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.
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.
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.
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.
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^ abBareggi, 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 Psychiatry14 (2): 163–170. doi:10.1016/0278-5846(90)90098-2. PMID2309034.
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