Dosulepin

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Dosulepin
Dosulepin2DACS2.svg
Dosulepin3Dan.gif
Systematic (IUPAC) name
(E,Z)-3-(dibenzo[b,e]thiepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
Clinical data
Trade names Dothep, Prothiaden
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU: C
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 30%[1]
Protein binding 84%[2]
Metabolism Hepatic (via N-demethylation to active metabolite northiaden, S-oxidation and glucuronidation)[2]
Biological half-life 51 hours,[2] 14-45 hours,[3][4][5] 54 hours (elderly)[5][6]
Excretion Urine (56%), faeces (15%)[2]
Identifiers
CAS Registry Number 113-53-1 YesY
ATC code N06AA16
PubChem CID: 13473
UNII W13O82Z7HL YesY
KEGG D07872 YesY
ChEMBL CHEMBL108947 N
Chemical data
Formula C19H21NS
Molecular mass 295.45 g/mol
 N (what is this?)  (verify)

Dosulepin (INN, BAN) formerly known as dothiepin (USAN), and marketed under the brand names Prothiaden, Dothep, Thaden, and Dopress, is a tricyclic antidepressant that is used in several European and South Asian countries, as well as Australia, South Africa, and New Zealand. It is not used in the United States.[7]

Medical uses[edit]

Dosulepin is used for the treatment of major depressive disorder and neuropathic pain.[1] Dosulepin is only TGA- and MHRA-approved for the treatment of major depressive disorder.[8][9] There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.[10]

Adverse effects[edit]

Common adverse effects:[2]

  • Drowsiness
  • Extrapyramidal symptoms
  • Tremor
  • Confusion
  • Disorientation
  • Dizziness
  • Paresthesias
  • Alterations to ECG patterns
  • Dry mouth
  • Sweating
  • Urinary retention
  • Hypotension
  • Postural hypotension
  • Tachycardia
  • Palpitations
  • Arrhythmias
  • Conduction defects
  • Increased or decreased libido
  • Nausea
  • Vomiting
  • Constipation
  • Blurred vision

Less common adverse effects:[2]

  • Disturbed concentration
  • Delusions
  • Hallucinations
  • Anxiety
  • Fatigue
  • Headaches
  • Restlessness
  • Excitement
  • Insomnia
  • Hypomania
  • Nightmares
  • Peripheral neuropathy
  • Ataxia
  • Incoordination
  • Seizures
  • Paralytic ileus
  • Hypertension
  • Heart block
  • Myocardial infarction
  • Stroke
  • Gynecomastia (swelling of breast tissue in males)
  • Testicular swelling
  • Impotence
  • Epigastric distress
  • Abdominal cramps
  • Parotid swellings
  • Diarrhea
  • Stomatitis (swelling of the mouth)
  • Black tongue
  • Peculiar taste sensations
  • Cholestatic jaundice
  • Altered liver function
  • Hepatitis (swelling of the liver)
  • Skin rash
  • Urticaria (hives)
  • Photosensitisation
  • Skin blisters
  • Angioneurotic edema
  • Weight loss
  • Urinary frequency
  • Mydriasis
  • Weight gain
  • Hyponatremia (low blood sodium)
  • Movement disorders
  • Dyspepsia (indigestion)
  • Increased intraocular pressure
  • Changes in blood sugar levels
  • Thrombocytopenia (an abnormally low number of platelets in the blood. This makes one more susceptible to bleeds)
  • Eosinophilia (an abnormally high amount of eosinophils in the blood)
  • Agranulocytosis (a dangerously low number of white blood cells in the blood leaving one open to potentially life-threatening infections)
  • Galactorrhea (lactation that is unassociated with breastfeeding and lactation)

Contraindications[edit]

Contraindications include:[2]

  • Epilepsy as it can lower the seizure threshold
  • TCAs should not be used concomitantly or within 14 days of treatment with monoamine oxidase inhibitors due to the risk for serotonin syndrome
  • Acute recovery phase following myocardial infarction as TCAs may produce conduction defects and arrhythmias
  • Liver failure
  • Hypersensitivity to dothiepin

Drug interactions[edit]

Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination.[2] TCAs potentiate the sedative effects of barbiturates, tranquillisers and CNS depressants.[2] Guanethidine and other adrenergic neurone blocking drugs can have their antihypertensive effects blocked by dosulepin.[2] Sympathomimetics may potentiate the sympathomimetic effects of dosulepin.[2] 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.[2] Dosulepin may have its postural hypotensive effects potentiated by diuretics.[2] Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.[2]

Overdose[edit]

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.[8] Dosulepin may be particularly toxic in overdose compared to other TCAs.[8] The onset of toxic effects is around 4–6 hours after dosulepin is ingested.[2] 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.[2] 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.[2] The medication should also be kept out of reach of children.[2]

Mechanism of action[edit]

Dosulepin is a serotonin-norepinephrine reuptake inhibitor (SNRI) with anticholinergic, antihistamine, and antiadrenergic effects.[11]

Receptor/Transporter Ki (nM)[12]
SERT 8.6
NET 46
DAT 5,310
5-HT1A 4,004
5-HT2A 152
M1 18
M2 109
M3 38
M4 61
M5 92
α1 419
α2 12
H1 4

Pharmacokinetics[edit]

Dothiepin is readily absorbed from the small intestine and is extensively metabolised on first-pass through the liver into its chief active metabolite, northiaden (desmethyldosulepin).[2] Peak plasma concentrations of between 30.4 ng/mL to 278.8 ng/mL occur within 2–3 hours of oral administration.[2] It is distributed in breast milk and crosses the placenta and blood-brain barrier.[2] It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.[2]

References[edit]

  1. ^ a b Lancaster, SG; Gonzalez, JP (July 1989). "Dothiepin: a review of its pharmcodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness". Drugs 38 (1): 123–147. doi:10.2165/00003495-198938010-00005. PMID 2670509. 
  2. ^ a b c d e f g h i j k l m n o p q r s t u v "Dothep Dothiepin hydrochloride" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 1 November 2013. Retrieved 3 December 2013. 
  3. ^ Rees, JA (1981). "Clinical interpretation of pharmacokinetic data on dothiepin hydrochloride (Dosulepin, Prothiaden)". Journal of International Medical Research 9 (2): 98–102. PMID 7227628. 
  4. ^ Maguire, KP; Burrows, GD; Norman, TR; Scoggins, BA (September 1981). "Metabolism and pharmacokinetics of dothiepin" (PDF). British Journal of Clinical Pharmacology 12 (3): 405–409. doi:10.1111/j.1365-2125.1981.tb01235.x. PMC 1401810. PMID 7295471. 
  5. ^ a b Bareggi, SR; Cavallaro, R; Pirola, R; Altamura, AC (1990). "Pharmacokinetics and adverse effects of single doses of dothiepin in young and elderly subjects". Progress in Neuro-Psychopharmacology and Biological Psychiatry 14 (2): 163–170. doi:10.1016/0278-5846(90)90098-2. PMID 2309034. 
  6. ^ Ogura, C; Kishimoto, A; Mizukawa, R; Hazama, H; Honma, H; Kawahara, K (1983). "Age differences in effects on blood pressure, flicker fusion frequency, salivation and pharmacokinetics of single oral doses of dothiepin and amitriptyline". European Journal of Clinical Pharmacology 25 (6): 811–814. doi:10.1007/BF00542525. PMID 6662179. 
  7. ^ Dosulepin Hydrochloride. Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). 5 December 2011. Retrieved 3 December 2013. 
  8. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  9. ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. 
  10. ^ C Feinmann, M Harris, and R Cawley (11 February 1984). "Psychogenic facial pain: presentation and treatment.". http://www.ncbi.nlm.nih.gov/. The National Center for Biotechnology Information. Retrieved 6 April 2014. 
  11. ^ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8. 
  12. ^ Roth, BL; Driscol, J (12 January 2011). "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 3 December 2013.