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Clinical data | |
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Trade names | Prothiaden, others |
Other names | IZ-914, KS-1596 [1] [2] [3] , dothiepin (USAN US) |
AHFS/Drugs.com | International Drug Names |
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Routes of administration | Oral |
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Pharmacokinetic data | |
Bioavailability | 30% [4] |
Protein binding | 84% [5] |
Metabolism | Hepatic (N-demethylation, S-oxidation, glucuronidation) [5] |
Metabolites | Northiaden, dothiepin sulfoxide, northiaden sulfoxide, glucuronide conjugates [4] |
Elimination half-life | Dothiepin: 14.4–23.9 hours [4] Dothiepin sulfoxide: 22.7–25.5 hours [4] Northiaden: 34.7–45.7 hours [4] Northiaden sulfoxide: 24.2–33.5 hours [4] |
Excretion | Urine: 56% [4] Feces: 15% [4] |
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ECHA InfoCard | 100.003.665 |
Chemical and physical data | |
Formula | C19H21NS |
Molar mass | 295.44 g·mol−1 |
3D model (JSmol) | |
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Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a tricyclic antidepressant (TCA) which is used in the treatment of depression. [4] [6] [7] Dosulepin was once the most frequently prescribed antidepressant in the United Kingdom, but it is no longer widely used due to its relatively high toxicity in overdose without therapeutic advantages over other TCAs. [6] [8] [9] It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) and also has other activities including antihistamine, antiadrenergic, antiserotonergic, anticholinergic, and sodium channel-blocking effects. [4] [10] [11]
Dosulepin is used for the treatment of major depressive disorder. [4] [5] [12] [13] There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year. [14]
Contraindications include: [5]
Common adverse effects: [5]
Less common adverse effects: [5]
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 of alcohol and at least one death has been attributed to this combination. [5] TCAs potentiate the sedative effects of barbiturates, tranquilizers and CNS depressants. [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]
Site | DSP | NTD | Species | Ref |
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SERT | 8.6–78 | 192 | Human/rat | [16] [11] |
NET | 46–70 | 25 | Human/rat | [16] [11] |
DAT | 5,310 | 2,539 | Human/rat | [16] [11] |
5-HT1A | 4,004 | 2,623 | Rat | [17] |
5-HT2A | 152 | 141 | Rat | [11] |
α1 | 419 | 950 | Rat | [11] |
α2 | 2,400 | ND | Human | [18] |
H1 | 3.6–4 | 25 | Human/rat | [11] [18] |
mACh | 25–26 | 110 | Human/rat | [11] [19] |
M1 | 18 | ND | Human | [20] |
M2 | 109 | ND | Human | [20] |
M3 | 38 | ND | Human | [20] |
M4 | 61 | ND | Human | [20] |
M5 | 92 | ND | Human | [20] |
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. |
Dosulepin is a reuptake inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET), thereby acting as an SNRI. [11] [10] 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). [11] [4] The antidepressant effects of dosulepin are thought to be due to inhibition of the reuptake of norepinephrine and possibly also of serotonin. [4]
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]
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 is a tricyclic compound, specifically a dibenzothiepine, and possesses three rings fused together with a side chain attached in its chemical structure. [23] It is the only TCA with a dibenzothiepine ring system to have been marketed. [23] [24] The drug is a tertiary amine TCA, with its side chain-demethylated metabolite northiaden (desmethyldosulepin) being a secondary amine. [25] [26] Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, doxepin, and trimipramine. [27] [28] Dosulepin exhibits (E) and (Z) stereoisomerism like doxepin but in contrast the pure E or trans isomer is used medicinally. [1] [10] [29] The drug is used commercially as the hydrochloride salt; the free base is not used.
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 the English and German generic name of the drug and its INN and BAN, while dosulepin hydrochloride is its BANM and JAN. [1] [2] [32] [3] Dothiepin is the former BAN of the drug while dothiepin hydrochloride is the former BANM and remains the current USAN. [1] [2] [32] [3] Its generic name in Spanish and Italian and its DCIT are dosulepina, in French and its DCF are dosulépine, and in Latin is dosulepinum. [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]
Dosulepin is marketed throughout Europe (as Prothiaden, Protiaden, and Protiadene), Australia (as Dothep and Prothiaden), New Zealand (as Dopress) and South Africa (as Thaden). [2] [3] [7] [12] [13] It is also available in Japan, Hong Kong, Taiwan, India, Singapore, and Malaysia. [2] [3] [7] The drug is not available in the United States or Canada. [2] [3] [7]
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.
Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their tetracyclic chemical structure, containing four rings of atoms, and are closely related to the tricyclic antidepressants (TCAs), which contain three rings of atoms.
Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to other secondary amine TCAs like nortriptyline and protriptyline, and has similar effects to them.
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, obsessive–compulsive disorder (OCD), social phobia, attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.
Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCA). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1980, approximately 10 to 20 years after most of the other TCAs were introduced in the United States.
Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth.
Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug is not considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.
Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used for the treatment of obsessive–compulsive disorder, panic disorder, major depressive disorder, and chronic pain. It may increase the risk of suicide in those under the age of 25. It is primarily taken by mouth. It has also been used to treat premature ejaculation.
Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. As with many antidepressants, its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18-24 population initiating treatment. Nortriptyline is a less preferred treatment for ADHD and stopping smoking. It is taken by mouth.
Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.
Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant medication which is used in the treatment of depression and for other uses. Nefazodone is still available in the United States, but was withdrawn from other countries due to rare liver toxicity. The medication is taken by mouth.
Butriptyline, sold under the brand name Evadyne among others, is a tricyclic antidepressant (TCA) that has been used in the United Kingdom and several other European countries for the treatment of depression but appears to no longer be marketed. Along with trimipramine, iprindole, and amoxapine, it has been described as an "atypical" or "second-generation" TCA due to its relatively late introduction and atypical pharmacology. It was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.
Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression. The TCAs are so named as they share the common property of having three rings in their chemical structure. Like most TCAs lofepramine is believed to work in relieving depression by increasing concentrations of the neurotransmitters norepinephrine and serotonin in the synapse, by inhibiting their reuptake. It is usually considered a third-generation TCA, as unlike the first- and second-generation TCAs it is relatively safe in overdose and has milder and less frequent side effects.
Protriptyline, sold under the brand name Vivactil among others, is a tricyclic antidepressant (TCA), specifically a secondary amine, indicated for the treatment of depression and attention-deficit hyperactivity disorder (ADHD). Uniquely among most of the TCAs, protriptyline tends to be energizing instead of sedating, and is sometimes used for narcolepsy to achieve a wakefulness-promoting effect.
Iprindole, sold under the brand names Prondol, Galatur, and Tertran, is an atypical tricyclic antidepressant (TCA) that has been used in the United Kingdom and Ireland for the treatment of depression but appears to no longer be marketed. It was developed by Wyeth and was marketed in 1967. The drug has been described by some as the first "second-generation" antidepressant to be introduced. However, it was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.
Opipramol, sold under the brand name Insidon among others, is an anxiolytic and tricyclic antidepressant that is used throughout Europe. Despite chemically being a tricyclic dibenzazepine (iminostilbene) derivative similar to imipramine, opipramol is not a monoamine reuptake inhibitor like most other tricyclic antidepressants, and instead, uniquely among antidepressants, acts primarily as a SIGMAR1 agonist. It was developed by Schindler and Blattner in 1961.
Oxaprotiline, also known as hydroxymaprotiline, is a norepinephrine reuptake inhibitor belonging to the tetracyclic antidepressant (TeCA) family and is related to maprotiline. Though investigated as an antidepressant, it was never marketed.
Quinupramine is a tricyclic antidepressant (TCA) used in Europe for the treatment of depression.
Nordoxepin, also known as N-desmethyldoxepin, is the major active metabolite of the tricyclic antidepressant (TCA) doxepin (Sinequan). It has been found to play a significant role in the antidepressant effects of doxepin.
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