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amitriptyline (Elavil, Endep)

Tradename: Elavil, Endep. Indications: 1) treatment of: a) depression b) neuropathic pain 2) prophylaxis for migraine headache 3) management of anxiety/panic attacks 4) bulimia nervosa [8] 5) post-traumatic stress disorder (PTSD) 6) fibromyalgia [8] Contraindications: 1) use of a monoamine oxidase (MAO) inhibitor within 14 days 2) narrow-angle glaucoma 3) pregnancy 4) severe benign prostatic hypertrophy (BPH) Caution: 1) to avoid cholinergic crisis, do not discontinue abruptly in patients taking high doses chronically 2) in patients with: a) cardiac conduction disturbances b) hyperthyroidism c) renal or liver impairment d) bipolar illness 3) use with caution or not at all in the elderly 4) may worsen symptoms of BPH * CPIC recommends alternative drug for CYP2D6 or CYP2C19 ultrarapid metabolizers & for CYP2D6 poor metabolizers [9] (see Laboratory) Dosage: - Start 25 mg PO TID or 75 mg PO QHS, max 300 mg/day. Tabs: 10, 25, 50, 75, 100, 150 mg. Pharmacokinetics: - metabolized by cyt P450 1A2, cyt P450 2C19 [6], cyt P450 2D6 - onset of therapeutic effect may take 3-4 weeks [6] Adverse effects: 1) anticholinergic effects a) may be pronounced b) moderate to marked sedation may occur c) tolerance usually occurs 2) common > 10% a) dizziness b) drowsiness c) headache d) dry mouth e) constipation f) increased appetite g) nausea h) unpleasant taste i) weight gain j) weakness 3) less common (1-10%) - hypotension, postural hypotension, arrhythmia, tachycardia, sudden death, nervousness, restlessness, parkinsonism, insomnia, sedation, fatigue, anxiety, impaired cognitive function, seizures, extrapyramidal symptoms, diarrhea, heartburn, impaired sexual function, urinary retention, tremor, eye pain, blurred vision, sweating 4) uncommon (< 1%) - alopecia, photosensitivity, breast enlargement, galactorrhea, SIADH (rare), gum disease, gastroesophageal reflux (GERD), testicular swelling, leukopenia, eosinophilia, agranulocytosis (rare), cholestatic jaundice, increased serum transaminases, increased intraocular pressure, tinnitus, hypersensitivity 5) other - QT prolongation [7] Overdose: see tricyclic antidepressant. Drug interactions: 1) decreases effect of guanethidine 2) increases effects of: a) other CNS depressants b) adrenergic agonists c) anticholinergic agents d) warfarin 3) concurrent use of MAO inhibitors may result in: - hyperpyrexia, tachycardia, hypertension, confusion, seizures death 4) cimetidine may decrease metabolism of amitriptyline 5) phenobarbital may increase metabolism of amitriptyline 6) concurrent use of clonidine may result in hypertensive crisis 7) avoid terfenadine, astemizole, cisapride 8) any drug which inhibits cyt P450 1A2 or cyt P450 2D6 can increase amitriptyline levels 9) any drug which induces cyt P450 1A2 or cyt P450 2D6 can diminish amitriptyline levels Laboratory: 1) specimen: a) serum, plasma (EDTA), amitriptyline in serum b) collect at steady-state trough, 12 hours after dose c) separate plasma from cells as soon as possible & refrigerate d) stable for 4 months at -20 degrees C 2) methods: HPLC, GLC, GC-MS, RIA 3) interferences: a) doxepin may interfere with some HPLC assays b) amitriptyline may be displaced from plasma proteins by plasticizers in collecting devices c) amitriptyline may falsely elevate plasma metanephrine [10] 4) CYP2D6 & CYP2C19 genotyping [9] - CPIC recommends alternative drug for CYP2D6 or CYP2C19 ultrarapid metabolizers & for CYP2D6 poor metabolizers - consider 50% dose reduction for CYP2C19 poor metabolizers & 25% dose reduction for CYP2D6 intermediate metabolizers [9] 5) other laboratory measurement with Loincs - amitriptyline in specimen - amitriptyline in hair - amitriptyline in body fluid - amitriptyline in blood - amitriptyline in dried blood spot - amitriptyline in gastric fluid - amitriptyline in urine Mechanism of action: - inhibition of re-uptake of serotonin & norepinephrine Notes: Amitriptyline is a tertiary amine.

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2) cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)

General

parasympatholytic (anticholinergic, antimuscarinic agent) tricyclic antidepressant (TCA)

Properties

MISC-INFO: elimination route LIVER 1/2life 9-25 HOURS therapeutic-range 100-250 NG/ML toxic-range >500 NG/ML protein-binding 82-96% elimination by hemodialysis - hemoperfusion - peritoneal dialysis - pregnancy-category B safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 56
  5. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  6. Prescriber's Letter 8(3):16-17 2001
  7. Castro VM et al QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ 2013;346:f288 PMID: 23360890 http://www.bmj.com/content/346/bmj.f288
  8. Deprecated Reference
  9. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline information for amitriptyline and CYP2C19, CYP2D6. https://www.pharmgkb.org/guideline/PA166105006
  10. Medical Knowledge Self Assessment Program (MKSAP) 18, American College of Physicians, Philadelphia 2018

Component-of

amitriptyline/chlordiazepoxide (Limbitrol) amitriptyline/diclofenac/lidocaine/prilocaine amitriptyline/perphenazine (Etrafon, Triavil)