II. Mechanism

  1. Fused three ring compound, active at central nerve Synapses
  2. Tricyclic Antidepressants block reuptake of monoamine Neurotransmitters (Norepinephrine and Serotonin)
  3. Reuptake inhibition increases Neurotransmitter concentrations at the Synapse, as well as down regulation of post-synaptic receptors
  4. Historically used as Antidepressants, and largely replaced by SSRI and SNRI Antidepressants

IV. Safety

  1. Avoid most Tricyclic Antidepressants in Pregnancy
    1. Exceptions in which Tricyclics are category C: Amitriptyline, Amoxapine, Clomipramine, Trimipramine
  2. Avoid most Tricyclic Antidepressants in Lactation
    1. Exceptions that appear safe in Lactation: Clomipramine, Desipramine, Nortriptyline, Protryptyline

V. Pharmacokinetics

  1. Tricyclic Antidepressants are well absorbed and widely distributed
  2. High plasma Protein binding
  3. Most commonly used Tricyclic Antidepressants have long half lives (up to 45 hours for Amitriptyline and Nortriptyline)
    1. Half life is even more prolonged in the elderly (slower Drug Metabolism)

VI. Preparations: Tricyclic Antidepressants - First generation (Tertiary amines)

  1. General
    1. Greater Analgesic properties than second generation
  2. Agents
    1. Amitriptyline (Elavil, Endep)
    2. Imipramine (Tofranil)
    3. Doxepin (Sinequan, Adapin)
    4. Clomipramine (Anafranil)
    5. Trimipramine (Surmontil)
      1. Dose in Major Depression
        1. Adult: Start 75 mg/day in divided doses and titrate 50 to 150 mg/day (max: 200 mg/day)
        2. Elderly and Teens: Start 50 mg/day in divided doses (max: 100 mg/day)
      2. Very sedating
      3. Half-Life: 7 to 30 hours

VII. Preparations: Tricyclic Antidepressants - Second generation (Secondary amines)

  1. General
    1. Less adverse effects (esp. Anticholinergic effects) than first generation
  2. Agents
    1. Nortriptyline (Pamelor, Aventyl)
    2. Desipramine (Norpramin)
    3. Protriptyline (Vivactil)

VIII. Preparations: Tetracyclic Antidepressants (rarely used)

  1. Maprotiline (Ludiomil)
    1. No longer available in the United States as of 2021
    2. Increased seizure Incidence
  2. Amoxapine (Asendin)
    1. Rarely used
    2. Dose in Major Depression
      1. Start 25 to 50 mg orally daily (or in divided doses) and titrate up to 200-300 mg/day in divided doses
    3. Half-Life 8 hours
      1. Shortest half life of the Tricyclic Antidepressants
    4. Adverse Effects
      1. Severe Extrapyramidal Side Effects
  3. Protriptyline (Vivactil)
    1. Dose in Major Depression
      1. Adult: 15 to 40 mg/day divided three times daily (max: 60 mg/day)
      2. Elderly and Teens: Start 15 mg divided three times daily (max: 20 mg/day)
    2. Half-Life 75 to 90 hours
    3. Longest Half-Life of the Tricyclic Antidepressants

IX. Adverse Effects

  1. General (applies primarily to the full doses historically used in Major Depression)
    1. Unable to tolerate full Major Depression dose: 80%
      1. Lower doses in Chronic Pain are better tolerated
      2. Medication discontinued due to adverse effects: 30%
    2. Secondary amines (e.g. Nortriptyline) are much better tolerated
  2. Anticholinergic Symptoms
    1. Dry Mouth
    2. Constipation
    3. Blurred Vision
  3. Antihistaminergic effects
    1. Sedation (limits use)
    2. Weight gain
  4. Serotoninergic Effects
    1. Sexual Dysfunction
  5. Cardiovascular effects: Orthostatic Hypotension
  6. Pro-Arrhythmic Effects (Class I Antiarrhythmic type)
    1. Sinus Tachycardia
    2. Supraventricular Tachycardia
    3. Ventricular Tachycardia
    4. Ventricular Fibrillation
    5. Prolongation of PR, QRS or QT Interval
    6. ST Segment and T Wave changes
    7. Bundle Branch Block or complete Heart Block
  7. Antidepressant Withdrawal (shaking chills, myalgias, malaise)
    1. See Antidepressant Withdrawal
    2. Prevent by tapering gradually, even over months

X. Drug Interactions: Cardiovascular

  1. Absolute Contraindications
    1. Clonidine (Hypotension)
    2. Monoamine Oxidase Inhibitors
    3. Class I Antiarrhythmics (e.g. Quinidine, Flecainide)
      1. Prolonged QT Interval
  2. Other interactions
    1. Coumadin (increases ProTime)
    2. Aspirin (increases Tricyclic Antidepressant level)
    3. Fluoxetine (increases Tricyclic Antidepressant level)

XI. Precautions: Overdosage effects

  1. See Tricyclic Antidepressant Overdose
  2. Cardiotoxicity
  3. Death

XII. References

  1. (2023) Med Lett Drugs Ther 62(1592): 25-32
  2. Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 36-7

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Related Studies

Cost: Medications

protriptyline (on 6/22/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
PROTRIPTYLINE HCL 10 MG TABLET Generic $2.45 each

Ontology: Tricyclic Antidepressive Agents (C0003290)

Definition (NCI_NCI-GLOSS) A type of drug used to treat depression.
Definition (NCI) Mood-stimulating agents which contain a tricyclic structure and are used primarily in the treatment of affective disorders and related conditions. This group of agents appear to act through brain catecholamine systems.
Definition (MSH) Substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system.
Definition (CSP) class of antidepressants with 3 ring chemical structures; mechanism unknown, but believed to involve serotonin metabolism, transport, or receptor sensitivity.
Concepts Pharmacologic Substance (T121)
MSH D000929
SnomedCT 283013009, 33219003, 373253007
LNC LP14735-2, MTHU001920
English Agents, Tricyclic Antidepressive, Antidepressants, Tricyclic, Antidepressive Agents, Tricyclic, Tricyclic Antidepressants, Antidepressant Drugs, Tricyclic, Drugs, Tricyclic Antidepressant, Tricyclic antidepressant drug, TRICYCLIC ANTIDEPRESSANTS, tricyclic antidepressive agents, tricyclic antidepressants (medication), tricyclic antidepressants, [CN601] TRICYCLIC ANTIDEPRESSANTS, Tricyclic Antidepressive Agents, anti depressant tricyclic, tricyclic antidepressant drugs, tricyclic anti depressant, tricyclic anti-depressants, antidepressant drug tricyclic, antidepressants tricyclic, anti depressants tricyclic, antidepressants tricyclics, Tricyclic Antidepressant, Tricyclic antidepressant drug (substance), Tricyclic antidepressants, tricyclic antidepressant, Tricyclic antidepressant, Tricyclic antidepressant (product), Tricyclic antidepressant (substance), Tricyclic antidepressant, NOS, Tricyclic Antidepressant Drugs, Tricyclics
French Médicaments antidépresseurs tricycliques, Antidépresseurs tricycliques
Swedish Antidepressiva medel, tricykliska
Czech antidepresiva tricyklická
Finnish Trisykliset masennuslääkkeet
Italian Farmaci antidepressivi triciclici, Antidepressivi triciclici
Russian ANTIDEPRESSIVNYE SREDSTVA TRITSIKLICHESKIE, ANTIDEPRESSANTY TRITSIKLICHESKIE, АНТИДЕПРЕССАНТЫ ТРИЦИКЛИЧЕСКИЕ, АНТИДЕПРЕССИВНЫЕ СРЕДСТВА ТРИЦИКЛИЧЕСКИЕ
Polish Leki przeciwdepresyjne trójcykliczne
Japanese 三環系抗うつ剤, 抗うつ剤-三環系, 三環式抗抑うつ薬, 三環系抗うつ薬, 三環系抗鬱剤, 抗鬱剤-三環系, 三環式抗抑鬱薬, 抗鬱薬-三環系
Portuguese Agentes Antidepressivos Tricíclicos, Antidepressivos Tricíclicos
Spanish Antidepresivos Tricíclicos, Agentes Antidepresivos Tricíclicos, antidepresivo tricíclico (producto), antidepresivo tricíclico (sustancia), antidepresivo tricíclico
German Antidepressiva, trizyklische, Antidepressivische Mittel, tricyclische, Trizyklische antidepressive Mittel

Ontology: Tetracyclic antidepressant (C0360108)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
SnomedCT 11430001, 372576002
English tetracyclic antidepressant, antidepressants tetracyclic, Tetracyclic antidepressant, Tetracyclic antidepressant drug, Tetracyclic antidepressant (product), Tetracyclic antidepressant (substance), Tetracyclic antidepressant, NOS
Spanish antidepresivo tetracíclico (producto), antidepresivo tetracíclico (sustancia), antidepresivo tetracíclico