II. Mechanism
- Fused three ring compound, active at central nerve Synapses
- Tricyclic Antidepressants block reuptake of monoamine Neurotransmitters (Norepinephrine and Serotonin)
- Reuptake inhibition increases Neurotransmitter concentrations at the Synapse, as well as down regulation of post-synaptic receptors
- Historically used as Antidepressants, and largely replaced by SSRI and SNRI Antidepressants
III. Indications
- Migraine Headache Prophylaxis
- Fibromyalgia
- Chronic Pain (esp. neuropathic pain)
- Insomnia
- Enuresis (e.g. Imipramine)
- Major Depression (historical use, replaced by SSRI and SNRI Antidepressants)
- Panic Disorder with Agoraphobia
- Obsessive Compulsive Disorder
IV. Safety
- Avoid most Tricyclic Antidepressants in Pregnancy
- Exceptions in which Tricyclics are category C: Amitriptyline, Amoxapine, Clomipramine, Trimipramine
- Avoid most Tricyclic Antidepressants in Lactation
- Exceptions that appear safe in Lactation: Clomipramine, Desipramine, Nortriptyline, Protryptyline
V. Pharmacokinetics
- Tricyclic Antidepressants are well absorbed and widely distributed
- High plasma Protein binding
- Most commonly used Tricyclic Antidepressants have long half lives (up to 45 hours for Amitriptyline and Nortriptyline)
- Half life is even more prolonged in the elderly (slower Drug Metabolism)
VI. Preparations: Tricyclic Antidepressants - First generation (Tertiary amines)
-
General
- Greater Analgesic properties than second generation
- Agents
- Amitriptyline (Elavil, Endep)
- Imipramine (Tofranil)
- Doxepin (Sinequan, Adapin)
- Clomipramine (Anafranil)
- Trimipramine (Surmontil)
- Dose in Major Depression
- Adult: Start 75 mg/day in divided doses and titrate 50 to 150 mg/day (max: 200 mg/day)
- Elderly and Teens: Start 50 mg/day in divided doses (max: 100 mg/day)
- Very sedating
- Half-Life: 7 to 30 hours
- Dose in Major Depression
VII. Preparations: Tricyclic Antidepressants - Second generation (Secondary amines)
-
General
- Less adverse effects (esp. Anticholinergic effects) than first generation
- Agents
- Nortriptyline (Pamelor, Aventyl)
- Desipramine (Norpramin)
- Protriptyline (Vivactil)
VIII. Preparations: Tetracyclic Antidepressants (rarely used)
- Maprotiline (Ludiomil)
- No longer available in the United States as of 2021
- Increased seizure Incidence
- Amoxapine (Asendin)
- Rarely used
- Dose in Major Depression
- Start 25 to 50 mg orally daily (or in divided doses) and titrate up to 200-300 mg/day in divided doses
- Half-Life 8 hours
- Shortest half life of the Tricyclic Antidepressants
- Adverse Effects
- Severe Extrapyramidal Side Effects
- Protriptyline (Vivactil)
- Dose in Major Depression
- Adult: 15 to 40 mg/day divided three times daily (max: 60 mg/day)
- Elderly and Teens: Start 15 mg divided three times daily (max: 20 mg/day)
- Half-Life 75 to 90 hours
- Longest Half-Life of the Tricyclic Antidepressants
- Dose in Major Depression
IX. Adverse Effects
-
General (applies primarily to the full doses historically used in Major Depression)
- Unable to tolerate full Major Depression dose: 80%
- Lower doses in Chronic Pain are better tolerated
- Medication discontinued due to adverse effects: 30%
- Secondary amines (e.g. Nortriptyline) are much better tolerated
- Unable to tolerate full Major Depression dose: 80%
- Anticholinergic Symptoms
-
Antihistaminergic effects
- Sedation (limits use)
- Weight gain
- Serotoninergic Effects
- Cardiovascular effects: Orthostatic Hypotension
- Pro-Arrhythmic Effects (Class I Antiarrhythmic type)
- Sinus Tachycardia
- Supraventricular Tachycardia
- Ventricular Tachycardia
- Ventricular Fibrillation
- Prolongation of PR, QRS or QT Interval
- ST Segment and T Wave changes
- Bundle Branch Block or complete Heart Block
-
Antidepressant Withdrawal (shaking chills, myalgias, malaise)
- See Antidepressant Withdrawal
- Prevent by tapering gradually, even over months
X. Drug Interactions: Cardiovascular
- Absolute Contraindications
- Clonidine (Hypotension)
- Monoamine Oxidase Inhibitors
- Class I Antiarrhythmics (e.g. Quinidine, Flecainide)
- Prolonged QT Interval
- Other interactions
- Coumadin (increases ProTime)
- Aspirin (increases Tricyclic Antidepressant level)
- Fluoxetine (increases Tricyclic Antidepressant level)
XI. Precautions: Overdosage effects
- See Tricyclic Antidepressant Overdose
- Cardiotoxicity
- Death
XII. References
- (2023) Med Lett Drugs Ther 62(1592): 25-32
- Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 36-7
Images: Related links to external sites (from Bing)
Related Studies
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 |