Protriptyline

{{Short description|Chemical compound}} {{Infobox drug | verifiedrevid = 464375600 | IUPAC_name = 3-(5''H''-dibenzo[''a'',''d''][7]annulen-5-yl)-''N''-methylpropan-1-amine | image = Protriptyline.svg | image_class = skin-invert-image | width = 200px | caption = Above: molecular structure of protriptyline Below: 3D representation of a protriptyline molecule | image2 = Protripyline 3D.png | image_class2 = bg-transparent | tradename = Vivactyl, others | Drugs.com = {{drugs.com|monograph|protriptyline-hydrochloride}} | MedlinePlus = a604025 | pregnancy_US = C | pregnancy_category = | legal_AU =  | legal_BR = C1 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}</ref> | legal_CA =  | legal_DE =  | legal_NZ =  | legal_UK =  | legal_US =  | legal_EU = | legal_UN =  | legal_status = Rx-only | routes_of_administration = Oral | bioavailability = 77–93%<ref name="LemkeWilliams2012">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA588|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=588–}}</ref> | protein_bound = 92%<ref name="LemkeWilliams2012" /> | metabolism = Hepatic | elimination_half-life = 54–92 hours | excretion = Urine: 50%<ref name="LemkeWilliams2012" /> Feces: minor<ref name="LemkeWilliams2012" /> | IUPHAR_ligand = 7285 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 438-60-8 | CAS_supplemental = 1225-55-4 (hydrochloride) | ATC_prefix = N06 | ATC_suffix = AA11 | PubChem = 4976 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00344 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4805 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 4NDU154T12 | KEGG = D08447 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 8597 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 668 | synonyms = Amimethyline; Protriptyline hydrochloride; MK-240 | C = 19 | H = 21 | N = 1 | SMILES = c3cc2c(\C=C/c1c(cccc1)C2CCCNC)cc3 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C19H21N/c1-20-14-6-11-19-17-9-4-2-7-15(17)12-13-16-8-3-5-10-18(16)19/h2-5,7-10,12-13,19-20H,6,11,14H2,1H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = BWPIARFWQZKAIA-UHFFFAOYSA-N }}

'''Protriptyline''', sold under the brand name '''Vivactil''' among others, is a tricyclic antidepressant (TCA), specifically a secondary amine. Uniquely among most of the TCAs, protriptyline tends to be energizing instead of sedating, and is sometimes used for narcolepsy to achieve a wakefulness-promoting effect.<ref>Schmidt, H. S., Clark, R. W., & Hyman, P. R. (1977). Protriptyline: An effective agent in the treatment of the narcolepsy-cataplexy syndrome and hypersomnia. ''The American Journal of Psychiatry, 134''(2), 183–185. https://doi.org/10.1176/ajp.134.2.183</ref>

TCAs including protriptyline are also used to reduce the incidence of recurring headaches such as migraine, and for other types of chronic pain.<ref>{{Cite journal |last=Cohen |first=G. L. |date=1997 |title=Protriptyline, chronic tension-type headaches, and weight loss in women |journal=Headache |volume=37 |issue=7 |pages=433–436 |doi=10.1046/j.1526-4610.1997.3707433.x |issn=0017-8748 |pmid=9277026}}</ref>

==Medical uses== Protriptyline is used primarily to treat depression and to treat the combination of symptoms of anxiety and depression.<ref name=DURAMED>DURAMED PHARMACEUTICALS, INC., . (Ed.). (2007). Protriptyline drug facts. Pomona, New York : Barr Pharmaceuticals, Inc.</ref> Like most antidepressants of this chemical and pharmacological class, protriptyline has also been used in limited numbers of patients to treat panic disorder, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, enuresis, eating disorders such as bulimia nervosa, cocaine dependency, and the depressive phase of bipolar disorder (manic-depressive) disorder. It has also been used to support smoking cessation programs.<ref name=ULTRAM>ULTRAM, . (Ed.). (2007). Protriptyline. Ortho-McNeil Pharmaceutical Inc.</ref>

Protriptyline is available as 5 mg and 10 mg tablets.<ref name=AHFS/> Doses range from 15 to 40 mg per day and can be taken in one daily dose or divided into up to four doses daily.<ref name=AHFS/> Some people with severe depression may require up to 60 mg per day.<ref name=AHFS/>

In adolescents and people over age 60, therapy should be initiated at a dose of 5 mg three times a day and increased under the supervision of a physician as needed.<ref name=AHFS/> Patients over age 60 who are taking daily doses of 20 mg or more should be closely monitored for side effects such as rapid heart rate and urinary retention.<ref name=AHFS/>

Like all TCAs, protriptyline should be used cautiously and with close physician supervision. This is especially so for persons with glaucoma, especially angle-closure glaucoma (the most severe form) or urinary retention, for men with benign prostatic hyperplasia (enlarged prostate gland), and for the elderly. Before starting treatment, people should discuss the relative risks and benefits of treatment with their doctors to help determine if protriptyline is the right antidepressant for them.<ref name=Kirchheiner04>{{cite journal | vauthors = Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, Brockmöller J | title = Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response | journal = Molecular Psychiatry | volume = 9 | issue = 5 | pages = 442–473 | date = May 2004 | pmid = 15037866 | doi = 10.1038/sj.mp.4001494 | doi-access = free }}</ref>

==Contraindications== Protriptyline may increase heart rate and stress on the heart.<ref name=Advameg/> It may be dangerous for people with cardiovascular disease, especially those who have recently had a heart attack, to take this drug or other antidepressants in the same pharmacological class.<ref name=Advameg/> In rare cases in which patients with cardiovascular disease must take protriptyline, they should be monitored closely for cardiac rhythm disturbances and signs of cardiac stress or damage.<ref name=Advameg/>

When protriptyline is used to treat the depressive component of schizophrenia, psychotic symptoms may be aggravated. Likewise, in manic-depressive psychosis, depressed patients may experience a shift toward the manic phase if they are treated with an antidepressant drug. Paranoid delusions, with or without associated hostility, may be exaggerated.<ref name=AHFS/> In any of these circumstances, it may be advisable to reduce the dose of protriptyline or to use an antipsychotic drug concurrently.<ref name=AHFS/>

==Side effects== Protriptyline shares side effects common to all TCAs.<ref name=DURAMED/> The most frequent of these are dry mouth, constipation, urinary retention, increased heart rate, sedation, irritability, decreased coordination, anxiety, blood disorders, confusion, decreased libido, dizziness, flushing, headache, impotence, insomnia, low blood pressure, nightmares, rapid or irregular heartbeat, rash, seizures, sensitivity to sunlight, stomach and intestinal problems.<ref name=AHFS/> Other more complicated side effects include; chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; sudden numbness or weakness, especially on one side of the body; sudden headache, confusion, problems with vision, speech, or balance; hallucinations, or seizure (convulsions); easy bruising or bleeding, unusual weakness; restless muscle movements in your eyes, tongue, jaw, or neck; urinating less than usual or not at all; extreme thirst with headache, nausea, vomiting, and weakness; or feeling light-headed or fainting.<ref name=AHFS/> Dry mouth, if severe to the point of causing difficulty speaking or swallowing, may be managed by dosage reduction or temporary discontinuation of the drug.<ref name=DURAMED/> Patients may also chew sugarless gum or suck on sugarless candy in order to increase the flow of saliva. Some artificial saliva products may give temporary relief.<ref name=DURAMED/> Men with prostate enlargement who take protriptyline may be especially likely to have problems with urinary retention.<ref name=AHFS/> Symptoms include having difficulty starting a urine flow and more difficulty than usual passing urine.<ref name=AHFS/> In most cases, urinary retention is managed with dose reduction or by switching to another type of antidepressant.<ref name=AHFS/> In extreme cases, patients may require treatment with bethanechol, a drug that reverses this particular side effect.<ref name=AHFS/>

A common problem with TCAs is sedation (drowsiness, lack of physical and mental alertness), but protriptyline is considered the least sedating agent among this class of agents.<ref name=Kirchheiner04/> Its side effects are especially noticeable early in therapy.<ref name=Kirchheiner04/> In most people, early TCA side effects decrease or disappear entirely with time, but, until then, patients taking protriptyline should take care to assess which side effects occur in them and should not perform hazardous activities requiring mental acuity or coordination.<ref name=DeVane90>DeVane, C. Lindsay, Pharm.D. "Drug Therapy for Mood Disorders." In Fundamentals of Monitoring Psychoactive Drug Therapy. Baltimore: Williams and Wilkins, 1990.</ref> Protriptyline may increase the possibility of having seizures.<ref name=DeVane90/>

===Withdrawal=== Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.<ref name=Advameg/>

===List of side effects=== *''Cardiovascular'': Myocardial infarction; stroke; heart block; arrhythmias; hypotension, particularly orthostatic hypotension; hypertension; tachycardia; palpitation.<ref>{{cite journal |vauthors=Sériès F, Cormier Y |title=Effects of protriptyline on diurnal and nocturnal oxygenation in patients with chronic obstructive pulmonary disease |journal=Ann. Intern. Med. |volume=113 |issue=7 |pages=507–11 |date=October 1990 |pmid=2393207 |doi=10.7326/0003-4819-113-7-507}}</ref> *''Psychiatric'': Confusional states (especially in the elderly) with hallucinations, disorientation, delusions, anxiety, restlessness, agitation; hypomania; exacerbation of psychosis; insomnia, panic, and nightmares.<ref name=DURAMED/> *''Neurological'': Seizures; incoordination; ataxia; tremors; peripheral neuropathy; numbness, tingling, and paresthesias of extremities; extrapyramidal symptoms; drowsiness; dizziness; weakness and fatigue; headache; syndrome of inappropriate ADH (antidiuretic hormone) secretion; tinnitus; alteration in EEG patterns.<ref name=DURAMED/> *''Anticholinergic'': Paralytic ileus; hyperpyrexia; urinary retention, delayed micturition, dilatation of the urinary tract; constipation; blurred vision, disturbance of accommodation, increased intraocular pressure, mydriasis; dry mouth and rarely associated sublingual adentitis.<ref name=DURAMED/> *''Allergic'': Drug fever; petechiae, skin rash, urticaria, itching, photosensitization (avoid excessive exposure to sunlight); edema (general, or of face and tongue).<ref name=DURAMED/> *''Hematologic'': Agranulocytosis; bone marrow depression; leukopenia;thrombocytopenia; purpura; eosinophilia.<ref name=DURAMED/> *''Gastrointestinal'': Nausea and vomiting; anorexia; epigastric distress; diarrhea; peculiar taste; stomatitis; abdominal cramps; black tongue.<ref name=DURAMED/> *''Endocrine'': Impotence, increased or decreased libido: gynecomastia in the male; breast enlargement and galactorrhea in the female; testicular swelling; elevation or depression of blood sugar levels.<ref name=DURAMED/> *''Other'': Jaundice (simulating obstructive); altered liver function; parotid swelling; alopecia; flushing; weight gain or loss; urinary frequency, nocturia; perspiration.<ref name=DURAMED/>

==Overdose== {{Main|Tricyclic antidepressant overdose}}

Deaths may occur from overdose with this class of drugs.<ref name=DeVane90/> Multiple drug ingestion (including alcohol) is common in deliberate TCA overdose.<ref name=DeVane90/> As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment.<ref name=DURAMED/> Signs and symptoms of toxicity develop rapidly after TCA overdose, therefore, hospital monitoring is required as soon as possible.<ref name=DeVane90/>

Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma.<ref name=AHFS/> Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of TCA toxicity.<ref name=AHFS/> Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia.<ref name=AHFS/>

==Interactions== The side effects of protriptyline are increased when it is taken with central nervous system depressants, such as alcoholic beverages, sleeping medications, other sedatives, or antihistamines, as well as with other antidepressants including SSRIs, SNRIs or monoamine oxidase inhibitors.<ref name=DeVane90/> It may be dangerous to take protriptyline in combination with these substances.<ref name=DeVane90/>

==Pharmacology==

===Pharmacodynamics=== {{See also|Pharmacology of antidepressants|Tricyclic antidepressant#Binding profiles}} {| class="wikitable floatright" style="font-size:small;" |+ Protriptyline<ref name="PDSP">{{cite web | title = PDSP Ki Database | work = Psychoactive Drug Screening Program (PDSP) | vauthors = Roth BL, Driscol J | author1-link = Bryan Roth | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 7 May 2022 | url = https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=Protriptyline&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref> |- ! Site !! Ki (nM) !! Species !! Ref |- | {{abbrlink|SERT|Serotonin transporter}} || 19.6 || Human || <ref name="pmid9537821">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = Eur. J. Pharmacol. | volume = 340 | issue = 2–3 | pages = 249–58 | year = 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9}}</ref> |- | {{abbrlink|NET|Norepinephrine transporter}} || 1.41 || Human || <ref name="pmid9537821" /> |- | {{abbrlink|DAT|Dopamine transporter}} || 2,100 || Human || <ref name="pmid9537821" /> |- | 5-HT1A || 3,800 || Human || <ref name="pmid3816971">{{cite journal | vauthors = Wander TJ, Nelson A, Okazaki H, Richelson E | title = Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro | journal = Eur. J. Pharmacol. | volume = 132 | issue = 2–3 | pages = 115–21 | year = 1986 | pmid = 3816971 | doi = 10.1016/0014-2999(86)90596-0}}</ref> |- | 5-HT2A || 70 || Human || <ref name="pmid3816971" /> |- | 5-HT2C || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} |- | α1 || 130 || Human || <ref name="pmid6086881">{{cite journal | vauthors = Richelson E, Nelson A | title = Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro | journal = J. Pharmacol. Exp. Ther. | volume = 230 | issue = 1 | pages = 94–102 | year = 1984 | doi = 10.1016/S0022-3565(25)21446-X | pmid = 6086881 }}</ref> |- | α2 || 6,600 || Human || <ref name="pmid6086881" /> |- | β || >10,000 || Monkey/rat || <ref name="pmid8699">{{cite journal | vauthors = Bylund DB, Snyder SH | title = Beta adrenergic receptor binding in membrane preparations from mammalian brain | journal = Mol. Pharmacol. | volume = 12 | issue = 4 | pages = 568–80 | year = 1976 | doi = 10.1016/S0026-895X(25)10785-2 | pmid = 8699 }}</ref> |- | D2 || 2,300 || Human || <ref name="pmid6086881" /> |- | H1 || 7.2–25 || Human || <ref name="pmid22033803">{{cite journal | vauthors = Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R | title = Interactions of recombinant human histamine H1R, H2R, H3R, and H4R receptors with 34 antidepressants and antipsychotics | journal = Naunyn-Schmiedeberg's Arch. Pharmacol. | volume = 385 | issue = 2 | pages = 145–70 | year = 2012 | pmid = 22033803 | doi = 10.1007/s00210-011-0704-0 | s2cid = 14274150 }}</ref><ref name="pmid6086881" /> |- | H2 || 398 || Human || <ref name="pmid22033803" /> |- | H3 || >100,000 || Human || <ref name="pmid22033803" /> |- | H4 || 15,100 || Human || <ref name="pmid22033803" /> |- | {{abbrlink|mACh|Muscarinic acetylcholine receptor}} || 25 || Human || <ref name="pmid6086881" /><ref name="pmid6297650">{{cite journal | vauthors = El-Fakahany E, Richelson E | title = Antagonism by antidepressants of muscarinic acetylcholine receptors of human brain | journal = Br. J. Pharmacol. | volume = 78 | issue = 1 | pages = 97–102 | year = 1983 | pmid = 6297650 | pmc = 2044798 | doi = 10.1111/j.1476-5381.1983.tb17361.x}}</ref> |- class="sortbottom" | colspan="4" style="width: 1px;" | Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. |}

Protriptyline acts by decreasing the reuptake of norepinephrine and to a lesser extent serotonin (5-HT) in the brain.<ref name=Advameg>Advameg, Inc. (2010). [http://www.minddisorders.com/Ob-Ps/Protriptyline.html Protriptyline] at MindDisorders.com</ref> Its affinity for the human norepinephrine transporter (NET) is 1.41 nM, 19.6 nM for the serotonin transporter and 2,100 nM for the dopamine transporter.<ref name="pdsp">{{cite web|title=PDSP Database - UNC|url=https://kidbdev.med.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testDDRadio=testDDRadio&testLigandDD=2268&testLigand=&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query|website=PDSP Ki Database|publisher=University of North Carolina|access-date=15 July 2017}}</ref> TCAs act to change the balance of naturally occurring chemicals in the brain that regulate the transmission of nerve impulses between cells. Protriptyline increases the concentration of norepinephrine and serotonin (both chemicals that stimulate nerve cells) and, to a lesser extent, blocks the action of another brain chemical, acetylcholine.<ref name= Advameg /> The therapeutic effects of protriptyline, like other antidepressants, appear slowly. Maximum benefit is often not evident for at least two weeks after starting the drug.<ref name= Advameg />

Protriptyline is a TCA.<ref name=AHFS>American Society of Health-System Pharmacists. ''AHFS Drug Information 2002''. Bethesda: American Society of Health-System Pharmacists, 2002.</ref> It was thought that TCAs work by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin by neurons.<ref name=AHFS/> However, this response occurs immediately, yet mood does not lift for around two weeks.<ref name=AHFS/> It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus.<ref name=AHFS/> The hippocampus is part of the limbic system, a part of the brain involved in emotions. TCAs are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain.<ref name=AHFS/> A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the central nervous system via an indirect serotonergic route. TCAs are also effective in migraine prophylaxis, but not in abortion of acute migraine attack.<ref name=AHFS/> The mechanism of their anti-migraine action is also thought to be serotonergic, similar to psilocybin.<ref name=AHFS/>

===Pharmacokinetics=== Metabolic studies indicate that protriptyline is well absorbed from the gastrointestinal tract and is rapidly sequestered in tissues.<ref name=DURAMED/> Relatively low plasma levels are found after administration, and only a small amount of unchanged drug is excreted in the urine of dogs and rabbits.<ref name=DURAMED/> Preliminary studies indicate that demethylation of the secondary amine moiety occurs to a significant extent, and that metabolic transformation takes place in the liver.<ref name=DURAMED/> It penetrates the brain rapidly in mice and rats, and moreover that which is present in the brain is almost all unchanged drug.<ref name=DURAMED/> Studies on the disposition of radioactive protriptyline in human test subjects showed significant plasma levels within 2 hours, peaking at 8 to 12 hours, then declining gradually.<ref name=DURAMED/>

Urinary excretion studies in the same subjects showed significant amounts of radioactivity in 2 hours.<ref name=DURAMED/> The rate of excretion was slow.<ref name=DURAMED/> Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.<ref name=DURAMED/>

Protriptyline has uniquely low dosing among TCAs, likely due to its exceptionally long terminal half-life.<ref name="Stahl2017">{{cite book| vauthors = Stahl SM |title=Prescriber's Guide: Stahl's Essential Psychopharmacology|url=https://books.google.com/books?id=9hssDwAAQBAJ&pg=PA619|date=31 March 2017|publisher=Cambridge University Press|isbn=978-1-108-22874-9|pages=619–}}</ref> It is used in dosages of 15 to 40 mg/day, whereas most other TCAs are used at dosages of 75 to 300 mg/day.<ref name="Stahl2017" /> The maximum dose is 60 mg/day.<ref name="Stahl2017" /> Therapeutic levels of protriptyline are typically in the range of 70 to 250 ng/mL (266-950 nmol/L), which is similar to that of other TCAs<ref name="LeeuwenBladh2016">{{cite book| vauthors = Van Leeuwen AM, Bladh ML |title=Textbook of Laboratory and Diagnostic Testing: Practical Application of Nursing Process at the Bedside|url=https://books.google.com/books?id=DEq8CwAAQBAJ&pg=PA28|date=19 February 2016|publisher=F.A. Davis|isbn=978-0-8036-5845-5|pages=28–}}</ref><ref name="PagliaroPagliaro1999">{{cite book| vauthors = Pagliaro LA, Pagliaro AM |title=Psychologists' Psychotropic Drug Reference|url=https://books.google.com/books?id=n2e2aAYnZYkC&pg=PA545|year=1999|publisher=Psychology Press|isbn=978-0-87630-964-3|pages=545–}}</ref><ref name="SchatzbergNemeroff2009">{{cite book| vauthors = Schatzberg AF, Nemeroff CB |title=The American Psychiatric Publishing Textbook of Psychopharmacology|url=https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA270|year=2009|publisher=American Psychiatric Pub|isbn=978-1-58562-309-9|pages=270–}}</ref>

==Chemistry== Protriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure.<ref name="Ritsner2013">{{cite book| vauthors = Ritsner MS |title=Polypharmacy in Psychiatry Practice, Volume I: Multiple Medication Use Strategies|url=https://books.google.com/books?id=jy-LMZU7338C&pg=PA270|date=15 February 2013|publisher=Springer Science & Business Media|isbn=978-94-007-5805-6|pages=270–271}}</ref> Other dibenzocycloheptadiene TCAs include amitriptyline, nortriptyline, and butriptyline.<ref name="Ritsner2013" /><ref name="LemkeWilliams2008">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA580|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=580–}}</ref> Protriptyline is a secondary amine TCA, with its ''N''-methylated analog ''N''–methylprotriptyline being a tertiary amine, and a structural isomer of amitriptyline.<ref name="CutlerSramek1994">{{cite book| vauthors = Cutler NR, Sramek JS, Narang PK |title=Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology|url=https://books.google.com/books?id=ncRXa8Dq88QC&pg=PA160|date=20 September 1994|publisher=John Wiley & Sons|isbn=978-0-471-95052-3|pages=160–}}</ref><ref name="AnzenbacherZanger2012">{{cite book| vauthors = Anzenbacher P, Zanger UM |title=Metabolism of Drugs and Other Xenobiotics|url=https://books.google.com/books?id=f-XHh17NfwgC&pg=PA302|date=23 February 2012|publisher=John Wiley & Sons|isbn=978-3-527-64632-6|pages=302–}}</ref> The tertiary amine analog of protriptyline, ''N''–methylprotriptyline, has not been marketed. Other secondary amine TCAs include desipramine and nortriptyline.<ref name="Anthony2002">{{cite book| vauthors = Anthony PK |title=Pharmacology Secrets|url=https://books.google.com/books?id=_QQsj3PAUrEC&pg=PA39|year=2002|publisher=Elsevier Health Sciences|isbn=978-1-56053-470-9|pages=39–}}</ref><ref name="CowenHarrison2012">{{cite book| vauthors = Cowen P, Harrison P, Burns T |title=Shorter Oxford Textbook of Psychiatry|url=https://books.google.com/books?id=Y1DtSGq-LnoC&pg=PA532|date=9 August 2012|publisher=OUP Oxford|isbn=978-0-19-162675-3|pages=532–}}</ref> The chemical name of protriptyline is 3-(5''H''-dibenzo[''a'',''d''][7]annulen-5-yl)-''N''-methylpropan-1-amine and its free base form has a chemical formula of C19H21N1 with a molecular weight of 263.377 g/mol.<ref name="Elks2014" /> The drug is used commercially mostly as the hydrochloride salt; the free base form is not used.<ref name="Elks2014" /><ref name="IndexNominum2000" /> The CAS Registry Number of the free base is 438-60-8 and of the hydrochloride is 1225-55-4.<ref name="Elks2014" /><ref name="IndexNominum2000" />

==History== Protriptyline was developed by Merck.<ref name="pmid19557250">{{cite journal | vauthors = Andersen J, Kristensen AS, Bang-Andersen B, Strømgaard K | title = Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters | journal = Chem. Commun. | issue = 25 | pages = 3677–92 | year = 2009 | pmid = 19557250 | doi = 10.1039/b903035m }}</ref> It was patented in 1962 and first appeared in the literature in 1964.<ref name="pmid19557250" /> The drug was first introduced for the treatment of depression in 1966.<ref name="pmid19557250" /><ref name="Dart2004">{{cite book| vauthors = Dart RC |title=Medical Toxicology|url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA836|year=2004|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2845-4|pages=836–}}</ref>

==Society and culture==

===Generic names=== ''Protriptyline'' is the English and French generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|DCF|Dénomination Commune Française}}, while ''protriptyline hydrochloride'' is its {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, and {{abbrlink|BANM|British Approved Name}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1040|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1040}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA894|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=894–}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA238|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=238–}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/protriptyline.html|title=Protriptyline Uses, Side Effects & Warnings}}</ref> Its generic name in Spanish and Italian and its {{abbrlink|DCIT|Denominazione Comune Italiana}} are ''protriptylina'', in German is ''protriptylin'', and in Latin is ''protriptylinum''.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

===Brand names=== Protriptyline is or has been marketed throughout the world under a variety of brand names including Anelun, Concordin, Maximed, Triptil, and '''Vivactil'''.<ref name="Elks2014" /><ref name="IndexNominum2000" />

===Availability=== The sale of protriptyline was discontinued in the United Kingdom, Australia, and Ireland in 2000.<ref>{{cite web |url=http://www.choiceandmedication.org/nsft/medications/92/ |title=Protriptyline |website=www.choiceandmedication.org |url-status=dead |archive-url=https://web.archive.org/web/20121122012810/http://www.choiceandmedication.org/nsft/medications/92 |archive-date=2012-11-22}}</ref> It remains available worldwide only in the United States as of 2024.<ref name="Drugs.com2">{{cite web | title=Protriptyline | website=Drugs.com | date=17 August 2017 | url=http://drugs.com/international/protriptyline.html | archive-url=https://web.archive.org/web/20170817034441/http://drugs.com/international/protriptyline.html | url-status=dead | archive-date=2017-08-17 | access-date=12 August 2024}}</ref><ref name="Drugs@FDA">{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=accessdata.fda.gov | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | access-date=12 August 2024}}</ref>

==See also== * List of antidepressants

==References== {{Reflist}}

{{Antidepressants}} {{ADHD pharmacotherapies}} {{Navboxes | title = Pharmacodynamics | titlestyle = background:#ccccff | list1 = {{Adrenergic receptor modulators}} {{Histamine receptor modulators}} {{Monoamine reuptake inhibitors}} {{Muscarinic acetylcholine receptor modulators}} {{Serotonin receptor modulators}} }} {{Tricyclics}}

Category:Alpha-1 blockers Category:Antihistamines Category:Dibenzocycloheptenes Category:Muscarinic antagonists Category:Secondary amines Category:Serotonin receptor antagonists Category:Serotonin–norepinephrine reuptake inhibitors Category:Tricyclic antidepressants Category:Wakefulness-promoting agents