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]
Dosulepin can potentiate the effects ofalcohol and at least one death has been attributed to this combination.[5] TCAs potentiate the sedative effects of barbiturates, tranquilizers andCNSTooltip central nervous systemdepressants.[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 bydiuretics.[5] Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.[5]
Dosulepin has threemetabolites, northiaden (desmethyldosulepin), dosulepin sulfoxide, and northiaden sulfoxide, which have longerterminal 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 aserotonin reuptake inhibitor,antihistamine, andanticholinergic and greater potency as anorepinephrine reuptake inhibitor,[11] similarly to othersecondary 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]
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 andblood–brain barrier.[5] It is highly bound to plasma proteins (84%), and has a whole-bodyelimination 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 theUnited Kingdom.[30][31]
Dosulepin is theEnglish andGermangeneric name of the drug and itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name, whiledosulepin hydrochloride is itsBANMTooltip British Approved Name andJANTooltip Japanese Accepted Name.[1][2][32][3]Dothiepin is the formerBANTooltip British Approved Name of the drug whiledothiepin hydrochloride is the formerBANMTooltip British Approved Name and remains the currentUSANTooltip United States Adopted Name.[1][2][32][3] Its generic name inSpanish andItalian and itsDCITTooltip Denominazione Comune Italiana aredosulepina, inFrench and itsDCFTooltip Dénomination Commune Française aredosulépine, and inLatin isdosulepinum.[2][3]
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.
^abcdefghijklmnopHeal D, Cheetham S, Martin K, Browning J, Luscombe G, Buckett R (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. Retrieved14 August 2017.
^abcTatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters".European Journal of Pharmacology.340 (2–3):249–258.doi:10.1016/s0014-2999(97)01393-9.PMID9537821.
^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.doi:10.1016/S0022-3565(25)21446-X.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.
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