Amitip

Approved Indications:

• Major Depressive Disorder (MDD):
  Indicated for the treatment of moderate to severe depression, particularly when accompanied by anxiety or sleep disturbance.
• Neuropathic Pain:
  Approved in several countries for chronic neuropathic pain, including diabetic peripheral neuropathy and post-herpetic neuralgia.

Clinically Accepted Off-Label Uses:

• Fibromyalgia:
  Low-dose amitriptyline is frequently used to reduce chronic widespread musculoskeletal pain and improve sleep quality.
• Migraine Prophylaxis:
  Preventive treatment for recurrent migraine attacks, especially in patients with comorbid depression or sleep disorders.
• Chronic Tension-Type Headache:
  Used to reduce frequency and severity of chronic tension headaches.
• Irritable Bowel Syndrome (IBS):
  Low-dose therapy can reduce abdominal pain and discomfort associated with IBS.
• Interstitial Cystitis/Bladder Pain Syndrome:
  Used to reduce urinary frequency, urgency, and pain.
• Insomnia (Resistant):
  Occasionally prescribed in low doses to manage persistent sleep disturbances.
• Enuresis (Nocturnal):
  Used in children over 6 years when other treatments fail (with caution and specialist guidance).

Adults:

• Depression:
  Initial dose: 25–50 mg/day at bedtime; may increase by 25 mg every few days.
  Usual maintenance dose: 75–150 mg/day in divided doses or as a single bedtime dose.
  Maximum dose: 300 mg/day in hospital settings.
• Neuropathic Pain / Fibromyalgia / Migraine Prophylaxis:
  Start with 10–25 mg at bedtime. Titrate gradually up to 50–75 mg/day as tolerated.
  Duration: Often continued long-term (≥6–12 weeks for effect, reassessed periodically).
• Irritable Bowel Syndrome / Chronic Pain Syndromes:
  Low dose (10–25 mg at bedtime), increased as needed to 50 mg/day.

Elderly or Frail Patients:

• Start with 10–25 mg/day at bedtime.
• Maximum dose typically should not exceed 100 mg/day.
• Monitor for anticholinergic side effects and orthostatic hypotension.

Pediatric Use (Enuresis):

• Children 6–10 years: 10–20 mg at bedtime.
• Children >11 years: 25–50 mg at bedtime.
• Maximum use: 3 months; reevaluate need for continued therapy.

Renal Impairment:

• No specific adjustment required, but start with low doses and monitor closely.

Hepatic Impairment:

• Use cautiously; lower starting doses recommended due to altered metabolism.

Administration Route:

• Oral only: Administer tablets once daily at bedtime (preferred to reduce daytime sedation) or in divided doses as needed.
• May take with or without food.

Amitriptyline is a tricyclic antidepressant (TCA) that works primarily by inhibiting the reuptake of norepinephrine (NE) and serotonin (5-HT) at presynaptic nerve terminals in the central nervous system, increasing their synaptic availability. It binds strongly to the serotonin transporter (SERT) and norepinephrine transporter (NET), enhancing monoaminergic neurotransmission. Additionally, it exhibits significant anticholinergic, antihistaminic, and alpha-adrenergic blocking activity, which contributes to its sedative and analgesic effects but also accounts for many of its side effects. The modulation of pain perception is thought to occur via inhibition of descending serotonergic and noradrenergic pain pathways in the spinal cord.

• Absorption: Rapidly and well absorbed after oral administration.
• Bioavailability: Approx. 30–60% due to first-pass hepatic metabolism.
• Distribution: Highly lipophilic; volume of distribution: 10–20 L/kg.
• Plasma Protein Binding: ~95%.
• Metabolism: Extensively metabolized in the liver via CYP2D6 and CYP2C19 into active metabolite nortriptyline.
• Half-life: 10–28 hours (amitriptyline); 18–44 hours (nortriptyline).
• Onset of Action: Antidepressant effects begin within 2–3 weeks; analgesic effects within days.
• Elimination: Primarily renal (as metabolites); <5% excreted unchanged in urine.

• Pregnancy:
  Previously classified as FDA Category C. Animal studies show fetal risks, but human data are limited.
  Use during pregnancy only if benefits outweigh potential risks. Some associations with neonatal withdrawal, respiratory distress, or jitteriness have been reported with late-pregnancy use.
• Lactation:
  Amitriptyline and nortriptyline are excreted in breast milk in low amounts.
  Generally considered compatible with breastfeeding at low maternal doses, though infant monitoring is advised for sedation or poor feeding.

• Primary Class: Tricyclic Antidepressant (TCA)
• Subclass: Non-selective monoamine reuptake inhibitor
• Other Properties: Sedative, analgesic, anxiolytic (due to antihistamine and anticholinergic effects)

• Known hypersensitivity to amitriptyline or other tricyclic antidepressants
• Recent myocardial infarction or significant cardiac conduction abnormalities
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuation
• Acute recovery phase after myocardial infarction
• Severe liver disease
• Narrow-angle glaucoma or urinary retention (due to anticholinergic effects)

• Suicidality in Children and Young Adults: Increased risk of suicidal thoughts; monitor closely, especially during initial treatment.
• Cardiac Toxicity: Risk of arrhythmias, QT prolongation, and sudden death at high doses or in overdose.
• Seizure Risk: Lowers seizure threshold; use with caution in epilepsy.
• Serotonin Syndrome: Risk when combined with SSRIs, SNRIs, or MAOIs.
• Orthostatic Hypotension and Falls: Especially in elderly patients.
• Anticholinergic Burden: May worsen glaucoma, urinary retention, cognitive decline.
• Hepatic Dysfunction: Dose adjustment or caution advised.
• Withdrawal Symptoms: Taper gradually after long-term use.

Common Side Effects:

• CNS: Drowsiness, dizziness, fatigue, headache, agitation
• Anticholinergic: Dry mouth, constipation, blurred vision, urinary retention
• CVS: Orthostatic hypotension, palpitations, tachycardia
• GI: Nausea, increased appetite, weight gain
• Reproductive: Libido changes, erectile dysfunction, menstrual irregularities

Serious or Rare Side Effects:

• Seizures
• Cardiac arrhythmias, QT prolongation, sudden death
• Hepatotoxicity (elevated liver enzymes, jaundice)
• Blood dyscrasias (rare): agranulocytosis, leukopenia
• Serotonin syndrome
• Angle-closure glaucoma
• Confusion or delirium in elderly

• MAOIs: Life-threatening hypertensive crisis or serotonin syndrome—contraindicated.
• SSRIs/SNRIs: Additive serotonergic effects—risk of serotonin syndrome.
• Anticholinergic drugs: Additive effects leading to cognitive impairment or severe constipation.
• CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): Increase plasma levels of amitriptyline—dose adjustment required.
• Alcohol and CNS depressants: Potentiated sedative and respiratory depressant effects.
• Antiarrhythmics (Class I/III): Increased risk of QT prolongation.
• Antihypertensives: May reduce efficacy or increase hypotension.

• 2023–2024 (NICE & EMA):
• Emphasized low-dose use for chronic pain and insomnia-related conditions.
• Reinforced guidance on gradual tapering to avoid discontinuation syndrome.
• FDA Advisory:
• Ongoing surveillance for cardiac toxicity and suicidality in pediatric populations.
• No new black box warnings added in recent updates.

• Tablets (Oral):
• Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C.
• Protect from moisture, light, and excessive heat.
• Keep in tightly closed container.
• Do not freeze or refrigerate.
• Handling Precautions:
• Keep out of reach of children.
• Dispose of unused medication safely as per local guidelines.