Chemistry:Pizotifen

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Pizotifen, also known as pizotyline and sold under the brand names Sandomigran and Mosegor among others, is an antimigraine agent of the tricyclic group which is used primarily as a preventative to reduce the frequency of recurrent migraine headaches.[1]

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,[2] evidence of efficacy in children is limited,[3] 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.[4] 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.[5]

Other applications for which pizotifen may be used include as an antidepressant, or for the treatment of anxiety or social phobia.[6][7] Animal studies also suggest that pizotyline could be used in the treatment of serotonin syndrome or MDMA overdose[8] in a similar manner to the closely related antihistamine/anti-serotonin medication cyproheptadine.

Pizotifen might be useful as a hallucinogen antidote or "trip killer" in blocking the effects of serotonergic psychedelics like psilocybin.[9] It might also be useful in the treatment of MDMA overdose.[10]

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.[11]

Pizotifen is contraindicated in patients who suffer from hypersensitivity to any of its components or have gastric outlet obstruction, angle-closure glaucoma, and difficulty urinating.[12] In addition, women who are pregnant should not take pizotifen.[12]

Adverse effects

Side effects include sedation, dry mouth, drowsiness, increased appetite and weight gain.[13] Occasionally it may cause nausea, headaches, or dizziness. In rare cases, anxiety, aggression and depression may also occur.

Pharmacology

Pharmacodynamics

Pizotifen activities
Target Affinity (Ki, nM) Species
5-HT1A 39–270 (Ki)
535 (EC50)
60% (Emax)		 Human
Human
Human
5-HT1B 1,415 Human
5-HT1D 770 Human
5-HT1E 820 Human
5-HT2A 2.0 Human
5-HT2B 2.0–2.3 Human
5-HT2C 8.4 Human
5-HT3 95 Human
5-HT4 ND Human
5-HT5A 110 Human
5-HT6 74 Human
5-HT7 17–25 Human
D1 3.5 Human
D2 2.4–87 Human
D3 ND ND
D4 64 Human
D5 50 Human
α1A 65 Human
α1B >10,000 Human
α2A 660 Human
α2B 225 Human
α2C 390 Human
β1 >10,000 Human
β2 >10,000 Human
H1 1.9 Human
H2 1.4 Human
M1 67 Human
M2 34 Human
M3 29 Human
M4 130 Human
M5 6.8 Human
I1 receptor 121 Human
σ1 receptor >10,000 Guinea pig
σ2 receptor 6,450 Rat
SERT >10,000 Human
NET 710 Human
DAT >10,000 Human
Note: The smaller the value, the more avidly the compound binds to or activates the site. Refs:[14][15][16][10][17][18]

Pizotifen is a serotonin antagonist acting mainly at the 5-HT2A, 5-HT2B, and 5-HT2C receptors. It also has some activity as an antihistamine as well as some anticholinergic activity.[19] The drug binds non-selectively to many targets, including serotonin, dopamine, adrenergic, histamine, and muscarinic acetylcholine receptors.[10] Besides its serotonin 5-HT2 receptor antagonism, pizotifen is a low-potency moderate-efficacy partial agonist of the serotonin 5-HT1A receptor.[18]

Pizotifen is able to dose-dependently and fully antagonize the discriminative stimulus effects of the serotonin–norepinephrine–dopamine releasing agent and serotonin 5-HT2 receptor agonist MDMA in rodent drug discrimination tests.[10] Conversely, the related drug cyproheptadine was only partially effective and clozapine was ineffective.[10] All three of these agents, pizotifen, cyproheptadine, and clozapine act as non-selective monoamine receptor antagonists.[10] Pizotifen also fully blocks the effects of serotonergic psychedelics, including LSD, mescaline, 5-MeO-DMT, and DOM, in drug discrimination tests.[10]

The antimigraine activity of pizotifen might be specifically due to serotonin 5-HT2B receptor blockade.[20]

Pharmacokinetics

The elimination half-life of pizotifen is 23 hours.[21][22]

Chemistry

Pizotifen is a tricyclic compound and is specifically a benzocycloheptene.[23][24]

Close analogues of pizotifen include ketotifen and cyproheptadine, among others.

History

Pizotifen was first described in the literature by 1964.[23]

Society and culture

Names

Pizotifen is the generic name of the drug and its INN and BAN, while pizotyline is its USAN.[23][24][25] Brand names of pizotifen include Sandomigran, Mosegor, and Litec, among others.[23][24][25][26]

Availability

Pizotifen is available widely throughout the world, including in Europe.[24][26]

References

  1. ↑ "Management of migraine in Australian general practice". The Medical Journal of Australia 187 (3): 142–146. August 2007. doi:10.5694/j.1326-5377.2007.tb01170.x. PMID 17680738. 
  2. ↑ "A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache". PLOS ONE 10 (7). 2015-07-14. doi:10.1371/journal.pone.0130733. PMID 26172390. Bibcode: 2015PLoSO..1030733J. 
  3. ↑ "Do pizotifen or propranolol reduce the frequency of migraine headache?". Archives of Disease in Childhood 89 (7): 684–685. July 2004. doi:10.1136/adc.2004.054668. PMID 15210509. 
  4. ↑ "Which therapy for which patient?". Neurological Sciences 27 (Suppl 2): S153–S158. May 2006. doi:10.1007/s10072-006-0592-0. PMID 16688621. 
  5. ↑ "Erythromelalgia: new theories and new therapies". Journal of the American Academy of Dermatology 43 (5 Pt 1): 841–847. November 2000. doi:10.1067/mjd.2000.109301. PMID 11050591. 
  6. ↑ "Pizotifen as an antidepressant". Acta Psychiatrica Scandinavica 56 (4): 276–279. October 1977. doi:10.1111/j.1600-0447.1977.tb00228.x. PMID 335788. 
  7. ↑ "Clinical observations with pizotifene (Sandomigran) in the treatment of nonmigrainous depressed women". Archiv für Psychiatrie und Nervenkrankheiten 225 (1): 67–72. March 1978. doi:10.1007/bf00367352. PMID 348154. 
  8. ↑ "Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA)". Pharmacology, Biochemistry, and Behavior 82 (2): 404–410. October 2005. doi:10.1016/j.pbb.2005.09.010. PMID 16253319. 
  9. ↑ "Drug-drug interactions involving classic psychedelics: A systematic review". J Psychopharmacol 38 (1): 3–18. January 2024. doi:10.1177/02698811231211219. PMID 37982394. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 "Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA)". Pharmacol Biochem Behav 82 (2): 404–410. October 2005. doi:10.1016/j.pbb.2005.09.010. PMID 16253319. 
  11. ↑ "SANDOMIGRAN® pizotifen 500 micrograms coated tablets". AFT Pharmaceuticals Ltd. Medsafe: New Zealand Medicines and Medical Devices Safety. 21 June 2019. https://www.medsafe.govt.nz/profs/datasheet/s/Sandomigrantab.pdf. 
  12. ↑ 12.0 12.1 "Pizotifen". Universal Reference Book of Medicines. http://lekarstwo.ru/en/preparati/pizotifen.html. 
  13. ↑ 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.
  14. ↑ "PDSP Database" (in zu). https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Pizotyline&kiAllRadio=all&doQuery=Submit+Query. 
  15. ↑ "PDSP Database" (in zu). https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Pizotifen&kiAllRadio=all&doQuery=Submit+Query. 
  16. ↑ "BindingDB BDBM82088 CAS_15574-96-6::NSC_27400::PIZOTIFEN". https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=82088. 
  17. ↑ "Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists". Bioorg Med Chem 21 (24): 7841–7852. December 2013. doi:10.1016/j.bmc.2013.10.010. PMID 24189186. 
  18. ↑ 18.0 18.1 "Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy". Naunyn Schmiedebergs Arch Pharmacol 355 (6): 682–688. June 1997. doi:10.1007/pl00005000. PMID 9205951. 
  19. ↑ "Pharmacological properties of 4(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene hydrogen maleate (pizotifen)". Arzneimittel-Forschung 27 (10): 1968–1979. 1977. PMID 411500. 
  20. ↑ "Putative role of 5-HT2B receptors in migraine pathophysiology". Cephalalgia 37 (4): 365–371. April 2017. doi:10.1177/0333102416646760. PMID 27127104. https://nbn-resolving.org/urn:nbn:de:bvb:29-opus4-112198. 
  21. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named DrugBank
  22. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Sandomigran-Monograph
  23. ↑ 23.0 23.1 23.2 23.3 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. 2014. p. 1002. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1002. Retrieved 24 November 2024. 
  24. ↑ 24.0 24.1 24.2 24.3 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 992. ISBN 978-3-88763-101-7. https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA992. Retrieved 24 November 2024. 
  25. ↑ 25.0 25.1 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. 2012. p. 225. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA225. Retrieved 24 November 2024. 
  26. ↑ 26.0 26.1 "Pizotifen (International database)". 3 November 2024. https://www.drugs.com/international/pizotifen.html. 



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