimination half-life: 24-48 hours (chlordiazepoxide); 14-95 hours (demoxepam).
Amitriptyline: Via urine (mainly as glucuronide or sulfate conjugate metabolites with small amounts of unchanged drug); faeces (small amounts). Elimination half-life: Approx 13-36 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 9916, Chlordiazepoxide hydrochloride. https://pubchem.ncbi.nlm.nih.gov/compound/Chlordiazepoxide-hydrochloride. Accessed Oct. 30, 2025.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 2160, Amitriptyline. https://pubchem.ncbi.nlm.nih.gov/compound/Amitriptyline. Accessed Apr. 28, 2023.

Store between 20-25°C. Protect from light and moisture.

Antidepressants / Anxiolytics

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