Chemistry:Dosulepin

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Short description: Antidepressant
Dosulepin
Clinical data
Trade namesProthiaden, others
Other namesIZ-914, KS-1596[1][2][3], dothiepin (USAN US)
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: C
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
Pharmacokinetic data
Bioavailability30%[4]
Protein binding84%[5]
MetabolismHepatic (N-demethylation, S-oxidation, glucuronidation)[5]
MetabolitesNorthiaden, dothiepin sulfoxide, northiaden sulfoxide, glucuronide conjugates[4]
Elimination half-lifeDothiepin: 14.4–23.9 hours[4]
Dothiepin sulfoxide: 22.7–25.5 hours[4]
Northiaden: 34.7–45.7 hours[4]
Northiaden sulfoxide: 24.2–33.5 hours[4]
ExcretionUrine: 56%[4]
Feces: 15%[4]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H21NS
Molar mass295.44 g·mol−1
3D model (JSmol)
 ☒NcheckY (what is this?)  (verify)

Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a tricyclic antidepressant (TCA) which is used in the treatment of depression.[4][6][7] Dosulepin was once the most frequently prescribed antidepressant in the United Kingdom , but it is no longer widely used due to its relatively high toxicity in overdose without therapeutic advantages over other TCAs.[6][8][9] It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) and also has other activities including antihistamine, antiadrenergic, antiserotonergic, anticholinergic, and sodium channel-blocking effects.[4][10][11]

Medical uses

Dosulepin is used for the treatment of major depressive disorder.[4][5][12][13] There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.[14]

Contraindications

Contraindications include:[5]

  • 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

Side effects

Common adverse effects:[5]

  • 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

Less common adverse effects:[5]

  • 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
  • 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)

Overdose

Main article: Medicine:Tricyclic antidepressant overdose

The symptoms and the treatment of an overdose are largely the same as for the other TCAs.[12] Dosulepin may be particularly toxic in overdose compared to other TCAs.[12] The onset of toxic effects is around 4–6 hours after dosulepin is ingested.[5] 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.[5] 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.[5] The medication should also be kept out of reach of children.[5]

Interactions

Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination.[5] TCAs potentiate the sedative effects of barbiturates, tranquilizers and CNS depressants.[5] Guanethidine and other adrenergic neuron blocking drugs can have their antihypertensive effects blocked by dosulepin.[5] Sympathomimetics may potentiate the sympathomimetic effects of dosulepin.[5] 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.[5] Dosulepin may have its postural hypotensive effects potentiated by diuretics.[5] Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.[5]

Pharmacology

Pharmacodynamics

Site DSP NTD Species Ref
NET 46–70 25 Human/rat [15][11]
DAT 5,310 2,539 Human/rat [15][11]
5-HT1A 4,004 2,623 Rat [16]
5-HT2A 152 141 Rat [11]
α1 419 950 Rat [11]
α2 2,400 ND Human [17]
H1 3.6–4 25 Human/rat [11][17]
  M1 18 ND Human [18]
  M2 109 ND Human [18]
  M3 38 ND Human [18]
  M4 61 ND Human [18]
  M5 92 ND Human [18]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Dosulepin is a reuptake inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET), thereby acting as an SNRI.[11][10] 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).[11][4] The antidepressant effects of dosulepin are thought to be due to inhibition of the reuptake of norepinephrine and possibly also of serotonin.[4]

Dosulepin has three metabolites, northiaden (desmethyldosulepin), dosulepin sulfoxide, and northiaden sulfoxide, which have longer terminal half-lives than that of dosulepin itself.[11] However, whereas northiaden has potent activity similarly to dosulepin, the two sulfoxide metabolites have dramatically reduced activity.[11] They have been described as essentially inactive, and are considered unlikely to contribute to either the therapeutic effects or side effects of dosulepin.[11] Relative to dosulepin, northiaden has reduced activity as a serotonin reuptake inhibitor, antihistamine, and anticholinergic and greater potency as a norepinephrine reuptake inhibitor,[11] similarly to other secondary amine TCAs.[19][20] Unlike the sulfoxide metabolites, northiaden is thought to play an important role in the effects of dosulepin.[11]

Although Heal & Cheetham (1992) reported relatively high Ki 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,[11] Richelson & Nelson (1984) found a low KD of only 2,400 nM for dosulepin at this receptor using human brain tissue.[17] This suggests that it in fact has low potency for this action, similarly to other TCAs.[17]

Pharmacokinetics

Dosulepin is readily absorbed from the small intestine and is extensively metabolized on first-pass through the liver into its chief active metabolite, northiaden.[5] Peak plasma concentrations of between 30.4 and 279 ng/mL (103–944 nmol/L) occur within 2–3 hours of oral administration.[5] It is distributed in breast milk and crosses the placenta and blood–brain barrier.[5] It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.[5]

Chemistry

Dosulepin is a tricyclic compound, specifically a dibenzothiepine, and possesses three rings fused together with a side chain attached in its chemical structure.[21] It is the only TCA with a dibenzothiepine ring system to have been marketed.[21][22] The drug is a tertiary amine TCA, with its side chain-demethylated metabolite northiaden (desmethyldosulepin) being a secondary amine.[23][24] Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, doxepin, and trimipramine.[25][26] Dosulepin exhibits (E) and (Z) stereoisomerism like doxepin but in contrast the pure E or trans isomer is used medicinally.[1][10][27] The drug is used commercially as the hydrochloride salt; the free base is not used.

History

Dosulepin was developed by SPOFA.[28] It was patented in 1962 and first appeared in the literature in 1962.[28] The drug was first introduced for medical use in 1969, in the United Kingdom .[28][29]

Society and culture

Generic names

Dosulepin is the English and German generic name of the drug and its INN and BAN, while dosulepin hydrochloride is its BANM and JAN.[1][2][30][3] Dothiepin is the former BAN of the drug while dothiepin hydrochloride is the former BANM and remains the current USAN.[1][2][30][3] Its generic name in Spanish and Italian and its DCIT are dosulepina, in French and its DCF are dosulépine, and in Latin is dosulepinum.[2][3]

Brand names

Dosulepin is marketed throughout the world mainly under the brand name Prothiaden.[2][3] 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.[1][30][2][3]

Availability

Dosulepin is marketed throughout Europe (as Prothiaden, Protiaden, and Protiadene), Australia (as Dothep and Prothiaden), New Zealand (as Dopress) and South Africa (as Thaden).[2][3][7][12][13] It is also available in Japan , Hong Kong, Taiwan, India , Singapore, and Malaysia.[2][3][7] The drug is not available in the United States or Canada .[2][3][7]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 468–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA468. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 369–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA369. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "Dosulepin". https://www.drugs.com/international/dosulepin.html. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 "Dothiepin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness". Drugs 38 (1): 123–47. 1989. doi:10.2165/00003495-198938010-00005. PMID 2670509. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 "Dothep Dothiepin hydrochloride" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 1 November 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04551-3. 
  6. ↑ 6.0 6.1 "The tolerability of dothiepin: a review of clinical studies between 1963 and 1990 in over 13,000 depressed patients". Prog. Neuropsychopharmacol. Biol. Psychiatry 18 (7): 1143–62. 1994. doi:10.1016/0278-5846(94)90117-1. PMID 7846285. 
  7. ↑ 7.0 7.1 7.2 7.3 Dosulepin Hydrochloride. London, UK: Pharmaceutical Press. 5 December 2011. http://www.medicinescomplete.com/mc/martindale/current/2512-p.htm. Retrieved 15 August 2017. 
  8. ↑ "Tricyclic antidepressant poisoning : cardiovascular toxicity". Toxicol Rev 24 (3): 205–14. 2005. doi:10.2165/00139709-200524030-00013. PMID 16390222. 
  9. ↑ "Tricyclic antidepressant pharmacology and therapeutic drug interactions updated". Br. J. Pharmacol. 151 (6): 737–48. 2007. doi:10.1038/sj.bjp.0707253. PMID 17471183. 
  10. ↑ 10.0 10.1 10.2 Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 24 January 2012. pp. 607–. ISBN 978-1-60913-345-0. https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA607. 
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 Cite error: Invalid <ref> tag; no text was provided for refs named HealCheetham1992
  12. ↑ 12.0 12.1 12.2 12.3 Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  13. ↑ 13.0 13.1 Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse. 
  14. ↑ "Psychogenic facial pain: presentation and treatment". British Medical Journal 288 (6415): 436–438. February 1984. doi:10.1136/bmj.288.6415.436. PMID 6419955. 
  15. ↑ 15.0 15.1 Cite error: Invalid <ref> tag; no text was provided for refs named pmid9537821
  16. ↑ "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cell. Mol. Neurobiol. 19 (4): 467–89. 1999. doi:10.1023/A:1006986824213. PMID 10379421. 
  17. ↑ 17.0 17.1 17.2 17.3 "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". J. Pharmacol. Exp. Ther. 230 (1): 94–102. 1984. PMID 6086881. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochem. Pharmacol. 45 (11): 2352–4. 1993. doi:10.1016/0006-2952(93)90211-e. PMID 8100134. 
  19. ↑ Essentials of Psychiatry. American Psychiatric Pub. 2011. pp. 468–. ISBN 978-1-58562-933-6. https://books.google.com/books?id=Hf50vMMMv_wC&pg=PA468. 
  20. ↑ Tietz Textbook of Clinical Chemistry and Molecular Diagnostics - E-Book. Elsevier Health Sciences. 14 October 2012. pp. 1129–. ISBN 978-1-4557-5942-2. https://books.google.com/books?id=BBLRUI4aHhkC&pg=PA1129. 
  21. ↑ 21.0 21.1 Meyler's Side Effects of Psychiatric Drugs. Elsevier. 2009. pp. 7–. ISBN 978-0-444-53266-4. https://books.google.com/books?id=AmYFTSO8jCkC&pg=PA7. 
  22. ↑ Polypharmacy in Psychiatry Practice, Volume I: Multiple Medication Use Strategies. Springer Science & Business Media. 15 February 2013. pp. 270–271. ISBN 978-94-007-5805-6. https://books.google.com/books?id=jy-LMZU7338C&pg=PA270. 
  23. ↑ Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology. John Wiley & Sons. 20 September 1994. pp. 160–. ISBN 978-0-471-95052-3. https://books.google.com/books?id=ncRXa8Dq88QC&pg=PA160. 
  24. ↑ Metabolism of Drugs and Other Xenobiotics. John Wiley & Sons. 23 February 2012. pp. 302–. ISBN 978-3-527-64632-6. https://books.google.com/books?id=f-XHh17NfwgC&pg=PA302. 
  25. ↑ Pharmacology Secrets. Elsevier Health Sciences. 2002. pp. 39–. ISBN 1-56053-470-2. https://books.google.com/books?id=_QQsj3PAUrEC&pg=PA39. 
  26. ↑ Shorter Oxford Textbook of Psychiatry. OUP Oxford. 9 August 2012. pp. 532–. ISBN 978-0-19-162675-3. https://books.google.com/books?id=Y1DtSGq-LnoC&pg=PA532. 
  27. ↑ Psychotropic Agents: Part I: Antipsychotics and Antidepressants. Springer Science & Business Media. 6 December 2012. pp. 354–. ISBN 978-3-642-67538-6. https://books.google.com/books?id=oK7tCAAAQBAJ&pg=PA354. 
  28. ↑ 28.0 28.1 28.2 "Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters". Chem. Commun. (25): 3677–92. 2009. doi:10.1039/b903035m. PMID 19557250. 
  29. ↑ Medical Toxicology. Lippincott Williams & Wilkins. 2004. pp. 836–. ISBN 978-0-7817-2845-4. https://books.google.com/books?id=BfdighlyGiwC&pg=PA836. 
  30. ↑ 30.0 30.1 30.2 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 105–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA105. 



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