Dosulepin

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Dosulepin
Dosulepin2DACS2.svg
Dosulepin-from-HCl-1987-xtal-CCDC-1160822.png
Clinical data
Trade names Prothiaden, others
Other namesIZ-914, KS-1596 [1] [2] [3] , dothiepin (USAN US)
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU:C
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
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]
Identifiers
  • (3E)-3-(6H-benzo[c][1]benzothiepin-11-ylidene)-N,N-dimethylpropan-1-amine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.003.665 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H21NS
Molar mass 295.44 g·mol−1
3D model (JSmol)
  • CN(C)CC/C=C/1\C2=CC=CC=C2CSC3=CC=CC=C31
  • InChI=1S/C19H21NS/c1-20(2)13-7-11-17-16-9-4-3-8-15(16)14-21-19-12-6-5-10-18(17)19/h3-6,8-12H,7,13-14H2,1-2H3/b17-11+ X mark.svgN
  • Key:PHTUQLWOUWZIMZ-GZTJUZNOSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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]

Contents

Medical uses

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

Contraindications include: [5]

Side effects

Common adverse effects: [5]

Less common adverse effects: [5]

Overdose

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 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]

Pharmacology

Pharmacodynamics

Dosulepin (and metabolite) [15]
SiteDSP NTD SpeciesRef
SERT 8.6–78192Human/rat [16] [11]
NET 46–7025Human/rat [16] [11]
DAT 5,3102,539Human/rat [16] [11]
5-HT1A 4,0042,623Rat [17]
5-HT2A 152141Rat [11]
α1 419950Rat [11]
α2 2,400NDHuman [18]
H1 3.6–425Human/rat [11] [18]
mACh 25–26110Human/rat [11] [19]
   M1 18NDHuman [20]
   M2 109NDHuman [20]
   M3 38NDHuman [20]
   M4 61NDHuman [20]
   M5 92NDHuman [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]

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]

Chemistry

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.

History

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]

Society and culture

Generic names

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]

Brand names

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]

Availability

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]

Related Research Articles

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<span class="mw-page-title-main">Tetracyclic antidepressant</span> Class of pharmaceutical drugs

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.

<span class="mw-page-title-main">Maprotiline</span> Antidepressant

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.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

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.

<span class="mw-page-title-main">Amoxapine</span> Chemical compound

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<span class="mw-page-title-main">Imipramine</span> Antidepressant

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<span class="mw-page-title-main">Desipramine</span> Antidepressant

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<span class="mw-page-title-main">Clomipramine</span> Antidepressant

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<span class="mw-page-title-main">Nortriptyline</span> Antidepressant medication

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<span class="mw-page-title-main">Butriptyline</span> Pharmaceutical drug

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