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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