Amitriptyline

Amitriptyline is a an Antidepressant agent belonging to Tricyclic Class

Amitriptyline is approved for the treatment of Major depressive disorder.

Amitriptyline is Readily and completely absorbed from the gastrointestinal tract. And is Widely distributed throughout the body. Crosses the placenta; enters breast milk (small amounts). Volume of distribution: Approx 18-22 L/kg. Plasma protein binding: >90% and get Metabolised in the liver by CYP3A4 and CYP2C19 via demethylation and by CYP2D6 via hydroxylation, followed by conjugation with glucuronic acid to form metabolites, nortriptyline (primary active metabolite), hydroxy and conjugated derivatives. Undergoes extensive first-pass metabolism. And get excreted 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.

The common side effects associated with Amitriptyline include Suicidal thoughts and behaviour (particularly in children and young adults); may precipitate mania or hypomania (particularly in patients with known manic-depressive illness), may aggravate psychotic symptoms (in schizophrenic patients); cardiac arrhythmias, QT interval prolongation, AV conduction disturbance.

Amitriptyline is available in the form of oral solid.

The molecule is available in India, USA, Germany, Japan.

Increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibiting their reuptake by the presynaptic neuronal membrane pump.

Onset of action of Amitriptyline was within 1`-2 weeks

Tmax of Amitriptyline was about Approx 2-5 hours.

Amitriptyline is available in Tablets

Oral: Administer higher doses preferably at late afternoon or as bedtime doses to minimize daytime sedation.

Amitriptyline can be used in the treatment of Major depressive disorder.

Amitriptyline is a tricyclic dibenzocycloheptadiene antidepressant. It inhibits the neuronal membrane pump mechanism responsible for serotonin (5-HT) and/or norepinephrine reuptake, hence extending and amplifying their activity in the brain. The recognised mechanism of action involved in the maintenance of neuropathic pain and prevention of chronic tension-type headache and migraine includes ion-channel blocking actions on Na, K, and NMDA channels at both the central and spinal cord levels. It also has varying degrees of affinity for muscarinic and histamine (H1) receptors.

Amitriptyline is approved for use in the following clinical indications

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder

• Although not approved there have been certain off labelled uses documented for Amitriptyline which include:

Chronic fatigue syndrome–related sleep disturbances and pain; Fibromyalgia; Functional dyspepsia; Headache, chronic tension-type (prevention); Interstitial cystitis (bladder pain syndrome); Irritable bowel syndrome; Migraine, prevention; Neuropathic pain, chronic (including diabetic neuropathy); Postherpetic neuralgia; Sialorrhea.

Chronic fatigue syndrome related sleep disorders and pain (off-label use): Based on limited evidence; recommendations based on expert opinion: Oral: Initial: 10 mg once daily 1 hour before bedtime; may increase dose gradually based on response and tolerability in 10 mg increments up to 50 mg/day at bedtime for sleep disorders; for patients with pain, titrate up to 100 mg/day given once daily at bedtime or in divided doses

Fibromyalgia (off-label use): Oral: Initial: 10 mg once daily, 1 to 3 hours before bedtime; gradually increase dose based on response and tolerability in 5 to 10 mg increments at intervals of ≥2 weeks up to 75 mg/day . Note: Some experts suggest lower starting doses of 5 mg once daily in patients sensitive to side effects and that a maintenance dose range of 20 to 30 mg/day is often adequate

Functional dyspepsia (alternative agent) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability at intervals of ≥2 weeks up to 75 mg/day . Some experts suggest a lower maintenance dose range of 20 to 30 mg/day. Allow for an 8- to 12-week trial before discontinuing due to ineffectiveness. If amitriptyline is effective, reassess at 6 months with an attempt to discontinue treatment; may resume if dyspepsia recurs

Headache, chronic tension-type (prevention) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may increase dose based on response and tolerability in 10 to 25 mg increments at intervals of ≥1 week up to 125 mg/day. A lower starting dose of 10 to 12.5 mg once daily at bedtime and smaller titration increments of 10 to 12.5 mg/day at 2- to 3-week intervals may reduce adverse effects and enhance adherence according to some experts

Interstitial cystitis (bladder pain syndrome) (off-label use): Oral: Initial: 10 mg once daily at bedtime; based on response and tolerability, increase dose after 1 week to 25 mg once daily and then at weekly intervals in 25 mg increments to a target dose of 75 to 100 mg/day . A maximum dose of up to 75 mg/day as tolerated is suggested by some experts

Irritable bowel syndrome (alternative agent) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability to a recommended dose of 50 to 100 mg/day. Some experts recommend 3 to 4 weeks of therapy before increasing the dose

Major depressive disorder (unipolar) (alternative agent): Oral: Initial: 25 to 50 mg/day as a single dose at bedtime or in divided doses; increase dose based on response and tolerability in 25 to 50 mg increments at intervals of ≥1 week up to a usual dose of 100 to 300 mg/day. Some experts suggest an initial dose of 25 mg/day at bedtime for most patients, although higher starting doses of 50 to 100 mg/day and more rapid titration (eg, every few days) may be considered in closely supervised (eg, hospitalized) settings; for patients sensitive to adverse effects, may initiate with 10 mg daily with gradual titration in steps of 10 mg/day every few days or longer (eg, at intervals ≥1 week)

Manufacturer's labeling: Dosing in prescribing information may not reflect current clinical practice. Oral: Initial: 75 to 100 mg/day as a single dose at bedtime or in divided doses

Migraine, prevention (off-label use):

Note: An adequate trial for assessment of effect is considered to be at least 2 to 3 months at a therapeutic dose

Oral: Initial: 10 to 25 mg once daily at bedtime; increase dose based on response and tolerability in 10 to 25 mg increments at intervals of ≥1 week up to 150 mg/day . Some experts suggest that a lower maintenance dose range of 10 to 100 mg once daily at bedtime is often adequate and better tolerated

Neuropathic pain, chronic (including diabetic neuropathy) (alternative agent) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability in 10 to 25 mg increments at intervals ≥1 week up to 150 mg/day given once daily at bedtime or in 2 divided doses

Postherpetic neuralgia (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability in 10 to 25 mg increments at intervals of ≥1 week up to 150 mg/day given once daily at bedtime or in 2 divided doses

Sialorrhea (off-label use): Oral: Usual dose: 10 to 25 mg once daily at bedtime. If necessary, may gradually increase dose based on response and tolerability up to 100 mg/day

(Amitriptyline can be administered orally before/ after meals. The dosage and duration of treatment should be as per the clinical judgement of the treating physician)

(The dosage and duration of treatment should be as per the clinical judgement of the treating physician).

10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg.

Tablets.

• Dose Adjustment in Kidney Patient

Altered kidney function: Mild to severe impairment: No dosage adjustment necessary ; use with caution.

Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (large V_d): No supplemental dose or dosage adjustment necessary ; however, dialysis patients have demonstrated increased sensitivity to the anticholinergic side effects of tricyclic antidepressants (TCAs) (potentially due to accumulation of glucuronide metabolites). Use with caution (or avoid use) along with close monitoring for both anticholinergic and QT prolonging effects .

Peritoneal dialysis: Unlikely to be dialyzed (large V_d): No dosage adjustment necessary ; however, dialysis patients have demonstrated increased sensitivity to the anticholinergic side effects of TCAs (potentially due to accumulation of glucuronide metabolites). Use with caution (or avoid use) along with close monitoring for both anticholinergic and QT prolonging effects.

CRRT: Unlikely to be dialyzed: No dosage adjustment necessary

PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be dialyzed: No dosage adjustment necessary.

• Dose Adjustment in Pediatric Patient:

Chronic pain management: Limited data available: Children and Adolescents: Oral: Initial: 0.1 mg/kg at bedtime, may advance as tolerated over 2 to 3 weeks to 0.5 to 2 mg/kg at bedtime .

Cyclic vomiting syndrome, prophylaxis: Limited data available:

Note: Prophylaxis is recommended for patients experiencing frequent symptoms (eg, monthly) or severe symptoms (eg, requiring hospitalization, lasting >2 days, resulting in significant school/work absences) .

Children ≥5 years and Adolescents: Oral: Initial: 0.2 to 0.5 mg/kg/day once daily, administered at bedtime. If needed, may titrate every 1 to 2 weeks (eg, by 5 to 10 mg increments) to a usual dose of 1 to 1.5 mg/kg/day; doses of 2 mg/kg/day or higher have been described; however, should be used with caution with careful titration, ECG monitoring, and therapeutic monitoring; doses may be divided for tolerability . In adults, the mean effective dose is 75 to 100 mg/day.

Depressive disorders: Note: Controlled clinical trials have not shown tricyclic antidepressants to be superior to placebo for the treatment of depression in children and adolescents; not recommended as first-line medication; may be beneficial for patients with comorbid conditions .

Children 9 to <12 years: Limited data available: Oral: Initial: 1 mg/kg/day in 3 divided doses; after 3 days, dose may be increased to 1.5 mg/kg/day in 3 divided doses ; dosing was reported in a small pilot study (n=9) .

Children ≥12 years and Adolescents:

Manufacturer's labeling: Oral: Usual initial dosage: 10 mg three times daily and 20 mg at bedtime. In general, lower doses are recommended compared to adults; maximum daily dose: 200 mg/day .

Alternate dosing: Oral: Usual range: 30 to 100 mg at bedtime or in divided doses twice daily; maximum daily dose: 200 mg/day . In adults, therapy is initiated with 25 to 50 mg daily single dose at bedtime or in divided doses .

Migraine, prophylaxis

Discontinuation of therapy: Consider planning antidepressant discontinuation for lower-stress times, recognizing non-illness-related factors could cause stress or anxiety and be misattributed to antidepressant discontinuation . Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. After long-term (years) antidepressant treatment, WFSBP guidelines recommend tapering over 4 to 6 months, with close monitoring during and for 6 months after discontinuation. If intolerable discontinuation symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate.

Amitriptyline should be used in the treatment of (approved indications) along with appropriate dietary restrictions

The dietary restriction should be individualized as per patient requirements.

Recent MI, any degree of heart block or cardiac rhythm disorders. Severe hepatic impairment. Children <6 years. Concomitant use with MAOIs or within 14 days of discontinuing non-selective, irreversible MAOIs. Concomitant use with cisapride.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities).

• GI motility: Use with caution in patients with decreased GI motility (eg, paralytic ileus) as anticholinergic effects may exacerbate underlying condition.

• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance is decreased, and plasma concentrations are increased. Due to the narrow therapeutic index, use lower initial and maintenance doses of tricyclic antidepressants. Use caution in patients with hepatic encephalopathy due to the risk of neurocognitive effects

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer may be effective for acute treatment of bipolar major depressive episodes, but should be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants. Patients presenting with depressive symptoms should be screened for bipolar disorder. Amitriptyline is not FDA approved for the treatment of bipolar depression.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition

• Ophthalmic conditions: Use with caution in patients with certain ophthalmic conditions (eg, increased intraocular pressure, narrow angle glaucoma, visual problems) as anticholinergic effects may exacerbate underlying condition.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.

• Urinary retention (eg, benign prostatic hyperplasia): Use with caution in patients with urinary retention as anticholinergic effects may exacerbate underlying condition.

May enhance the sedative effect of alcohol.

Amitriptyline and the metabolite nortriptyline are present in breast milk.

Pregnancy Category C

Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose ). Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations. Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity. In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of cranial bones.

Amitriptyline has been shown to cross the placenta. Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy.

There are no adequate and well-controlled studies in pregnant women. Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

May reduce plasma concentrations with St. John's wort.

The adverse reactions related to Amitriptyline can be categorized as

Common

Suicidal thoughts and behaviour (particularly in children and young adults); may precipitate mania or hypomania (particularly in patients with known manic-depressive illness), may aggravate psychotic symptoms (in schizophrenic patients); cardiac arrhythmias, QT interval prolongation, AV conduction disturbance

Less Common

Tachycardia, palpitations. Eye disorders: Accommodation disorder, mydriasis.

Rare

Headache, dizziness, somnolence, tremor, speech disorder (dysarthria), paraesthesia, ataxia, disturbance in attention.

The clinically relevant drug interactions of Amitriptyline is briefly summarized here

May increase the risk of serotonin syndrome with opioids (e.g. buprenorphine, tramadol). May increase the risk of arrhythmias and hypotension with anaesthetics. Concomitant use with anticholinergics or neuroleptics, particularly in hot weather, may cause hyperpyrexia. May potentiate the CV effects of sympathomimetic agents (e.g. epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine, phenylpropanolamine). May enhance the sedative effects of barbiturates and other CNS depressants. May reduce the antihypertensive effects of adrenergic neurone blockers (e.g. guanethidine, betanidine, reserpine, clonidine, methyldopa). May increase the risk of ventricular arrhythmias with antiarrhythmics (e.g. quinidine, amiodarone), certain antihistamines (e.g. astemizole, terfenadine), certain antipsychotics (e.g. pimozide, sertindole, thioridazine), halofantrine, and sotalol. Potential additive effects on QT interval and increased risk of serious CV effects when used with methadone. Concomitant use with diuretics (e.g. furosemide) may increase the risk of hypokalaemia. May increase serum concentrations with fluconazole, fluvoxamine, Na valproate, valpromide, topiramate, CYP2D6 inhibitors (e.g. duloxetine, terbinafine, bupropion, fluoxetine, paroxetine, quinidine), and other CYP450 inhibitors (e.g. cimetidine, diltiazem, verapamil). May reduce plasma concentrations with CYP450 inducers (e.g. oral contraceptives, rifampicin, phenytoin, barbiturates, carbamazepine). Risk of delirium with disulfiram. Increased anticholinergic adverse effects with nefopam. May increase the risk of bleeding with antiplatelets and anticoagulants. May increase the risk of bone fractures with SSRIs.

The common side of Amitriptyline include the following

Suicidal thoughts and behaviour (particularly in children and young adults); may precipitate mania or hypomania (particularly in patients with known manic-depressive illness), may aggravate psychotic symptoms (in schizophrenic patients); cardiac arrhythmias, QT interval prolongation, AV conduction disturbance.

Pregnancy Considerations: Amitriptyline is Pregnancy Category C medicine, and it can cross the placenta. There is no causal relationship, but a few reports of adverse reactions, including limb deformities, developmental delay, and CNS effects in infants whose mothers had used amitriptyline during pregnancy. There is a lack of well-controlled clinical studies on pregnant women. Amitriptyline should be used in pregnancy only if the potential benefit to her than the risk to the mother and fetus. American College of Obstetricians (ACOG) and the American Psychiatry Association (APA) have created treatment algorithms for periconceptional and antenatal management.

Breastfeeding Considerations: Amitriptyline can pass into breast milk. Maternal exposure to amitriptyline would usually not cause any adverse reactions in breastfed infants, especially infants older than two months. A safety scoring system finds amitriptyline use possible with caution while breastfeeding.[13] However, rare sedation is reported in neonates. Therefore, other medicines with fewer active metabolites should be preferred when large amitriptyline doses are required or nursing a preterm infant or a newborn.

Pediatric Patients: Because of the lack of experience using this drug in pediatric patients, it should not be recommended for patients under 12 years.

Adolescent and Geriatric Patients: In general, start at lower dosages for these patients. The recommendation is to start with a lower dosage (around 10 mg/day) in the geriatric population.[14] The maintenance dose can be divided, i.e., 10 mg three times a day with 20 mg at bedtime who do not tolerate higher dosages.

Patients with Renal Impairment: There is no information provided by the manufacturer, and in mild to moderate impairment, no dose adjustments are needed.

Patients with Hepatic Impairment: Amitriptyline hydrochloride should be used with caution in patients with impaired liver function.

Hospitalized Patients: They may require 100 mg a day initially, which can be increased gradually to 200 mg a day if needed.

Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible.

Pharmacodynamics

Amitriptyline is an antidepressant with sedative effects. Its mechanism of action in man is not known. It is not a monoamine oxidase inhibitor and it does not act primarily by stimulation of the central nervous system.

Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically, this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline.

Pharmacokinetics

Absorption: Readily and completely absorbed from the gastrointestinal tract. Bioavailability: Approx 43-46%. Time to peak plasma concentration: Approx 2-5 hours.

Distribution: Widely distributed throughout the body. Crosses the placenta; enters breast milk (small amounts). Volume of distribution: Approx 18-22 L/kg. Plasma protein binding: >90%.

Metabolism: Metabolised in the liver by CYP3A4 and CYP2C19 via demethylation and by CYP2D6 via hydroxylation, followed by conjugation with glucuronic acid to form metabolites, nortriptyline (primary active metabolite), hydroxy and conjugated derivatives. Undergoes extensive first-pass metabolism.

Excretion: 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.

1. https://www.uptodate.com/contents/amitriptyline-drug-information?search=amitriptyline&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F23890541
2. https://www.mims.com/india/drug/info/amitriptyline?type=full
3. https://www.ncbi.nlm.nih.gov/books/NBK537225/
4. https://go.drugbank.com/drugs/DB00321
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/071297s030lbl.pdf