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.[5] TCAs potentiate the sedative effects of barbiturates, tranquilizers and CNSdepressants.[5]Guanethidine and other adrenergic neuron blocking drugs can have their antihypertensive effects blocked by dosulepin.[5] Sympathomimetics may potentiate the sympathomimetic effects of dosulepin.[5] 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.[5] Dosulepin may have its postural hypotensive effects potentiated by diuretics.[5] Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.[5]
Dosulepin has three metabolites, northiaden (desmethyldosulepin), dosulepin sulfoxide, and northiaden sulfoxide, which have longer terminal half-lives than that of dosulepin itself.[11] However, whereas northiaden has potent activity similarly to dosulepin, the two sulfoxide metabolites have dramatically reduced activity.[11] They have been described as essentially inactive, and are considered unlikely to contribute to either the therapeutic effects or side effects of dosulepin.[11] Relative to dosulepin, northiaden has reduced activity as a serotonin reuptake inhibitor, antihistamine, and anticholinergic and greater potency as a norepinephrine reuptake inhibitor,[11] similarly to other 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.[5] Peak plasma concentrations of between 30.4 and 279 ng/mL (103–944 nmol/L) occur within 2–3 hours of oral administration.[5] It is distributed in breast milk and crosses the placenta and blood-brain barrier.[5] It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.[5]
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]
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]
^ abcdefghijklmLancaster SG, Gonzalez JP (1989). "Dothiepin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness". Drugs. 38 (1): 123–47. doi:10.2165/00003495-198938010-00005. PMID2670509.
^ abDonovan S, Dearden L, Richardson L (1994). "The tolerability of dothiepin: a review of clinical studies between 1963 and 1990 in over 13,000 depressed patients". Prog. Neuropsychopharmacol. Biol. Psychiatry. 18 (7): 1143–62. doi:10.1016/0278-5846(94)90117-1. PMID7846285. S2CID29749302.
^ abcdDosulepin Hydrochloride. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. 5 December 2011. Retrieved 15 August 2017.
^ abcdefghijklmnopHeal, David; Cheetham, Sharon; Martin, Keith; Browning, John; Luscombe, Graham; Buckett, Roger (1992). "Comparative pharmacology of dothiepin, its metabolites, and other antidepressant drugs". Drug Development Research. 27 (2): 121–135. doi:10.1002/ddr.430270205. ISSN0272-4391. S2CID95382318.
^ abcdRossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN978-0-9805790-9-3.
^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.
^ abcTatsumi M, Groshan K, Blakely RD, Richelson E (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur. J. Pharmacol. 340 (2–3): 249–58. doi:10.1016/s0014-2999(97)01393-9. PMID9537821.
^Sánchez C, Hyttel J (1999). "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cell. Mol. Neurobiol. 19 (4): 467–89. doi:10.1023/A:1006986824213. PMID10379421. S2CID19490821.
^ abcdRichelson E, Nelson A (1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". J. Pharmacol. Exp. Ther. 230 (1): 94–102. PMID6086881.
^Cusack B, Nelson A, Richelson E (1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology. 114 (4): 559–65. doi:10.1007/bf02244985. PMID7855217. S2CID21236268.
^ abcdeStanton T, Bolden-Watson C, Cusack B, Richelson E (1993). "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochem. Pharmacol. 45 (11): 2352–4. doi:10.1016/0006-2952(93)90211-e. PMID8100134.
^ abcAndersen J, Kristensen AS, Bang-Andersen B, Strømgaard K (2009). "Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters". Chem. Commun. (25): 3677–92. doi:10.1039/b903035m. PMID19557250.