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. 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, tranquilizers and depressants. Guanethidine and other adrenergic neuron 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. Pharmacology Pharmacodynamics Dosulepin is a reuptake inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET), thereby acting as an SNRI. It is also an antagonist of the histamine H1 receptor, α1-adrenergic receptor, serotonin 5-HT2 receptors, and muscarinic acetylcholine receptors (mACh), as well as a blocker of voltage-gated sodium channels (VGSCs). The antidepressant effects of dosulepin are thought to be due to inhibition of the reuptake of norepinephrine and possibly also of serotonin. Dosulepin has three metabolites, northiaden (desmethyldosulepin), dosulepin sulfoxide, and northiaden sulfoxide, which have longer terminal half-lives than that of dosulepin itself. However, whereas northiaden has potent activity similarly to dosulepin, the two sulfoxide metabolites have dramatically reduced activity. They have been described as essentially inactive, and are considered unlikely to contribute to either the therapeutic effects or side effects of dosulepin. Relative to dosulepin, northiaden has reduced activity as a serotonin reuptake inhibitor, antihistamine, and anticholinergic and greater potency as a norepinephrine reuptake inhibitor, similarly to other secondary amine TCAs. Unlike the sulfoxide metabolites, northiaden is thought to play an important role in the effects of dosulepin. 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