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{{drugbox |
{{Drugbox
| IUPAC_name = ''2-((8-Chlorodibenzo(''b,f'')thiepin-<BR>10-yl)oxy)-''N,N''-dimethylethylamine''
| Verifiedfields = changed
| image = Zotepine structure.png
| verifiedrevid = 477869681
| width = 225
| IUPAC_name = 2-[(8-&#x200b;chlorodibenzo(''b,f'')&#x200b;thiepin-&#x200b;10-&#x200b;yl)oxy]-&#x200b;''N,N''-&#x200b;dimethylethanamine
| image = Zotepine2D1.svg
| width = 200
| image2 = Zotepine3Dan3.gif
| width2 = 250
 
<!--Clinical data-->
| tradename =  Zoleptil
| Drugs.com = {{drugs.com|international|zotepine}}
| pregnancy_category = 
| legal_status = Rx-only
| routes_of_administration = Oral
 
<!--Pharmacokinetic data-->
| bioavailability = 7-13% (Oral)<ref name = "DRUGDEX">Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jun 25]. Greenwood Village, CO: Thomsen Healthcare; 2013.</ref>
| metabolism =  N-desmethylation to norzotepine (30-40%)<ref name = "DRUGDEX" />
| elimination_half-life =  13.7-15.9 hours, 12 hours (Norzotepine)<ref name = "DRUGDEX" />
| excretion =  17% (Urine)<ref name = "DRUGDEX" />
 
<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 26615-21-4
| CAS_number = 26615-21-4
| ATC_prefix = N05
| ATC_prefix = N05
| ATC_suffix = AX11
| ATC_suffix = AX11
| PubChem = 5736
| PubChem = 5736
| IUPHAR_ligand = 103
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = none
| DrugBank = none
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5534
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = U29O83JAZW
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01321
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 32316
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 285802
<!--Chemical data-->
| C=18 | H=18 | Cl=1 | N=1 | O=1 | S=1
| C=18 | H=18 | Cl=1 | N=1 | O=1 | S=1
| molecular_weight = 331.86
| molecular_weight = 331.86
| bioavailability =  
| smiles = Clc2cc1C(/OCCN(C)C)=C\c3c(Sc1cc2)cccc3
| metabolism =  
| InChI = 1/C18H18ClNOS/c1-20(2)9-10-21-16-11-13-5-3-4-6-17(13)22-18-8-7-14(19)12-15(16)18/h3-8,11-12H,9-10H2,1-2H3
| elimination_half-life =
| InChIKey = HDOZVRUNCMBHFH-UHFFFAOYAX
| excretion =  
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| pregnancy_category =  
| StdInChI = 1S/C18H18ClNOS/c1-20(2)9-10-21-16-11-13-5-3-4-6-17(13)22-18-8-7-14(19)12-15(16)18/h3-8,11-12H,9-10H2,1-2H3
| legal_status = Unscheduled, Rx Only (US)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| routes_of_administration = Oral
| StdInChIKey = HDOZVRUNCMBHFH-UHFFFAOYSA-N
}}
}}
'''Zotepine''' (Nipolept, Losizopilon, Lodopin) is an [[atypical antipsychotic]] indicated for acute and chronic [[schizophrenia]]. It has been used in Germany since 1990 and Japan since 1982.


The most common dosage used is 150mg daily. It is suggested that zotepine therapy starts at 75mg to 150mg divided into three daily doses. Some people may need to have their dosage increased to 300mg.
'''Zotepine''' (brand names: '''Losizopilon''' <small>([[Japan|JP]])</small>, '''Lodopin''' <small>([[Indonesia|ID]], [[Japan|JP]])</small>, '''Setous''' <small>([[Japan|JP]])</small>, '''Zoleptil''' <small>([[Czech Republic|CZ]], [[Portugal|PT]], [[Turkey|TR]], [[United Kingdom|UK]]†)</small>; where † indicates a formulation that has been discontinued) is an [[atypical antipsychotic]] [[drug]] indicated for acute and chronic [[schizophrenia]]. It has been used in [[Germany]] since 1990 (although it has been discontinued in Germany) and [[Japan]] since 1982.
 
Zotepine is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.<ref name = Martindale>{{cite web|title=Zotepine|date=16 August 2013|accessdate=2 November 2013|url=http://www.medicinescomplete.com/mc/martindale/current/2479-d.htm?|publisher=Royal Pharmaceutical Society of Great Britain|work=Martindale: The Complete Drug Reference}}</ref>
 
== Medical Uses ==
Zotepine's primary use is as a treatment for schizophrenia<ref name = "BNF 58"/> although clinical trials have been conducted (with positive results) into its efficacy as an antimanic agent in patients with acute bipolar mania.<ref>{{cite journal|title=A single-blind, comparative study of zotepine versus haloperidol in combination with a mood stabilizer for patients with moderate-to-severe mania|journal=Psychiatry and Clinical Neurosciences|author=Chan, HY; Jou, SH; Juang, YY; Chang, CJ; Chen, JJ; Chen, CH; Chiu, NY|date=April 2010|pmid=20447012|doi=10.1111/j.1440-1819.2010.02066.x|volume=64|issue=2|pages=162–169}}</ref><ref>{{cite journal|title=Antimanic effect of zotepine|journal=Clinical Therapeutics|year=1986|volume=8|issue=4|pages=406–414|pmid=3089626|author=Harada, T; Otsuki, S}}</ref><ref>{{cite journal|title=Zotepine loading in acute and severely manic patients: a pilot study|journal=Bipolar Disorders|date=October 2005|volume=7|issue=5|pages=471–476|author=Amann, B; Sterr, A; Mergl, R; Dittmann, S; Seemüller, F; Dobmeier, M; Orth, M; Schaefer, M; Grunze, H|doi=10.1111/j.1399-5618.2005.00241.x|pmid=16176441}}</ref>
 
== Side effects ==
 
;Common<ref name = "DRUGDEX" /><ref name = "BNF 58">British National Formulary 58. British Medical Association and Royal Pharmaceutical Society of Great Britain; 2009.</ref>
{{colbegin|4}}
* [[Tachycardia]]
* [[Hypotension]]
* [[Orthostatic hypotension]]
* [[Palpitations]]
* [[Hyperprolactinaemia]]
* Weight gain (produces a similar degree of weight gain to that seen with [[clozapine]] and [[olanzapine]] treatment)<ref name = "Lancet" />
* [[Somnolence]] (2nd highest effect size for causing sedation out of fifteen antipsychotics compared in a recent meta-analysis)<ref name = "Lancet">{{cite journal|title=Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis|journal=Lancet|date=September 2013|volume=382|issue=9896|pages=951–962|doi=10.1016/S0140-6736(13)60733-3|pmid=23810019|author=Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM}}</ref>
* [[Extrapyramidal side effects]] [EPSE] (2nd largest odds ratio for causing EPSE out of fifteen antipsychotics compared in a recent meta-analysis, second only to haloperidol)<ref name = "Lancet" />
* Constipation
* [[Xerostomia]] (dry mouth)
* Blurred vision
* [[Hypersalivation]] (drooling)
* [[Mydriasis]]
* Anxiety
* Agitation
* Rhinitis
* [[Sexual dysfunction]]
* [[Dyspnoea]]
* Diarrhoea
* Influenza-like symptoms
* Cough
* Vertigo
* Confusion
* [[Dyspepsia]]
* Flushing dry skin
* [[Arthralgia]]
* [[Myalgia]]
* Acne
* [[Conjunctivitis]]
* [[Thrombocythaemia]]
{{colend}}


==Pharmacology==
;Unknown Frequency<ref name = "DRUGDEX" /><ref name = "BNF 58" />
The antipsychotic effect of zotepine is thought to be mediated through antagonist activity at dopamine and serotonin receptors. Zotepine has a high affinity for the [[dopamine]] D1 and D2 recepetors. It also affects the 5HT2a, 5HT2c, 5HT6, and 5HT7 receptors. In addition, it inhibits the reuptake of [[noradrenaline]]. It is thought that this is why zotepine has a high efficacy for the negative symptoms of schizophrenia.
{{colbegin|3}}
* [[QT interval]] prolongation
* [[Hyperthermia]]
* [[Hypothermia]]
* Increased serum [[creatinine]]
* [[Hyperglycaemia]]
* [[Hypoglycaemia]]
* [[Hyperlipidaemia]]
* Thirst
* Urinary incontinence
{{colend}}


==Side effects==
;Rare<ref name = "DRUGDEX" /><ref name = "BNF 58" />
The most common side effect of Zotepine is weight gain. This weight gain side effect compares badly to the older [[typical antipsychotic]]s. [[Somnolence]] is the second most common side effect. [[Constipation]], [[asthenia]], dry mouth, and [[akathisia]] are also reported.
{{colbegin|4}}
* [[Angle-closure glaucoma]]
* [[Agranulocytosis]]
* [[Neutropaenia]]
* [[Eosinophilia]]
* [[Leukocytopenia]]
* [[Hypoesthesia]]
* [[Anaemia]]
* [[Myoclonus]]
* [[muscle weakness|Myasthenia]]
* [[Alopecia]]
* [[Thrombocytopaenia]]
* [[Bradycardia]]
* [[Epistaxis]]
* Abdominal enlargement
* [[Deep vein thrombosis]]
* Paralytic [[ileus]]
* [[Leukopenia]]
* [[Tardive dyskinesia]]
* [[Neuroleptic malignant syndrome]]
* [[Laryngeal edema]]
* [[Urinary retention]]
* Depression
* [[Ataxia]]
* [[Amnesia]]
* Seizure (dose-dependent risk)<ref name = Martindale/>
* [[Metabolic syndrome]]
* [[Diabetes mellitus]] type II
* [[Cholestasis]]
* Increased liver enzymes
* Photosensitivity
* Exanthema
* Pruritus
* [[Hypouricemia]]
* [[Oedema]]
{{colend}}


The likelihood of side effects are as follows:
== Pharmacology ==


Weight gain: Medium to high
The antipsychotic effect of zotepine is thought to be mediated through [[receptor antagonist|antagonist]] activity at [[dopamine receptor|dopamine]] and [[serotonin receptor]]s. Zotepine has a high [[affinity (pharmacology)|affinity]] for the [[D1 receptor|D<sub>1</sub>]] and [[D2 receptor|D<sub>2</sub> receptor]]s. It also affects the [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], [[5-HT6 receptor|5-HT<sub>6</sub>]], and [[5-HT7 receptor|5-HT<sub>7</sub> receptor]]s.<ref name = PDSP>{{cite web|title=PDSD Ki Database|date=12 January 2011|accessdate=2 November 2013|publisher=University of North Carolina|place=Chapel Hill (NC)|author=National Institute of Mental Health|url=http://pdsp.med.unc.edu/pdsp.php}}</ref> In addition, its active metabolite, norzotepine, serves as a potent [[norepinephrine reuptake inhibitor]].<ref>{{cite journal|title=Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake|journal=The Journal of Pharmacology and Experimental Therapeutics|volume=333|issue=3|date=June 2010|url=http://jpet.aspetjournals.org/content/333/3/772.full.pdf|doi=10.1124/jpet.110.166264|pmid=20223878|pages=772–781|author=Shobo, M; Kondo, Y; Yamada, H; Mihara, T; Yamamoto, N; Katsuoka, M; Harada, K; Ni, K; Matsuoka, N}}</ref>
Hyperprolactinemia: high
Sexual problems: high
Sedation: high
EPSE's (Assumes that normal doses are used but may vary with the dose given):Low
Hypotension: Medium
Hyperglycaemia: Low


==References==
{| class="wikitable"
|-
! Macromolecule (Receptor or transporter protein) !! K<sub>i</sub> [nM]<ref name = PDSP/>
|-
| [[Serotonin transporter|SERT]] || 151
|-
| [[Norepinephrine transporter|NET]] || 530
|-
| [[Dopamine transporter|DAT]] || 3621
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 470.5
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 59.5
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 119
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]] || 700
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 2.7
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 2.6
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || 472
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] || 29
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || 6
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || 12
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]] || 7
 
|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || 5
|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || 180
|-
| [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]] || 5.35
|-
| [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] || 106
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || 18
|-
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]] || 140
|-
| [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]] || 73
|-
| [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]] || 77
|-
| [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]] || 260
|-
| [[Dopamine D1 receptor|D<sub>1</sub>]] || 71
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || 25
|-
| D<sub>2S</sub> || 5.4
|-
| D<sub>2L</sub> || 11
|-
| [[Dopamine D3 receptor|D<sub>3</sub>]] || 6.4
|-
| [[Dopamine D4 receptor|D<sub>4</sub>]] || 18
|-
| [[Dopamine D5 receptor|D<sub>5</sub>]] || 248
|-
| [[Histamine H1 receptor|H<sub>1</sub>]] || 3.21
|-
| [[Histamine H2 receptor|H<sub>2</sub>]] || 500
|-
| [[Histamine H4 receptor|H<sub>4</sub>]] || 1977
|}
 
== Dosing ==
 
The most common dosage used is 150&nbsp;mg daily. It is suggested that zotepine therapy starts at 75&nbsp;mg to 150&nbsp;mg divided into three daily doses. Some people may need to have their dosage increased to 300&nbsp;mg.<ref name = Martindale/>
 
[[File:ロドピン50㎎ヒート.jpg|thumb|left|50 mg Lodopin® pills]]
 
== References ==
{{reflist}}
* http://www.priory.com/focus11.htm
* http://www.priory.com/focus11.htm
* http://www.nyrdtc.nhs.uk/docs/nde/Zotepine.pdf -
* http://www.nyrdtc.nhs.uk/docs/nde/Zotepine.pdf -
* [http://di.m-pharma.co.jp/file/if/f_los.pdf LOSIZOPILON SUGAR-COATED TABLETS & FINE GRANULES] (PDF)
* [http://di.m-pharma.co.jp/file/if/f_los.pdf LOSIZOPILON SUGAR-COATED TABLETS & FINE GRANULES] (PDF)
* [http://psychodoc.eek.jp/abare/gallery/lodopin1982.jpg ロドピン®（ゾテピン） 1982年　精神神経学雑誌]
* [http://psychodoc.eek.jp/abare/gallery/lodopin1982.jpg ロドピン（ゾテピン） 1982年　精神神経学雑誌]


{{Antipsychotics}}
{{Antipsychotics}}
 
{{Adrenergics}}
<!--[[es:Zotepina]]
{{Cholinergics}}
[[la:Zotepinum]]
{{Dopaminergics}}
[[ja:ゾテピン]]
{{Histaminergics}}
-->
{{Serotonergics}}
{{Tricyclics}}


[[Category:Atypical antipsychotics]]
[[Category:Atypical antipsychotics]]
 
[[Category:Dibenzothiepines]]
 
[[Category:Organochlorides]]
{{pharma-stub}}
[[Category:Ethers]]
[[de:Zotepin]]
{{WikiDoc Sources}}

Revision as of 13:19, 13 April 2015

Zotepine
File:Zotepine2D1.svg
Clinical data
Trade namesZoleptil
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability7-13% (Oral)[1]
MetabolismN-desmethylation to norzotepine (30-40%)[1]
Elimination half-life13.7-15.9 hours, 12 hours (Norzotepine)[1]
Excretion17% (Urine)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC18H18ClNOS
Molar mass331.86
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Zotepine (brand names: Losizopilon (JP), Lodopin (ID, JP), Setous (JP), Zoleptil (CZ, PT, TR, UK†); where † indicates a formulation that has been discontinued) is an atypical antipsychotic drug indicated for acute and chronic schizophrenia. It has been used in Germany since 1990 (although it has been discontinued in Germany) and Japan since 1982.

Zotepine is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.[2]

Medical Uses

Zotepine's primary use is as a treatment for schizophrenia[3] although clinical trials have been conducted (with positive results) into its efficacy as an antimanic agent in patients with acute bipolar mania.[4][5][6]

Side effects

Common[1][3]
Unknown Frequency[1][3]
Rare[1][3]

Pharmacology

The antipsychotic effect of zotepine is thought to be mediated through antagonist activity at dopamine and serotonin receptors. Zotepine has a high affinity for the D1 and D2 receptors. It also affects the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors.[8] In addition, its active metabolite, norzotepine, serves as a potent norepinephrine reuptake inhibitor.[9]

Macromolecule (Receptor or transporter protein) Ki [nM][8]
SERT 151
NET 530
DAT 3621
5-HT1A 470.5
5-HT1B 59.5
5-HT1D 119
5-HT1E 700
5-HT2A 2.7
5-HT2C 2.6
5-HT3 472
5-HT5A 29
5-HT6 6
5-HT7 12
α1A 7
α1B 5
α2A 180
α2B 5.35
α2C 106
M1 18
M2 140
M3 73
M4 77
M5 260
D1 71
D2 25
D2S 5.4
D2L 11
D3 6.4
D4 18
D5 248
H1 3.21
H2 500
H4 1977

Dosing

The most common dosage used is 150 mg daily. It is suggested that zotepine therapy starts at 75 mg to 150 mg divided into three daily doses. Some people may need to have their dosage increased to 300 mg.[2]

File:ロドピン50㎎ヒート.jpg
50 mg Lodopin® pills

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jun 25]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  2. ↑ 2.0 2.1 2.2 "Zotepine". Martindale: The Complete Drug Reference. Royal Pharmaceutical Society of Great Britain. 16 August 2013. Retrieved 2 November 2013.
  3. ↑ 3.0 3.1 3.2 3.3 British National Formulary 58. British Medical Association and Royal Pharmaceutical Society of Great Britain; 2009.
  4. ↑ Chan, HY; Jou, SH; Juang, YY; Chang, CJ; Chen, JJ; Chen, CH; Chiu, NY (April 2010). "A single-blind, comparative study of zotepine versus haloperidol in combination with a mood stabilizer for patients with moderate-to-severe mania". Psychiatry and Clinical Neurosciences. 64 (2): 162–169. doi:10.1111/j.1440-1819.2010.02066.x. PMID 20447012.
  5. ↑ Harada, T; Otsuki, S (1986). "Antimanic effect of zotepine". Clinical Therapeutics. 8 (4): 406–414. PMID 3089626.
  6. ↑ Amann, B; Sterr, A; Mergl, R; Dittmann, S; Seemüller, F; Dobmeier, M; Orth, M; Schaefer, M; Grunze, H (October 2005). "Zotepine loading in acute and severely manic patients: a pilot study". Bipolar Disorders. 7 (5): 471–476. doi:10.1111/j.1399-5618.2005.00241.x. PMID 16176441.
  7. ↑ 7.0 7.1 7.2 Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
  8. ↑ 8.0 8.1 National Institute of Mental Health (12 January 2011). "PDSD Ki Database". Chapel Hill (NC): University of North Carolina. Retrieved 2 November 2013.
  9. ↑ Shobo, M; Kondo, Y; Yamada, H; Mihara, T; Yamamoto, N; Katsuoka, M; Harada, K; Ni, K; Matsuoka, N (June 2010). "Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 333 (3): 772–781. doi:10.1124/jpet.110.166264. PMID 20223878.

Template:Tricyclics

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