Dosulepin

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Dosulepin
Dosulepin2DACS2.svg
Dosulepin3Dan.gif
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
category
  • AU: C
Legal status
  • AU: S4 (Prescription only)
  • US: POM
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability 30%[1]
Protein binding 84%[2]
Metabolism Hepatic (via N-demethylation to active metabolite northiaden, S-oxidation and glucuronidation)[2]
Biological 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 YesY
ATC code N06AA16 (WHO)
PubChem CID: 13473
ChemSpider 4447605
UNII W13O82Z7HL YesY
KEGG D07872 YesY
ChEMBL CHEMBL108947 N
Chemical data
Formula C19H21NS
Molecular mass 295.45 g/mol
  • CN(C)CC/C=C/1\c2ccccc2CSc3c1cccc3
  • 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+
  • Key:PHTUQLWOUWZIMZ-GZTJUZNOSA-N
 NYesY (what is this?)  (verify)

Dosulepin (INN, BAN) formerly known as dothiepin (USAN), and marketed under the brand names Prothiaden, Dothep, Thaden, and Dopress, 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]

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]

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  • 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]

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  • 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
  • Liver 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

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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 antiadrenergic 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]

See also

References

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  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 Lua error in package.lua at line 80: module 'strict' not found.
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  8. ↑ 8.0 8.1 8.2 Lua error in package.lua at line 80: module 'strict' not found.
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  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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