View source for Pizotifen

{{Short description|Drug used to reduce frequency of headaches}}
{{cs1 config|name-list-style=vanc}}
{{Infobox drug
| Verifiedfields = verified
| verifiedrevid = 464208411
| IUPAC_name = 4-(1-methyl-4-piperidylidine)-9,10-dihydro -4''H''-benzo-[4,5]cyclohepta[1,2]-thiophene
| image = Pizotifen structure.svg
| width = 180px

<!--Clinical data-->
| tradename = Sandomigran, Mosegor, Litec, others
| Drugs.com = {{drugs.com|international|pizotifen}}
| pregnancy_AU = B1
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =  
| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = <!-- OTC / Rx-only  / Schedule I, II, III, IV, V -->
| legal_status =  
| routes_of_administration = [[Oral administration|Oral]]

<!--Pharmacokinetic data-->
| bioavailability = 78%
| protein_bound = 91%
| metabolism = Glucuronidation (main route). ''N''-glucuronide accounts for >50% of plasma and 60–70% of urinary excreted drug
| elimination_half-life = 23 hours
| excretion = 18% feces, 55% urine (both as metabolites)

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 15574-96-6
| ATC_prefix = N02
| ATC_suffix = CX01
| PubChem = 27400
| IUPHAR_ligand = 93
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06153
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 25497
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 0BY8440V3N
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D05523
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 294951
| synonyms = Pizotyline; BC-105

<!--Chemical data-->
| C=19 | H=21 | N=1 | S=1 
| SMILES = s1c3c(cc1)C(\c2c(cccc2)CC3)=C4/CCN(C)CC4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H21NS/c1-20-11-8-15(9-12-20)19-16-5-3-2-4-14(16)6-7-18-17(19)10-13-21-18/h2-5,10,13H,6-9,11-12H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FIADGNVRKBPQEU-UHFFFAOYSA-N
}}

'''Pizotifen''', also known as '''pizotyline''' and sold under the brand names '''Sandomigran''' and '''Mosegor''' among others, is an [[antimigraine agent]] of the [[tricyclic compound|tricyclic]] group which is used primarily as a [[prophylaxis|preventative]] to reduce the frequency of recurrent [[migraine]] headaches.<ref name="pmid17680738">{{cite journal | vauthors = Stark RJ, Valenti L, Miller GC | title = Management of migraine in Australian general practice | journal = The Medical Journal of Australia | volume = 187 | issue = 3 | pages = 142–146 | date = August 2007 | pmid = 17680738 | doi = 10.5694/j.1326-5377.2007.tb01170.x | s2cid = 10357983 }}</ref>

==Medical uses==
===Migraine headaches===
The main medical use for pizotifen is for the prevention of [[migraine]] and [[cluster headache]]. Pizotifen is one of a range of medications used for this purpose, other options include [[propranolol]], [[topiramate]], [[valproic acid]], [[cyproheptadine]] and [[amitriptyline]]. While pizotifen is effective in adults,<ref>{{cite journal | vauthors = Jackson JL, Cogbill E, Santana-Davila R, Eldredge C, Collier W, Gradall A, Sehgal N, Kuester J | display-authors = 6 | title = A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache | journal = PLOS ONE | volume = 10 | issue = 7 | pages = e0130733 | date = 2015-07-14 | pmid = 26172390 | pmc = 4501738 | doi = 10.1371/journal.pone.0130733 | doi-access = free | bibcode = 2015PLoSO..1030733J }}</ref> evidence of efficacy in children is limited,<ref name="pmid15210509">{{cite journal | vauthors = Barnes N, Millman G | title = Do pizotifen or propranolol reduce the frequency of migraine headache? | journal = Archives of Disease in Childhood | volume = 89 | issue = 7 | pages = 684–685 | date = July 2004 | pmid = 15210509 | pmc = 1719986 | doi = 10.1136/adc.2004.054668 }}</ref> and its use is limited by side effects, principally drowsiness and weight gain, and it is usually not the first choice medicine for preventing migraines, instead being used as an alternative when other drugs have failed to be effective.<ref>{{cite journal | vauthors = Pierangeli G, Cevoli S, Sancisi E, Grimaldi D, Zanigni S, Montagna P, Cortelli P | title = Which therapy for which patient? | journal = Neurological Sciences | volume = 27 | issue = Suppl 2 | pages = S153–S158 | date = May 2006 | pmid = 16688621 | doi = 10.1007/s10072-006-0592-0 | s2cid = 24217802 }}</ref> It is not effective in relieving migraine attacks once in progress.

===Other uses===
Pizotifen has also been reported as highly effective in a severe case of [[erythromelalgia]], a rare neurovascular disease that is sometimes refractory to the other drugs named above.<ref name="pmid11050591">{{cite journal | vauthors = Cohen JS | title = Erythromelalgia: new theories and new therapies | journal = Journal of the American Academy of Dermatology | volume = 43 | issue = 5 Pt 1 | pages = 841–847 | date = November 2000 | pmid = 11050591 | doi = 10.1067/mjd.2000.109301 | s2cid = 40807034 }}</ref>

Other applications for which pizotifen may be used include as an [[antidepressant]], or for the treatment of [[anxiety]] or [[social anxiety disorder|social phobia]].<ref name="pmid335788">{{cite journal | vauthors = Standal JE | title = Pizotifen as an antidepressant | journal = Acta Psychiatrica Scandinavica | volume = 56 | issue = 4 | pages = 276–279 | date = October 1977 | pmid = 335788 | doi = 10.1111/j.1600-0447.1977.tb00228.x | s2cid = 6445059 }}</ref><ref name="pmid348154">{{cite journal | vauthors = Banki CM | title = Clinical observations with pizotifene (Sandomigran) in the treatment of nonmigrainous depressed women | journal = Archiv für Psychiatrie und Nervenkrankheiten | volume = 225 | issue = 1 | pages = 67–72 | date = March 1978 | pmid = 348154 | doi = 10.1007/bf00367352 | s2cid = 13510725 }}</ref> Animal studies also suggest that pizotyline could be used in the treatment of [[serotonin syndrome]] or [[MDMA]] [[overdose]]<ref name="pmid16253319">{{cite journal | vauthors = Young R, Khorana N, Bondareva T, Glennon RA | title = Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA) | journal = Pharmacology, Biochemistry, and Behavior | volume = 82 | issue = 2 | pages = 404–410 | date = October 2005 | pmid = 16253319 | doi = 10.1016/j.pbb.2005.09.010 | s2cid = 20885754 }}</ref> in a similar manner to the closely related antihistamine/antiserotonin medication [[cyproheptadine]].

Pizotifen might be useful as a [[trip killer|hallucinogen antidote or "trip killer"]] in blocking the effects of [[serotonergic psychedelic]]s like [[psilocybin]].<ref name="HalmanKongSarris2024">{{cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 | url = }}</ref> It might also be useful in the treatment of [[MDMA]] [[overdose]].<ref name="YoungKhoranaBondareva2005" />

==Contraindications==
Caution is required in patients having closed angle [[glaucoma]] and in patients with a predisposition to [[urinary retention]] as the medication exhibits a relatively small anticholinergic effect. Dose adjustment is required in people who have [[chronic kidney disease]]. Liver injury has also been reported. Pizotifen treatment should be discontinued if there is any clinical evidence of liver dysfunction during treatment. Caution is advised in patients having a history of [[epilepsy]].
Withdrawal symptoms like depression, tremor, nausea, anxiety, malaise, dizziness, sleep disorder and weight decrease have been reported following abrupt cessation of pizotifen.<ref>{{cite web|url=https://www.medsafe.govt.nz/profs/datasheet/s/Sandomigrantab.pdf|title=SANDOMIGRAN® pizotifen 500 micrograms coated tablets | work = AFT Pharmaceuticals Ltd | date = 21 June 2019 | publisher = Medsafe: New Zealand Medicines and Medical Devices Safety }}</ref>

Pizotifen is contraindicated in patients who suffer from hypersensitivity to any of its components, also Pizotifen is contraindicated in [[gastric outlet obstruction]], [[pregnancy]], angle-closure glaucoma and difficulty urinating.<ref>{{cite web|url=http://lekarstwo.ru/en/preparati/pizotifen.html | title = Pizotifen | work = Universal reference book of medicines | via = Likarstwo.ru}}</ref>

==Adverse effects==
[[Adverse drug reaction|Side effects]] include [[sedation]], [[dry mouth]], drowsiness, increased appetite and weight gain.<ref>Crowder D, Maclay WP. Pizotifen once daily in the prophylaxis of migraine: results of a multi-centre general practice study. Current Medical Research and Opinion. 1984;9(4):280-5.</ref> Occasionally it may cause nausea, headaches, or dizziness. In rare cases, anxiety, aggression and depression may also occur.

==Pharmacology==
===Pharmacodynamics===
{| class="wikitable floatright" style="font-size:small;"
|+ {{Nowrap|Pizotifen activities}}
|-
! [[Biological target|Target]] !! [[Affinity (pharmacology)|Affinity]] (K<sub>i</sub>, nM) !! Species
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 200–270 || Human
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 1415 || Human
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 770 || Human
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]] || 820 || Human
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 2.0 || Human
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]] || 2.0–2.3 || Human
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 8.4 || Human
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || 95 || Human
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]] || {{Abbr|ND|No data}} || Human
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] || 110 || Human
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || 74 || Human
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || 17–25 || Human
|-
| [[D1 receptor|D<sub>1</sub>]] || 3.5 || Human
|-
| [[D2 receptor|D<sub>2</sub>]] || 2.4–87 || Human
|-
| [[D3 receptor|D<sub>3</sub>]] || {{Abbr|ND|No data}} || {{Abbr|ND|No data}}
|-
| [[D4 receptor|D<sub>4</sub>]] || 64 || Human
|-
| [[D5 receptor|D<sub>5</sub>]] || 50 || Human
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]] || 65 || Human
|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || >10000 || Human
|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || 660 || Human
|-
| [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]] || 225 || Human
|-
| [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] || 390 || Human
|-
| [[Beta-1 adrenergic receptor|β<sub>1</sub>]] || >10000 || Human
|-
| [[Beta-2 adrenergic receptor|β<sub>2</sub>]] || >10000 || Human
|-
| [[H1 receptor|H<sub>1</sub>]] || 1.9 || Human
|-
| [[H2 receptor|H<sub>2</sub>]] || 1.4 || Human
|-
| [[Muscarinic acetylcholine M1 receptor|M<sub>1</sub>]] || 67 || Human
|-
| [[Muscarinic acetylcholine M2 receptor|M<sub>2</sub>]] || 34 || Human
|-
| [[Muscarinic acetylcholine M3 receptor|M<sub>3</sub>]] || 29 || Human
|-
| [[Muscarinic acetylcholine M4 receptor|M<sub>4</sub>]] || 130 || Human
|-
| [[Muscarinic acetylcholine M5 receptor|M<sub>5</sub>]] || 6.8 || Human
|-
| [[Imidazoline I1 receptor|I<sub>1</sub> receptor]] || 121 || Human
|-
| [[Sigma-1 receptor|σ<sub>1</sub> receptor]] || >10000 || Guinea pig
|-
| [[Sigma-2 receptor|σ<sub>2</sub> receptor]] || 6450 || Rat
|-
| {{Abbrlink|SERT|Serotonin transporter}} || >10000 || Human
|-
| {{Abbrlink|NET|Norepinephrine transporter}} || 710 || Human
|-
| {{Abbrlink|DAT|Dopamine transporter}} || >10000 || Human
|-
| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Note:''' The smaller the value, the more avidly the compound binds to or activates the site. '''Refs:''' <ref name="PDSP-Ki-Database-Pizotyline">{{cite web | title=PDSP Database | website=UNC | url=https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Pizotyline&kiAllRadio=all&doQuery=Submit+Query | language=zu | access-date=24 November 2024}}</ref><ref name="PDSP-Ki-Database-Pizotifen">{{cite web | title=PDSP Database | website=UNC | url=https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Pizotifen&kiAllRadio=all&doQuery=Submit+Query | language=zu | access-date=24 November 2024}}</ref><ref name="BindingDB">{{cite web | last=Liu | first=Tiqing | title=BindingDB BDBM82088 CAS_15574-96-6::NSC_27400::PIZOTIFEN | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=82088 | access-date=24 November 2024}}</ref><ref name="YoungKhoranaBondareva2005">{{cite journal | vauthors = Young R, Khorana N, Bondareva T, Glennon RA | title = Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA) | journal = Pharmacol Biochem Behav | volume = 82 | issue = 2 | pages = 404–410 | date = October 2005 | pmid = 16253319 | doi = 10.1016/j.pbb.2005.09.010 | url = }}</ref><ref name="MoritomoYamadaWatanabe2013">{{cite journal | vauthors = Moritomo A, Yamada H, Watanabe T, Itahana H, Akuzawa S, Okada M, Ohta M | title = Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists | journal = Bioorg Med Chem | volume = 21 | issue = 24 | pages = 7841–7852 | date = December 2013 | pmid = 24189186 | doi = 10.1016/j.bmc.2013.10.010 | url = }}</ref>
|}

Pizotifen is a [[serotonin antagonist]] acting mainly at the [[5-HT2A receptor|5-HT<sub>2A</sub>]] and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]]s. It also has some activity as an [[antihistamine]] as well as some [[anticholinergic]] activity.<ref name="pmid411500">{{cite journal | vauthors = Dixon AK, Hill RC, Roemer D, Scholtysik G | title = Pharmacological properties of 4(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene hydrogen maleate (pizotifen) | journal = Arzneimittel-Forschung | volume = 27 | issue = 10 | pages = 1968–1979 | date = 1977 | pmid = 411500 }}</ref> The drug binds [[binding selectivity|non-selective]]y to many [[biological target|target]]s, including [[serotonin receptor|serotonin]], [[dopamine receptor|dopamine]], [[adrenergic receptor|adrenergic]], [[histamine receptor|histamine]], and [[muscarinic acetylcholine receptor]]s.<ref name="YoungKhoranaBondareva2005" />

Pizotifen is able to [[dose dependence|dose-dependently]] and fully antagonize the [[discriminative stimulus]] effects of the [[serotonin–norepinephrine–dopamine releasing agent]] and [[serotonin]] [[5-HT2 receptor|5-HT<sub>2</sub> receptor]] [[agonist]] [[MDMA]] in rodent [[drug discrimination]] tests.<ref name="YoungKhoranaBondareva2005" /> Conversely, the related drug [[cyproheptadine]] was only partially effective and [[clozapine]] was ineffective.<ref name="YoungKhoranaBondareva2005" /> All three of these agents, pizotifen, cyproheptadine, and clozapine act as non-selective [[monoamine receptor]] antagonists.<ref name="YoungKhoranaBondareva2005" /> Pizotifen also fully blocks the effects of [[serotonergic psychedelic]]s, including [[LSD]], [[mescaline]], [[5-MeO-DMT]], and [[DOM (drug)|DOM]], in drug discrimination tests.<ref name="YoungKhoranaBondareva2005" />

==Chemistry==
Pizotifen is a [[tricyclic compound]] and is specifically a [[benzocycloheptene]].<ref name="Elks2014" /><ref name="IndexNominum2004" />

Close [[structural analog|analogue]]s of pizotifen include [[ketotifen]] and [[cyproheptadine]], among others.

==History==
Pizotifen was first described in the literature by 1964.<ref name="Elks2014" />

==Society and culture==
===Names===
''Pizotifen'' is the [[generic term|generic name]] of the drug and its {{Abbrlink|INN|International Nonproprietary Name}} and {{Abbrlink|BAN|British Approved Name}}, while ''pizotyline'' is its {{Abbrlink|USAN|United States Adopted Name}}.<ref name="Elks2014">{{cite book | last=Elks | first=J. | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1002 | access-date=24 November 2024 | page=1002}}</ref><ref name="IndexNominum2004">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | series=Index Nominum: International Drug Directory | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA992 | access-date=24 November 2024 | page=992}}</ref><ref name="MortonHall2012">{{cite book | last=Morton | first=I.K. | last2=Hall | first2=J.M. | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA225 | access-date=24 November 2024 | page=225}}</ref> Brand names of pizotifen include Sandomigran, Mosegor, and Litec, among others.<ref name="Elks2014" /><ref name="IndexNominum2004" /><ref name="MortonHall2012" /><ref name="Drugs.com-International" />

===Availability===
Pizotifen is available widely throughout the world, including in [[Europe]].<ref name="IndexNominum2004" /><ref name="Drugs.com-International">{{cite web | title=Pizotifen (International database) | website=Drugs.com | date=3 November 2024 | url=https://www.drugs.com/international/pizotifen.html | access-date=24 November 2024}}</ref>

== References ==
{{Reflist}}

== External links ==
* [http://www.medsafe.govt.nz/profs/datasheet/s/Sandomigrantab.pdf Sandomigran drug data sheet]

{{Antimigraine preparations}}
{{Navboxes
| title = [[Pharmacodynamics]]
| titlestyle = background:#ccccff
| list1 = 
{{Adrenergic receptor modulators}}
{{Dopamine receptor modulators}}
{{Histamine receptor modulators}}
{{Muscarinic acetylcholine receptor modulators}}
{{Serotonin receptor modulators}}
}}
{{Tricyclics}}

[[Category:5-HT2 antagonists]]
[[Category:Alpha-1 blockers]]
[[Category:Antimigraine drugs]]
[[Category:Benzocycloheptathiophenes]]
[[Category:Dopamine receptor modulators]]
[[Category:H1 receptor antagonists]]
[[Category:Muscarinic antagonists]]
[[Category:Piperidines]]