Dosulepin

Dosulepin

Clinical data
Trade names	Dothep, Prothiaden
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: C
Routes of administration	Oral
ATC code	N06AA16 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: POM
Pharmacokinetic data
Bioavailability	30%
Protein binding	84%
Metabolism	Hepatic (via N-demethylation to active metabolite northiaden, S-oxidation and glucuronidation)
Elimination half-life	51 hours, 14-45 hours, 54 hours (elderly)
Excretion	Urine (56%), faeces (15%)
Identifiers
IUPAC name (E,Z)-3-(dibenzo[b,e]thiepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
CAS Number	113-53-1 Y
PubChem CID	13473
UNII	W13O82Z7HL
KEGG	D07872 Y
ChEMBL	ChEMBL108947 N
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C19H21NS
Molar mass	295.45 g/mol
NY (what is this?)  (verify)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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.

Medical uses

Dosulepin is used for the treatment of major depressive disorder and neuropathic pain. Dosulepin is only TGA- and MHRA-approved for the treatment of major depressive disorder. There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.

Adverse effects

Common adverse effects:

• 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:

• 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:

• 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. TCAs potentiate the sedative effects of barbiturates, tranquillisers and CNS depressants. Guanethidine and other adrenergic neurone 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.

Overdose

Main article: Tricyclic antidepressant overdose

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants. 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.

Mechanism of action

Dosulepin is a serotonin-norepinephrine reuptake inhibitor (SNRI) with anticholinergic, antihistamine, and antiadrenergic effects.

Receptor/Transporter	Ki (nM)
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). Peak plasma concentrations of between 30.4 ng/mL to 278.8 ng/mL 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.

Chemistry

Dosulepin is also the dibenzothiepine analogue of doxepin, from which it differs by the replacement of the oxygen position with that of sulfur.

File:Dothiepin Synthesis.png

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.

References

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