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| Systematic (IUPAC) name | |
|---|---|
| (E,Z)-3-(dibenzo[b,e]thiepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine | |
| Clinical data | |
| Trade names | Dothep, Prothiaden |
| AHFS/Drugs.com | International Drug Names |
| Pregnancy cat. | C (AU) |
| Legal status | Prescription Only (S4) (AU) POM (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | 30%[1] |
| Protein binding | 84%[2] |
| Metabolism | Hepatic (via N-demethylation to active metabolite northiaden, S-oxidation and glucuronidation)[2] |
| Half-life | 51 hours,[2] 14-45 hours,[3][4][5] 54 hours (elderly)[5][6] |
| Excretion | Urine (56%), faeces (15%)[2] |
| Identifiers | |
| CAS number | 113-53-1 Y |
| ATC code | N06AA16 |
| PubChem | CID 13473 |
| UNII | W13O82Z7HL Y |
| KEGG | D07872 Y |
| ChEMBL | CHEMBL108947 N |
| Chemical data | |
| Formula | C19H21NS |
| Mol. mass | 295.45 g/mol |
| N (what is this?) (verify) | |
Dosulepin (INN, BAN) formerly known as dothiepin (USAN) and by the brand names Prothiaden, Dothep, Thaden and Dopress. Dosulepin is a tricyclic antidepressant that is used in several European and South Asian countries, as well as Australia, South Africa, and New Zealand. It is not used in the United States.[7]
Contents
- 1 Medical uses
- 2 Adverse effects
- 2.1 Contraindications
- 2.2 Drug interactions
- 2.3 Overdose
- 3 Mechanism of action
- 4 Pharmacokinetics
- 5 Chemistry
- 6 See also
- 7 References
Medical uses
Dosulepin is used for the treatment of major depressive disorder and neuropathic pain.[1] Dosulepin is only TGA- and MHRA-approved for the treatment of major depressive disorder.[8][9] There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.[10]
Adverse effects
Common adverse effects:[2]
- Drowsiness
- Extrapyramidal symptoms
- Tremor
- Confusion
- 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:[2]
- 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 amount 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)
Contraindications
Contraindications include:[2]
- 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
- Hepatic failure
- Hypersensitivity to dothiepin
Drug interactions
Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination.[2] TCAs potentiate the sedative effects of barbiturates, tranquillisers and CNS depressants.[2] Guanethidine and other adrenergic neurone blocking drugs can have their antihypertensive effects blocked by dosulepin.[2] Sympathomimetics may potentiate the sympathomimetic effects of dosulepin.[2] 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.[2] Dosulepin may have its postural hypotensive effects potentiated by diuretics.[2] Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.[2]
Overdose
Main article: Tricyclic antidepressant overdose
The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.[8] Dosulepin may be particularly toxic in overdose compared to other TCAs.[8] The onset of toxic effects is around 4–6 hours after dosulepin is ingested.[2] 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.[2] 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.[2] The medication should also be kept out of reach of children.[2]
Mechanism of action
Dosulepin is a serotonin-norepinephrine reuptake inhibitor (SNRI) with anticholinergic, antihistamine and α1 adrenoceptor blocking effects.[11]
| Receptor/Transporter | Ki (nM)[12] |
|---|---|
| SERT | 8.6 |
| NET | 46 |
| DAT | 5,310 |
| 5-HT1A | 4,004 |
| 5-HT2A | 152 |
| M1 | 18 |
| M2 | 109 |
| M3 | 38 |
| M4 | 61 |
| M5 | 92 |
| α1 | 419 |
| α2 | 12 |
| H1 | 4 |
Pharmacokinetics
Dothiepin is readily absorbed from the small intestine and is extensively metabolised on first-pass through the liver into its chief active metabolite, northiaden (desmethyldosulepin).[2] Peak plasma concentrations of between 30.4 ng/mL to 278.8 ng/mL occur within 2–3 hours of oral administration.[2] It is distributed in breast milk and crosses the placenta and blood-brain barrier.[2] It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.[2]
Chemistry
Dosulepin is also the dibenzothiepine analogue of doxepin, from which it differs by the replacement of the oxygen position with that of sulfur.
The synthesis of this agent is quite similar to that used for its oxygen analogue, doxepin (), though with a reversed functionality. The sequence in the present case starts with the alkylation of thiosalicylic acid () with benzyl chloride () to give the thioether (). The product is then cyclized by means of polyphosphoric acid to give the ketone (). Condensation with the familiar dimethylpropylamine Grignard reagent serves to introduce the side chain (). Dehydration of the tertiary alcohol then affords dothiepin () as a mixture of isomers.[13]
See also
- Tricyclic antidepressant
References
- ^ a b Lancaster, SG; Gonzalez, JP (July 1989). "Dothiepin: a review of its pharmcodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness". Drugs 38 (1): 123–147. doi:10.2165/00003495-198938010-00005. PMID 2670509.
- ^ a b c d e f g h i j k l m n o p q r s t u v "Dothep Dothiepin hydrochloride" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 1 November 2013. Retrieved 3 December 2013.
- ^ Rees, JA (1981). "Clinical interpretation of pharmacokinetic data on dothiepin hydrochloride (Dosulepin, Prothiaden)". Journal of International Medical Research 9 (2): 98–102. PMID 7227628.
- ^ Maguire, KP; Burrows, GD; Norman, TR; Scoggins, BA (September 1981). "Metabolism and pharmacokinetics of dothiepin" (PDF). British Journal of Clinical Pharmacology 12 (3): 405–409. doi:10.1111/j.1365-2125.1981.tb01235.x. PMC 1401810. PMID 7295471.
- ^ a b Bareggi, SR; Cavallaro, R; Pirola, R; Altamura, AC (1990). "Pharmacokinetics and adverse effects of single doses of dothiepin in young and elderly subjects". Progress in Neuro-Psychopharmacology and Biological Psychiatry 14 (2): 163–170. doi:10.1016/0278-5846(90)90098-2. PMID 2309034.
- ^ Ogura, C; Kishimoto, A; Mizukawa, R; Hazama, H; Honma, H; Kawahara, K (1983). "Age differences in effects on blood pressure, flicker fusion frequency, salivation and pharmacokinetics of single oral doses of dothiepin and amitriptyline". European Journal of Clinical Pharmacology 25 (6): 811–814. doi:10.1007/BF00542525. PMID 6662179.
- ^ "Dosulepin Hydrochloride". Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). 5 December 2011. Retrieved 3 December 2013.
- ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. edit
- ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. edit
- ^ C Feinmann, M Harris, and R Cawley (11 February 1984). "Psychogenic facial pain: presentation and treatment.". http://www.ncbi.nlm.nih.gov/. The National Center for Biotechnology Information. Retrieved 6 April 2014.
- ^ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (in English) (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8. edit
- ^ 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 3 December 2013.
- ^ Zirkle, C. L.; 1971, U.S. Patent 3,609,167.
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UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
- 1. 三環系抗うつ剤および四環系抗うつ剤：薬理学、投与、および副作用 tricyclic and tetracyclic drugs pharmacology administration and side effects
English Journal
- Spectroscopic, electrochemical and molecular docking studies of dothiepin and doxepin with bovine serum albumin and DNA base.
- Rajendiran N1, Thulasidhasan J1.
- Luminescence : the journal of biological and chemical luminescence.Luminescence.2016 Dec;31(8):1438-1447. doi: 10.1002/bio.3126. Epub 2016 Mar 17.
- PMID 26991906
- Antidepressants detection and quantification in whole blood samples by GC-MS/MS, for forensic purposes.
- Truta L1, Castro AL2, Tarelho S3, Costa P4, Sales MG5, Teixeira HM6.
- Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2016 Sep 5;128:496-503. doi: 10.1016/j.jpba.2016.06.027. Epub 2016 Jun 23.
- PMID 27376459
- A change in the trend in dosulepin usage following the introduction of a prescribing indicator but not after two national safety warnings.
- Deslandes PN1,2, Jenkins KS1, Haines KE1, Hutchings S1, Cannings-John R3, Lewis TL, Bracchi RC1, Routledge PA1,4.
- Journal of clinical pharmacy and therapeutics.J Clin Pharm Ther.2016 Apr;41(2):224-8. doi: 10.1111/jcpt.12376. Epub 2016 Mar 2.
- PMID 26936206
Japanese Journal
- 症例報告 自殺目的で塩酸セルトラリン,スルピリド,塩酸ドスレピン,フマル酸クエチアピン,塩酸トラゾドンを含む多剤大量服用後,悪性症候群もしくはセロトニン症候群を併発した1例
- 柳川 洋一,西 紘一郎,宮崎 誠樹
- 防衛衛生 55(4), 71-74, 2008-04
- NAID 40015997038
- Effects of antidepressants trazodone, dosulepin and amitriptyline on cardiac conduction in the canine heart after myocardial infarction
- Nishimoto Masahiko,Hashimoto Hisakuni,Ikeda Yasuhiko [他]
- 聖マリアンナ医学研究誌 7 (82), 73-80, 2007
- NAID 40015443850
- 難治性めまいとうつ傾向
- 安田 宏一
- Equilibrium research 58(4), 317-322, 1999-08-01
- … If the case is especially severe, change maprotiline to dosulepin (75 mg). …
- NAID 10008712867
Related Pictures
★リンクテーブル★
| リンク元 | 「ドスレピン」「dothiepin」 |
| 拡張検索 | 「dosulepin hydrochloride」 |