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tricyclic antidepressant (TCA)

Indications: 1) depression 2) neuropathic pain syndromes Contraindications: - avoid use within 6 months of coronary syndrome Dosage: -> low-dose (< 100 mg/day) may be effective, with reduced risk of adverse effects [1] Pharmacokinetics: - metabolism by cyt P450 2D6 > 2C9, 2C10, 2C19 - slow onset of action with several weeks to achieve full effects Adverse effects: 1) anticholinergic effects a) tinnitus b) constipation c) confusion d) mydriasis e) tachycardia -> amitriptyline > doxepin > nortriptyline > desipramine f) in general, NOT a good class of agents for the elderly 2) arrhythmic effects [3,5] a) overdose results in prolongation of the QT interval b) patients with a bundle branch block are at higher risk c) risk of torsades de pointes d) avoid use within 6 months of coronary syndrome 3) cholinergic symptoms with abrupt withdrawal -> abdominal cramping & diarrhea 4) increased risk of seizures [2] 5) orthostatic hypotension - doxepin = amitriptyline > imipramine = nortriptyline > desipramine 6) galactorrhea, hyperprolactinemia [3] Overdose: 1) clinical manifestations - progressive somnolence, hypotension, widened QRS interval, seizures, & parasympatholytic signs (fever, tachycardia, mydriasis, diminished peristalsis) - case report of cardiac arrest in a young woman with irregular, wide-complex rhythm, & a QRS width of up to 220 msec [6] 2) management a) early endotracheal intubation, hyperventilation b) fluid resusitation c) gastric lavage followed by activated charcoal even with delayed presentation d) EKG monitoring: QRS complex > 100 msec predicts seizures e) bicarbonate - bolus 1-2 meq/kg every 3-5 minutes until QRS complex narrows or blood pressure improves - bicarbonate drip titrated to QRS width & blood pressure - monitor serum K+, signs of fluid overload f) norepinephrine for hypotension not responsive to bicarbonate g) lidocaine for ventricular arrhythmias h) benzodiazepines for seizures - avoid phenytoin - propofol or barbiturates for refractory seizures Drug interactions: 1) TCA may potentiate adverse effects of opiate agonists 2) flumazenil (Romazicon) may potentiate toxic effects of TCA 3) TCA block the uptake of guanethidine, guanadrel 4) TCA inhibit the action of centrally-acting antihypertensives: a) clonidine 2) alpha-methyldopa 5) SSRI: paroxetine, fluoxetine (metabolized by same P450s) 6) class 1A antiarrhythmic agents 7) effects additive with EtOH Laboratory: - CYPD2D6 genotyping may be indicated - CYPD2C19 genotyping may be indicated - tricyclic antidepressants in specimen - tricyclic antidepressants in blood (suspected overdose) - may increase plasma metanephrine & plasma normetanephrine [7] Mechanism of action: 1) Histamine H1 antagonist - doxepin >> amitriptyline >> nortriptyline = imipramine >> nortriptyline = desipramine 3) serotonin antagonist 2) alpha-1-adrenergic receptor antagonist - doxepin = amitriptyline > nortriptyline = imipramine = desipramine 3) nortriptyline, its metabolite, is a norepinephrine reuptake inhibitor

Interactions

drug interactions drug adverse effects (more general classes)

Related

amitriptyline/chlordiazepoxide (Limbitrol) amitriptyline/perphenazine (Etrafon, Triavil) cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6) tricyclic antidepressants (TCA) in serum/plasma

Specific

amitriptyline (Elavil, Endep) amoxapine (Asendin) clomipramine (Anafranil) desipramine (Norpramin, Pertofrane) dothiepin (Prothiaden) doxepin (Sinequan, Adapin, Zonalon, Silenor) imipramine (Tofranil, Janimine) maprotiline (Ludiomil) nortriptyline (Aventyl, Pamelor) protriptyline (Vivactil, Concordin) tianeptine trimipramine (Surmontil)

General

antidepressant dibenzazepine; iminostilbene

References

  1. Journal Watch 23(1):11, 2003 Furukawa TA et al, Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review BMJ 325:991, 2002 PMID: 12411354 http://bmj.com/cgi/content/full/325/7371/991
  2. Medications Can Cause Seizures Prescriber's Letter 10(3):16 2003 Detail-Document#: 190320 (subscription needed) http://www.prescribersletter.com
  3. Medical Knowledge Self Assessment Program (MKSAP) 14, 15, 16, 18 American College of Physicians, Philadelphia 2006, 2009, 2012, 2018.
  4. The Washington Manual of Medical Therapeutics, 33rd edition Foster C et al (eds) Lippincott, Williams & Wilkins, Philadelphia, 2010, pg 957
  5. Body R, Bartram T, Azam F, Mackway-Jones K. Guidelines in Emergency Medicine Network (GEMNet): guideline for the management of tricyclic antidepressant overdose. Emerg Med J. 2011 Apr;28(4):347-68 PMID: 21436332
  6. Goldstein JN, Dudzinski DM, Erickson TB, Linder G. Case 12-2018: A 30-Year-Old Woman with Cardiac Arrest. N Engl J Med 2018; 378:1538-1549. April 19, 2018 PMID: 29669228 http://www.nejm.org/doi/full/10.1056/NEJMcpc1800322
  7. NEJM Knowledge+ Question of the Week. December 18, 2018 https://knowledgeplus.nejm.org/question-of-week/803/