Dosulepin

Source: Wikipedia, the free encyclopedia.
Not to be confused with Doxepin.
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)
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
  • (3E)-3-(6H-benzo[c][1]benzothiepin-11-ylidene)-N,N-dimethylpropan-1-amine
JSmol)
  • CN(C)CC/C=C/1\C2=CC=CC=C2CSC3=CC=CC=C31
  • InChI=1S/C19H21NS/c1-20(2)13-7-11-17-16-9-4-3-8-15(16)14-21-19-12-6-5-10-18(17)19/h3-6,8-12H,7,13-14H2,1-2H3/b17-11+ ☒N
  • Key:PHTUQLWOUWZIMZ-GZTJUZNOSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a

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
  • 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: 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.

diuretics.[5] Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.[5]

Pharmacology

Pharmacodynamics

See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Dosulepin (and metabolite)[15]
Site DSP NTDTooltip Northiaden Species Ref
SERTTooltip Serotonin transporter 8.6–78 192 Human/rat [16][11]
NETTooltip Norepinephrine transporter 46–70 25 Human/rat [16][11]
DATTooltip Dopamine transporter 5,310 2,539 Human/rat [16][11]
5-HT1A 4,004 2,623 Rat [17]
5-HT2A 152 141 Rat [11]
α1 419 950 Rat [11]
α2 2,400 ND Human [18]
H1 3.6–4 25 Human/rat [11][18]
mAChTooltip Muscarinic acetylcholine receptor 25–26 110 Human/rat [11][19]
  M1 18 ND Human [20]
  M2 109 ND Human [20]
  M3 38 ND Human [20]
  M4 61 ND Human [20]
  M5 92 ND Human [20]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Dosulepin is a

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

secondary amine TCAs.[21][22] 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.[18] This suggests that it in fact has low potency for this action, similarly to other TCAs.[18]

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.

elimination half-life of 51 hours.[5]

Chemistry

Dosulepin is a

secondary amine.[25][26] Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, doxepin, and trimipramine.[27][28] Dosulepin exhibits (E) and (Z) stereoisomerism like doxepin but in contrast the pure E or trans isomer is used medicinally.[1][10][29] The drug is used commercially as the hydrochloride salt
; the free base is not used.

History

Dosulepin was developed by SPOFA.[30] It was patented in 1962 and first appeared in the literature in 1962.[30] The drug was first introduced for medical use in 1969, in the United Kingdom.[30][31]

Society and culture

Generic names

Dosulepin is the

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][32][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. ^
    ISBN 978-1-4757-2085-3
    .
  2. ^
    ISBN 978-3-88763-075-1
    .
  3. ^ a b c d e f g h i "Dosulepin".
  4. ^
    PMID 2670509
    .
  5. ^ a b c d e f g h i j k l m n o p q r s t u "Dothep Dothiepin hydrochloride" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 1 November 2013. Retrieved 3 December 2013.
  6. ^
    S2CID 29749302
    .
  7. ^ a b c d Dosulepin Hydrochloride. London, UK: Pharmaceutical Press. 5 December 2011. Retrieved 15 August 2017. {{cite book}}: |work= ignored (help)
  8. S2CID 44532041
    .
  9. PMID 17471183
    .
  10. ^
    ISBN 978-1-60913-345-0
    .
  11. ^
    S2CID 95382318
    .
  12. ^
    ISBN 978-0-9805790-9-3
    .
  13. ^
    ISBN 978-0-85711-084-8
    .
  14. PMID 6419955
    .
  15. ^ Roth BL, Driscol J. "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 14 August 2017.
  16. ^
    PMID 9537821
    .
  17. S2CID 19490821
    .
  18. ^
    PMID 6086881
    .
  19. S2CID 21236268
    .
  20. ^
    PMID 8100134
    .
  21. ISBN 978-1-58562-933-6
    .
  22. ISBN 978-1-4557-5942-2
    .
  23. ^
    ISBN 978-0-444-53266-4
    .
  24. ISBN 978-94-007-5805-6
    .
  25. ISBN 978-0-471-95052-3
    .
  26. ISBN 978-3-527-64632-6
    .
  27. ISBN 1-56053-470-2
    .
  28. ISBN 978-0-19-162675-3
    .
  29. ISBN 978-3-642-67538-6
    .
  30. ^
    PMID 19557250
    .
  31. ISBN 978-0-7817-2845-4
    .
  32. ^
    ISBN 978-94-011-4439-1
    .