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Imipramine

Imipramine's structure, the first TCA to be developed

Tricyclic antidepressants (TCAs) are an older, yet diverse group of antidepressants (as far as their pharmacology and side effects) that are classed together due to the three rings that are present in their chemical structures. Their chief mechanism of action is that they inhibit the reuptake of the monoamine neurotransmitters, especially serotonin and noradrenaline. They also often antagonize the muscarinic acetylcholine receptors, histamine H1 receptors, α1 adrenergic receptors, which are believed to contribute to their side effects such as dry mouth, constipation, blurred vision, dizziness, sedation, memory problems, weight gain, changes in blood sugar levels, orthostatic hypotension, etc. They are also particularly toxic in cases of overdose as most of them have significant effects on the electrical cycle of the heart (what is measured using a ECG).

Medical usesEdit

They are primarily used to treat depression, although different TCAs may have additional uses; refer to the table below.

Drug Flag of the United States
FDA-approved indications
Flag of Australia
TGA-approved indications
Flag of the United Kingdom
MHRA-approved indications
Other indications; notes
Amineptine Never approved. Never approved. Never approved. Depression; approved for this indication in Greece, previously approved in Brazil, France, Italy, Portugal and Spain. Removed from the market amidst concerns over its hepatotoxicty, abuse potential and severe acne-type skin reactions.[1]
Amitriptyline Depression. Major depression; bed-wetting. Depression. Neuropathic pain; migraine prevention and urinary urge incontinence.[2] It is on the World Health Organization's List of Essential Medicines (WHO-EM).[3]
Amoxapine Depression. Never approved. No longer approved; previously depression. Schizophrenia.[4][5][6]
Butriptyline Never approved. Never approved. Once approved for depression, no longer. Depression; withdrawn from clinical use in Europe.
Clomipramine Obsessive-compulsive disorder (OCD). OCD, major depression and cataplexy associated with narcolepsy (CD). Depression, panic disorder, OCD, adjunct in the management of CD. Premature ejaculation (PE); chronic pain; bed-wetting.
Desipramine Depression. No longer approved; once approved to treat depression. No longer approved; once approved to treat depression. ADHD, cocaine dependence and neuropathic pain.[7][8]
Dibenzepin Never approved. Never approved. Never approved. Depression, currently approved for clinical use in Czech Republic and Switzerland, once approved in Germany, Israel, Netherlands, Poland and South Africa, amongst other countries.
Dosulepin Not approved. Major depression. Depression. None.
Doxepin Depression, anxiety, insomnia and itching. Major depression. Depression; itching in eczema. Chronic pain.[9]
Imipramine Depression. Major depression; bed-wetting. Depression; bed-wetting. Off-label use including panic disorder and urinary urge incontinence.[10]
Lofepramine Not FDA approved. Not TGA approved. Depression. None.
Maprotiline Depression. Not TGA approved. Previously approved for the treatment of depression. Anxiety associated with depression.
Melitracen Not FDA approved. Not TGA approved. Not MHRA approved. Currently approved in India for the treatment of depression; also approved in Austria, Belgium, China, Hong Kong, India, Singapore, Spain, Switzerland and Thailand in combination with flupentixol for the treatment of anxiety with depression.[11]
Nortriptyline Depression. Depression. Depression. Urinary urge incontinence, neuropathic pain, chronic hives, ADHD and as an aid to quit smoking.
Opipramol Not FDA approved. Not TGA approved. Not MHRA approved. Approved to treat generalized anxiety disorder in Austria, Germany, Greece, Poland, Switzerland and Turkey.[12]
Pipofezine Not FDA approved. Not TGA approved. Not MHRA approved. Approved to treat depression in Russia.
Protriptyline Depression. Not approved. Once approved for the treatment of depression; no longer approved, however.  Obstructive sleep apnoea.[13]
Tianeptine Not approved. Not approved. Not approved. Approved for the treatment of depression in Argentina, Austria, Brazil, China, Czech Republic, France, Hungary, India, Indonesia, Malaysia, Mexico, Philippines, Poland, Portugal, Russia, Singapore, Thailand, Turkey, Ukraine and Venezuela.[14] It is also used to treat asthma and irritable bowel syndrome.[15][16][17]
Trimipramine Depression. Depression; discontinued by the TGA in December 2013. Depression. None.

Side effectsEdit

Most TCAs produce anticholinergic, α-adrenergic, antihistamine and cardiotoxic (that is, it alters the electrical activity of the heart, hence leading to ECG anomalies and if severe enough arrhythmias and death) effects.

Drug mAChR effects α effects H1 effects Other notable side effects
Amineptine - - - Hepatotoxicity, addiction and severe acne-like skin reactions.[1]
Amitriptyline ++++ +++ +++ More prone to cause hepatotoxicity than other antidepressants, although not problematic enough to require regular monitoring.[18]
Amoxapine + + + Movement disorders, high blood prolactin and other metabolic effects. Very toxic to the kidneys in cases of overdose.
Butriptyline  ?  ? +/- None notable.
Clomipramine ++ ++ +++ None notable.
Desipramine +  ? + None notable.
Dosulepin ++ ++ ++ None notable.
Doxepin +++ +++ ++++ None notable.
Imipramine ++ ++ ++ None notable.
Iprindole +/- +/- +/- None notable.
Lofepramine +/- +/- +/- Liver injury reported rarely.
Maprotiline + + ++++ None notable.
Melitracen  ?  ?  ? None notable.
Nortriptyline + + ++ None notable.
Opipramol ++/+ ++/+ ++/+ None notable.
Pipofezine  ?  ?  ? None notable.
Protriptyline ++  ? ++/+ None notable.
Tianeptine - - - Rare cases of liver injury reported.
Trimipramine ++++  ? ++++ None notable.

Where:

- indicates the side effect is negligible/absent.

+ indicates the side effect is usually minor/infrequent.

++ indicates a moderate/frequent side effect.

+++ indicates a severe/very frequent side effect.

++++ indicates a very profound side effect. 

OverdoseEdit

TCAs are notorious for their toxicity in overdoses; of them amoxapine, maprotiline, desipramine, amitriptyline and doxepin, in order (most to least toxic), are the most toxic.[19][20][21] Likewise lofepramine, tianeptine and trimipramine are likely the least toxic.[19][20]

PharmacologyEdit

Most TCAs produce their antidepressant effects by inhibiting the reuptake of serotonin and noradrenaline; some, however, act at different sites. For example, amineptine, is a noradrenaline-dopamine reuptake inhibitor, opipramol is a sigma receptor agonist, tianeptine works by enhancing the reuptake of serotonin while simultaneously modulating the ionotropic glutamate receptors and agonizing the mu and delta opioid receptors and iprindole acts predominantly by antagonizing the 5-HT2 receptors.

Binding affinities (Ki)[note 1] of some common TCAs[22][23]
Drug SERT NET DAT H1 M1 M3 α1 5-HT2 D2
Amitriptyline 3.13 22.43 4443 0.5 11 39 24 18 1460
Amoxapine 58 16 4310 25 1000  ? 50 0.5 20.8
Butriptyline 1360 5100 3940  ?  ?  ?  ?  ?  ?
Clomipramine 0.21 45.85 2605 31.2 37  ? 3.2 35.5 119.8
Desipramine 179 2.14 >3190 52.7 110 210 100 350 1561
Dosulepin 8.6 46 5310 4 18 38 419 152  ?
Doxepin 68 29.5 >10000 0.24 38 52 23.5 27 360
Imipramine 10.4 51.67 >8500 37 42 60 32 150 726
Iprindole 1620 1262 6530 120  ?  ?  ? 217  ?
Lofepramine 70 5.4 >10000 360 67 130 100 200 2000
Maprotiline 5,800 11.1 1000 2 560  ? 91 51 665
Nortriptyline 16.5 1.65 3100 15.1 40 50 55 41 2570
Protriptyline 19.6 1.41 2100 25 25  ? 130  ?  ?
Trimipramine 149 2450 3780 0.3 59  ? 23.8 19.5  ?

PropertiesEdit

Most TCAs have half-lives such that once or twice daily dosing is possible, although there are a couple of exceptions, for instance amoxapine, doxepin, lofepramine and tianeptine need to be dosed two-four times a day. As a general rule of thumb the half-life of a drug tells one how many hours should be between doses, ideally. Unless, of course, the drug has an equally or more active metabolite.

Pharmacokinetics of TCAs
Drug Brand names Plasma protein binding Metabolism Half-life
[note 2]
Dosing frequency
Amineptine Survector  ?  ?  ?  ?
Amitriptyline Elavil, Endep  ? N-demethylation via CYP2C9, CYP2D6, CYP3A4 to nortriptyline; hydroxylation too. 9-25 hours; 28-31 hours for nortriptyline qDay Nocte
Amoxapine Asendin, Asendis 90% Hydroxylated to 7- and 8-hydroxyamoxapine 8 hours; 30 hours for 7-hydroxyamoxapine q8-12hr.
Clomipramine Anafranil, Placip 97-98% N-demethylation to desmethylclomipramine. 21 hours; 36 hours (for desmethylclomipramine). q12-24hr Nocte.
Desipramine Norpramin, Pertofrane  ? CYP2D6-mediated metabolism 15-24 hours q12-24hr. Nocte.
Dosulepin (dothiepin) Dothep, Prothiaden  ? N-desmethylation. 14-24 hours q12-24hr. Nocte.
Doxepin Deptran, Sinequan, Zonalon 76% CYP2C19, CYP2D6-mediated metabolism. 8-24 hours q12hr.
Imipramine Tofranil, Tolerade 90% CYP1A2, CYP2C19, CYP2D6-mediated metabolism; mostly via hydroxylation and N-oxidation to desipramine. 9-28 hours q8-24hr.
Lofepramine Lomont 99%  ? 5 hours q8-12hr.
Maprotiline Ludiomil 88-89% N-oxidation and hydroxylation to desmethylmaprotiline and maprotiline-N-oxide. 43 hours (60-90 hours for active metabolites) qDay.
Nortriptyline Allegron, Aventyl, Pamelor 93-95% Hydroxylation to 10-hydroxynortriptyline. 28-31 hours q6-24hr (depends on the use and dosage).
Protriptyline Concordin, Vivactil 92% Oxidation, hydroxylation and glucuronidation. 55-198 hours q6-8hr.
Tianeptine Coaxil, Stablon. 95% Beta-oxidation. 2.5-6.3 hours q6-12hr.
Trimipramine Surmontil 95% Desmethyltrimipramine 23 hours qHS.
Chemical properties of TCAs
Drug Molecular formula Molar mass Chemical structure
Amineptine C22H27NO2 337.463 g/mol Amineptine
Amitriptyline C20H23N 277.411 g/mol Amitriptyline
Amoxapine C17H16ClN3O 313.79 g/mol Amoxapine
Butriptyline C21H27N 293.454 g/mol Butriptyline
Clomipramine C19H23ClN2 314.86 g/mol Clomipramine
Desipramine C18H22N2 266.388 g/mol Desipramine
Dosulepin C19H21NS 295.44 g/mol Dosulepin
Doxepin C19H21NO 279.383 g/mol Doxepin
Imipramine C19H24N2 280.415 g/mol Imipramine
Lofepramine C26H27ClN2O 418.97 g/mol Lofepramine
Maprotiline C20H23N 277.411 g/mol Maprotiline
Melitracen C21H25N 291.438 g/mol Melitracen
Nortriptyline C19H21N 263.384 g/mol Nortriptyline
Pipofezine C16H19N5O 297.362 g/mol Pipofezine
Protriptyline C19H21N 263.384 g/mol Protriptyline
Tianeptine C21H25ClN2O4S 436.95 g/mol Tianeptine
Trimipramine C20H26N2 294.442 g/mol Trimipramine

NotesEdit

  1. Kis are a numerical way of stating how potently drugs bind to their respective receptor/transporter sites; the lower the Ki the more potently the drug binds to the protein in question. All in nanomolars (nM).
  2. Derived from Martindale and Medscape Reference

Reference listEdit

  1. 1.0 1.1 Brayfield, A, ed. (11 August 2014). "Amineptine Hydrochloride". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. 
  2. Rossi, S, ed. (July 2014). "Amitriptyline". Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 11 August 2014. 
  3. "WHO Model List of Essential Medicines". WHO. World Health Organization. October 2013. Retrieved 11 August 2014. 
  4. Apiquian, R; Ulloa, E; Fresan, A; Loyzaga, C; Nicolini, H; Kapur, S (January 2003). "Amoxapine shows atypical antipsychotic effects in patients with schizophrenia: results from a prospective open-label study.". Schizophrenia Research 59 (1): 35–9. PMID 12413640. doi:10.1016/S0920-9964(01)00342-5. 
  5. Apiquian, R; Fresan, A; Ulloa, RE; de la Fuente-Sandoval, C; Herrera-Estrella, M; Vazquez, A; Nicolini, H; Kapur, S (December 2005). "Amoxapine as an atypical antipsychotic: a comparative study vs risperidone.". Neuropsychopharmacology 30 (12): 2236–44. PMID 15956984. doi:10.1038/sj.npp.1300796. 
  6. Chaudhry, IB; Husain, N; Khan, S; Badshah, S; Deakin, B; Kapur, S (December 2007). "Amoxapine as an antipsychotic: comparative study versus haloperidol.". Journal of Clinical Psychopharmacology 27 (6): 575–81. PMID 18004123. doi:10.1097/jcp.0b013e31815a4424. 
  7. O'Connor, AB; Noyes, K; Holloway, RG (August 2007). "A cost-effectiveness comparison of desipramine, gabapentin, and pregabalin for treating postherpetic neuralgia.". Journal of the American Geriatrics Society 55 (8): 1176–84. PMID 17661955. doi:10.1111/j.1532-5415.2007.01246.x. 
  8. Ghanizadeh, A (2013 Jul). "A systematic review of the efficacy and safety of desipramine for treating ADHD.". Current Drug Safety 8 (3): 169–74. PMID 23914752. doi:10.2174/15748863113089990029.  Check date values in: |date= (help)
  9. Aronoff, GM; Evans, WO (August 1982). "Doxepin as an adjunct in the treatment of chronic pain.". The Journal of Clinical Psychiatry 43 (8 Pt 2): 42–7. PMID 7047506. 
  10. Rossi, S, ed. (July 2014). "Imipramine". Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 11 August 2014. 
  11. Brayfield, A, ed. (23 September 2011). "Melitracen Hydrochloride". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 11 August 2014. 
  12. Boerner, RJ (November 2007). "Generalisierte Angststörung: Diagnostik und Therapie" [Generalized anxiety disorder (GAD)--diagnosis and therapy] (PDF). Medizinische Monatsschrift fur Pharmazeuten 30 (11): 401–8; quiz 409–10. PMID 18062331. doi:10.3238/arztebl.2013.0300. 
  13. Smith, IE; Quinnell, TG (2004). "Pharmacotherapies for obstructive sleep apnoea: where are we now?". Drugs 64 (13): 1385–99. PMID 15212557. doi:10.2165/00003495-200464130-00001. 
  14. Brayfield, A, ed. (13 December 2013). "Tianeptine Sodium". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 11 August 2014. 
  15. Lechin, F; van der Dijs, B; Lechin, AE (November 2004). "Treatment of bronchial asthma with tianeptine.". Methods and Findings in Experimental and Clinical Pharmacology 26 (9): 697–701. PMID 15632955. doi:10.1358/mf.2004.26.9.872567. 
  16. Sohn, W; Lee, OY; Kwon, JG; Park, KS; Lim, YJ; Kim, TH; Jung, SW; Kim, JI (September 2012). "Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open-label, non-inferiority, randomized controlled study.". Neurogastroenterology and Motility 24 (9): 860–e398. PMID 22679908. doi:10.1111/j.1365-2982.2012.01945.x. 
  17. Chojnacki, C; Walecka-Kapica, E; Mokwinska, M; Romanowski, M; Pawlowicz, M; Chojnacki, J; Klupinska, G (April 2013). "Influence of tianeptine on melatonin homeostasis and psychosomatic symptoms in patients with irritable bowel syndrome." (PDF). Journal of Physiology and Pharmacology 64 (2): 177–83. PMID 23756392. 
  18. Voican, CS; Corruble, E; Naveau, S; Perlemuter, G (April 2014). "Antidepressant-induced liver injury: a review for clinicians.". The American Journal of Psychiatry 171 (4): 404–15. PMID 24362450. doi:10.1176/appi.ajp.2013.13050709. 
  19. 19.0 19.1 Kerr, GW; McGuffie, AC; Wilkie, S (July 2001). "Tricyclic antidepressant overdose: a review.". Emergency Medicine Journal 18 (4): 236–41. PMC 1725608. PMID 11435353. doi:10.1136/emj.18.4.236. 
  20. 20.0 20.1 White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type.". Journal of Medical Toxicology 4 (4): 238–50. PMC 3550116. PMID 19031375. doi:10.1007/BF03161207. 
  21. Hawton, K; Bergen, H; Simkin, S; Cooper, J; Waters, K; Gunnell, D; Kapur, N (May 2010). "Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose.". The British Journal of Psychiatry 196 (5): 354–8. PMC 2862059. PMID 20435959. doi:10.1192/bjp.bp.109.070219. 
  22. Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 10 August 2014. 
  23. Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York, USA: McGraw-Hill Professional. ISBN 978-0-07-162442-8. 

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