dosulepin

Dosulepin is used for the treatment of major depressive disorder.{{cite web|title=Dothep Dothiepin hydrochloride|work=TGA eBusiness Services|publisher=Alphapharm Pty Limited|date=1 November 2013|access-date=3 December 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04551-3|format=PDF}}{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}{{cite book | isbn = 978-0-85711-084-8 | title = British National Formulary (BNF) | last1 = Joint Formulary Committee | year = 2013 | publisher = Pharmaceutical Press | location = London, UK | edition = 65 | url-access = registration | url = https://archive.org/details/bnf65britishnati0000unse }} There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.{{cite journal | vauthors = Feinmann C, Harris M, Cawley R | title = Psychogenic facial pain: presentation and treatment | journal = British Medical Journal | volume = 288 | issue = 6415 | pages = 436–438 | date = February 1984 | pmid = 6419955 | pmc = 1444752 | doi = 10.1136/bmj.288.6415.436 }}

Contraindications include:

• Epilepsy as it can lower the seizure threshold
• TCAs should not be used concomitantly or within 14 days of treatment with monoamine oxidase inhibitors due to the risk for serotonin syndrome
• Acute recovery phase following myocardial infarction as TCAs may produce conduction defects and arrhythmias
• Liver failure
• Hypersensitivity to dosulepin

Common adverse effects:

{{div col|colwidth=18em}}

• Drowsiness
• Extrapyramidal symptoms
• Tremor
• Disorientation
• Dizziness
• Paresthesias
• Alterations to ECG patterns
• Dry mouth
• Sweating
• Urinary retention
• Hypotension
• Postural hypotension
• Tachycardia
• Palpitations
• Arrhythmias
• Conduction defects
• Increased or decreased libido
• Nausea
• Vomiting
• Constipation
• Blurred vision

{{div col end}}

Less common adverse effects:

{{div col|colwidth=22em}}

• Disturbed concentration
• Delusions
• Hallucinations
• Anxiety
• Fatigue
• Headaches
• Restlessness
• Excitement
• Insomnia
• Hypomania
• Nightmares
• Peripheral neuropathy
• Ataxia
• Incoordination
• Seizures
• Paralytic ileus
• Hypertension
• Heart block
• Myocardial infarction
• Stroke
• Gynecomastia (swelling of breast tissue in males)
• Testicular swelling
• Impotence
• Epigastric distress
• Abdominal cramps
• Parotid swellings
• Diarrhea
• Stomatitis (swelling of the mouth)
• Black tongue
• Peculiar taste sensations
• Cholestatic jaundice
• Altered liver function
• Hepatitis (swelling of the liver)
• Skin rash
• Urticaria (hives)
• Photosensitisation
• Skin blisters
• Angioneurotic edema
• Weight loss
• Urinary frequency
• Mydriasis
• Weight gain
• Hyponatremia (low blood sodium)
• Movement disorders
• Dyspepsia (indigestion)
• Increased intraocular pressure
• Changes in blood sugar levels

{{div col end}}

• Thrombocytopenia (an abnormally low number of platelets in the blood. This makes one more susceptible to bleeds)
• Eosinophilia (an abnormally high number of eosinophils in the blood)
• Agranulocytosis (a dangerously low number of white blood cells in the blood leaving one open to potentially life-threatening infections)
• Galactorrhea (lactation that is unassociated with breastfeeding and lactation)

{{Main|Tricyclic antidepressant overdose}}

The symptoms and the treatment of an overdose are largely the same as for the other TCAs. Dosulepin may be particularly toxic in overdose compared to other TCAs. The onset of toxic effects is around 4–6 hours after dosulepin is ingested. In order to minimise the risk of overdose it is advised that patients only receive a limited number of tablets at a time so as to limit their risk of overdosing. It is also advised that patients are not prescribed any medications that are known to increase the risk of toxicity in those receiving dosulepin due to the potential for mixed overdoses. The medication should also be kept out of reach of children.

Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination. TCAs potentiate the sedative effects of barbiturates, tranquilizers and {{abbrlink|CNS|central nervous system}} depressants. Guanethidine and other adrenergic neuron blocking drugs can have their antihypertensive effects blocked by dosulepin. Sympathomimetics may potentiate the sympathomimetic effects of dosulepin. Due to the anticholinergic and antihistamine effects of dosulepin anticholinergic and antihistamine medications may have their effects potentiated by dosulepin and hence these combinations are advised against. Dosulepin may have its postural hypotensive effects potentiated by diuretics. Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.

{{See also|Pharmacology of antidepressants|Tricyclic antidepressant#Binding profiles}}

Dosulepin is a reuptake inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET), thereby acting as an SNRI. It is also an antagonist of the histamine H₁ receptor, α₁-adrenergic receptor, serotonin 5-HT₂ receptors, and muscarinic acetylcholine receptors (mACh), as well as a blocker of voltage-gated sodium channels (VGSCs). The antidepressant effects of dosulepin are thought to be due to inhibition of the reuptake of norepinephrine and possibly also of serotonin.

Dosulepin has three metabolites, northiaden (desmethyldosulepin), dosulepin sulfoxide, and northiaden sulfoxide, which have longer terminal half-lives than that of dosulepin itself. However, whereas northiaden has potent activity similarly to dosulepin, the two sulfoxide metabolites have dramatically reduced activity. They have been described as essentially inactive, and are considered unlikely to contribute to either the therapeutic effects or side effects of dosulepin. Relative to dosulepin, northiaden has reduced activity as a serotonin reuptake inhibitor, antihistamine, and anticholinergic and greater potency as a norepinephrine reuptake inhibitor, similarly to other secondary amine TCAs.{{cite book| vauthors = Hales RE, Yudofsky SC, Gabbard GO |title=Essentials of Psychiatry|url=https://books.google.com/books?id=Hf50vMMMv_wC&pg=PA468|year=2011|publisher=American Psychiatric Pub|isbn=978-1-58562-933-6|pages=468–}}{{cite book| vauthors = Burtis CA, Ashwood ER, Bruns DE |title=Tietz Textbook of Clinical Chemistry and Molecular Diagnostics - E-Book|url=https://books.google.com/books?id=BBLRUI4aHhkC&pg=PA1129|date=14 October 2012|publisher=Elsevier Health Sciences|isbn=978-1-4557-5942-2|pages=1129–}} Unlike the sulfoxide metabolites, northiaden is thought to play an important role in the effects of dosulepin.

Although Heal & Cheetham (1992) reported relatively high K_i values of 12 and 15 nM for dosulepin and northiaden at the rat α₂-adrenergic receptor and suggested that antagonism of the receptor could be involved in the antidepressant effects of dosulepin, Richelson & Nelson (1984) found a low K_D of only 2,400 nM for dosulepin at this receptor using human brain tissue. This suggests that it in fact has low potency for this action, similarly to other TCAs.

Dosulepin is readily absorbed from the small intestine and is extensively metabolized on first-pass through the liver into its chief active metabolite, northiaden. Peak plasma concentrations of between 30.4 and 279 ng/mL (103–944 nmol/L) occur within 2–3 hours of oral administration. It is distributed in breast milk and crosses the placenta and blood–brain barrier. It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.

Dosulepin is a tricyclic compound, specifically a dibenzothiepine, and possesses three rings fused together with a side chain attached in its chemical structure.{{cite book| vauthors = Aronson JK |title=Meyler's Side Effects of Psychiatric Drugs|url=https://books.google.com/books?id=AmYFTSO8jCkC&pg=PA7|year=2009|publisher=Elsevier|isbn=978-0-444-53266-4|pages=7–}} It is the only TCA with a dibenzothiepine ring system to have been marketed.{{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}} The drug is a tertiary amine TCA, with its side chain-demethylated metabolite northiaden (desmethyldosulepin) being a secondary amine.{{cite book| vauthors = Cutler NR, Sramek JJ, 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–}}{{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–}} Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, doxepin, and trimipramine.{{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=1-56053-470-2|pages=39–}}{{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–}} Dosulepin exhibits (E) and (Z) stereoisomerism like doxepin but in contrast the pure E or trans isomer is used medicinally.{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA607|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=607–}}{{cite book|title=Psychotropic Agents: Part I: Antipsychotics and Antidepressants|url=https://books.google.com/books?id=oK7tCAAAQBAJ&pg=PA354|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-67538-6|pages=354–}} The drug is used commercially as the hydrochloride salt; the free base is not used.

Dosulepin was developed by SPOFA.{{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 }} It was patented in 1962 and first appeared in the literature in 1962. The drug was first introduced for medical use in 1969, in the United Kingdom.{{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–}}

Dosulepin is the English and German generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}, while dosulepin hydrochloride is its {{abbrlink|BANM|British Approved Name}} and {{abbrlink|JAN|Japanese Accepted Name}}.{{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=PA468|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=468–}}{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA369|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=369–}}{{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=PA105|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=105–}}{{Cite web|url=https://www.drugs.com/international/dosulepin.html|title = Dosulepin}} Dothiepin is the former {{abbrlink|BAN|British Approved Name}} of the drug while dothiepin hydrochloride is the former {{abbrlink|BANM|British Approved Name}} and remains the current {{abbrlink|USAN|United States Adopted Name}}. Its generic name in Spanish and Italian and its {{abbrlink|DCIT|Denominazione Comune Italiana}} are dosulepina, in French and its {{abbrlink|DCF|Dénomination Commune Française}} are dosulépine, and in Latin is dosulepinum.

Dosulepin is marketed throughout the world mainly under the brand name Prothiaden. It is or has been marketed under a variety of other brand names as well, including Altapin, Depresym, Dopress, Dothapax, Dothep, Idom, Prepadine, Protiaden, Protiadene, Thaden, and Xerenal.

Dosulepin is marketed throughout Europe (as Prothiaden, Protiaden, and Protiadene), Australia (as Dothep and Prothiaden), New Zealand (as Dopress) and South Africa (as Thaden).{{cite book|title=Dosulepin Hydrochloride|work=Martindale: The Complete Drug Reference|date=5 December 2011|access-date=15 August 2017|url=http://www.medicinescomplete.com/mc/martindale/current/2512-p.htm|publisher=Pharmaceutical Press|location=London, UK}} It is also available in Japan, Hong Kong, Taiwan, India, Singapore, and Malaysia. The drug is not available in the United States or Canada.

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{{Neuropathic pain and fibromyalgia pharmacotherapies}}

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{{Tricyclics}}

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