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Cyproheptadine

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Cyproheptadine
Clinical data
Pronunciation(/ˌsaɪproʊˈhɛptədiːn/[1]
Trade namesPeriactin, others
AHFS/Drugs.comMonograph
MedlinePlusa682541
License data
Pregnancy
category
  • AU: A
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding96 to 99%
MetabolismHepatic.[3][4] Mostly CYP3A4 meditated.
Elimination half-life8.6 hours[2]
ExcretionFaecal (2-20%; 34% of this as unchanged drug) and renal (40%; none as unchanged drug)[3][4]
Identifiers
  • 4-(5H-dibenzo [a,d]cyclohepten-5-ylidene)-1-methylpiperidine hydrochloride
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.482 Edit this at Wikidata
Chemical and physical data
FormulaC21H21N
Molar mass287.398 g/mol g·mol−1
3D model (JSmol)
  • c43\C(=C1/CCN(C)CC1)c2ccccc2\C=C/c3cccc4
  • InChI=1S/C21H21N/c1-22-14-12-18(13-15-22)21-19-8-4-2-6-16(19)10-11-17-7-3-5-9-20(17)21/h2-11H,12-15H2,1H3 checkY
  • Key:JJCFRYNCJDLXIK-UHFFFAOYSA-N checkY
  (verify)

Cyproheptadine, sold under the brand name Periactin among others, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.

Medical uses

Periactin (cyproheptadine) 4 mg tablets
  • Cyproheptadine is used to treat allergic reactions (specifically hay fever).[5] The evidence for its use for this purpose in children is weak and ketotifen and loratadine showed equal or better results in the small trials in which they have been compared.[6]
  • It is sometimes used, especially in its liquid formulation, as a preventive measure against migraine in children and adolescents,[7] but as of 2017 the evidence for this was weak.[6][8] This use is on the label in the UK and some other countries.[6] In Australia this is the only indication for which cyproheptadine is subsidised by the PBS.[9]
  • It is also used off-label in the treatment of cyclical vomiting syndrome in infants; the only evidence for this use comes from retrospective studies.[10]
  • Cyproheptadine is sometimes used off label to improve akathisia in people on antipsychotic medications.[11]
  • It used off-label to treat various dermatological conditions, including psychogenic itch[12] drug-induced hyperhidrosis (excessive sweating),[13] and prevention of blister formation for some people with epidermolysis bullosa simplex.[14]
  • One of the side effects of the drug is increased appetite and weight gain, which has led to its off-label use for this purpose in children who are wasting as well as people with cystic fibrosis. The evidence for the efficacy in light of other side effects is weak.[6][15]
  • It is sometimes used off-label in the management of moderate to severe cases of serotonin syndrome, a complex of symptoms associated with the use of serotonergic drugs, such as selective serotonin reuptake inhibitors and monoamine oxidase inhibitors), and in cases of high levels of serotonin in the blood resulting from a serotonin-producing carcinoid tumor.[9][16]

Adverse effects

Adverse effects include:[3][4]

  • Sedation and sleepiness (often transient)
  • Dizziness
  • Disturbed coordination
  • Confusion
  • Restlessness
  • Excitation
  • Nervousness
  • Tremor
  • Irritability
  • Insomnia
  • Paresthesias
  • Neuritis
  • Convulsions
  • Euphoria
  • Hallucinations
  • Hysteria
  • Faintness
  • Allergic manifestation of rash and edema
  • Diphoresis
  • Urticaria
  • Photosensitivity
  • Acute labyrinthitis
  • Diplopia (seeing double)
  • Vertigo
  • Tinnitus
  • Hypotension (low blood pressure)
  • Palpitation
  • Extrasystoles
  • Anaphylactic shock
  • Hemolytic anemia
  • Blood dyscrasias such as leukopenia, agranulocytosis and thrombocytopenia
  • Cholestasis
  • Hepatic (liver) side effects such as:
- Hepatitis
- Jaundice
- Hepatic failure[17]
- Hepatic function abnormality
- Blurred vision
- Constipation
- Xerostomia (dry mouth)
- Tachycardia (high heart rate)
- Urinary retention
- Difficulty passing urine
- Nasal congestion
- Nasal or throat dryness
  • Urinary frequency
  • Early menses
  • Thickening of bronchial secretions
  • Tightness of chest and wheezing
  • Fatigue
  • Chills
  • Headache
  • Erectle Dysfunction
  • Increased appetite
  • Weight gain

Overdose

Gastric decontamination measures such as activated charcoal are sometimes recommended in cases of overdose. The symptoms are usually indicative of CNS depression (or conversely CNS stimulation in some) and excess anticholinergic side effects. The LD50 in mice is 123 mg/kg and 295 mg/kg in rats.[3][4]

Pharmacology

Cyproheptadine
Site Ki (nM) Species
SERTTooltip Serotonin transporter 4,100 Rat
NETTooltip Norepinephrine transporter 290 Rat
DATTooltip Dopamine transporter ? Human
H1 0.06 Human
H2 ? Human
H3 >10,000 Human
H4 202 Human
M1 12 Human
M2 7 Human
M3 12 Human
M4 8 Human
M5 11.8 Human
5-HT1A 59 Human
5-HT2A 1.67 Human
5-HT2B 1.54 Human
5-HT2C 2.23 Human
5-HT3 228 Mouse
5-HT6 142 Human
5-HT7 123 Human
D1 117 Human
D2 112 Human
D3 8 Human

Cyproheptadine is a very potent antihistamine or antagonist of the H1 receptor. At higher concentrations, it also has anticholinergic, antiserotonergic, and antidopaminergic activities. Of the serotonin receptors, it is an especially potent antagonist of the 5-HT2 receptors, and this underlies its effectiveness in the treatment of serotonin syndrome.

Cyproheptadine is known to be an antagonist or inverse agonist of all of the receptors listed in the table to the right.[18]

Pharmacokinetics

Cyproheptadine is well-absorbed following oral ingestion, with peak plasma levels occurring after 1 to 3 hours.[19] Its terminal half-life when taken orally is approximately 8 hours.[2]

Chemistry

Cyproheptadine is a tricyclic benzocycloheptene and is closely related to pizotifen and ketotifen as well as to tricyclic antidepressants.

Research

Cyproheptadine was studied in one small (N=18) trial as an adjunct in people with schizophrenia whose condition was stable and were on other medication; while attention and verbal fluency appeared to be improved, the study was too small to draw generalizations from.[20] It has also been studied as an adjuvant in two other trials in people with schizophrenia, around fifty people overall, and did not appear to have an effect.[21]

There have been some trials to see if cyproheptadine could reduce sexual dysfunction caused by antipsychotics; it failed to show an effect.[22]

As of 2012, descriptions of the use of cyproheptadine to reduce the number of nightmares in around 12 people with post-traumatic stress syndrome had been published; it appeared to be helpful in all of them.[21]

Veterinary use

Cyproheptadine is used in cats as an appetite stimulant[23] and as an adjunct in the treatment of asthma.[24] Possible adverse effects include excitement and aggressive behavior.[25] The elimination half-life of cyproheptadine in cats is 12 hours.[24]

Cyproheptadine is a second line treatment for pituitary pars intermedia dysfunction in horses.[26][27]

References

  1. ^ "Cyproheptadine". Dictionary.com Unabridged (Online). n.d.
  2. ^ a b Gunja N, Collins M, Graudins A (2004). "A comparison of the pharmacokinetics of oral and sublingual cyproheptadine". Journal of Toxicology. Clinical Toxicology. 42 (1): 79–83. doi:10.1081/clt-120028749. PMID 15083941.
  3. ^ a b c d "CYPROHEPTADINE HYDROCHLORIDE tablet [Boscogen, Inc.]" (PDF). DailyMed. Boscogen, Inc. November 2010. Retrieved 26 October 2013.
  4. ^ a b c d "PRODUCT INFORMATION PERIACTIN® (cyproheptadine hydrochloride)" (PDF). Aspen Pharmacare Australia. Aspen Pharmacare Australia Pty Ltd. 17 November 2011. Retrieved 26 October 2013.
  5. ^ MedlinePlus Drug Information: Cyproheptadine
  6. ^ a b c d De Bruyne, P; Christiaens, T; Boussery, K; Mehuys, E; Van Winckel, M (January 2017). "Are antihistamines effective in children? A review of the evidence". Archives of disease in childhood. 102 (1): 56–60. doi:10.1136/archdischild-2015-310416. PMID 27335428.
  7. ^ Merison, K; Jacobs, H (November 2016). "Diagnosis and Treatment of Childhood Migraine". Current treatment options in neurology. 18 (11): 48. doi:10.1007/s11940-016-0431-4. PMID 27704257.
  8. ^ Saito, Y; Yamanaka, G; Shimomura, H; Shiraishi, K; Nakazawa, T; Kato, F; Shimizu-Motohashi, Y; Sasaki, M; Maegaki, Y (May 2017). "Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences". Brain & development. 39 (5): 386–394. doi:10.1016/j.braindev.2016.11.011. PMID 27993427.
  9. ^ a b Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  10. ^ Salvatore, S; Barberi, S; Borrelli, O; Castellazzi, A; Di Mauro, D; Di Mauro, G; Doria, M; Francavilla, R; Landi, M; Martelli, A; Miniello, VL; Simeone, G; Verduci, E; Verga, C; Zanetti, MA; Staiano, A; SIPPS Working Group on, FGIDs. (16 July 2016). "Pharmacological interventions on early functional gastrointestinal disorders". Italian journal of pediatrics. 42 (1): 68. doi:10.1186/s13052-016-0272-5. PMC 4947301. PMID 27423188.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ Taylor, David; Paton, Carol; Kapur, Shitij (2015). The Maudsley Prescribing Guidelines in Psychiatry. John Wiley & Sons. p. 85. ISBN 9781118754573.
  12. ^ Szepietowski, JC; Reszke, R (2016). "Psychogenic Itch Management". Current problems in dermatology. 50: 124–32. doi:10.1159/000446055. PMID 27578081.
  13. ^ Ashton AK, Weinstein WL (May 2002). "Cyproheptadine for drug-induced sweating". American Journal of Psychiatry. 159 (5): 874–5. doi:10.1176/appi.ajp.159.5.874-a. PMID 11986151.
  14. ^ Pfendner, Ellen G.; Bruckner, Anna L. (October 13, 2016). "Epidermolysis Bullosa Simplex". GeneReviews. University of Washington, Seattle. PMID 20301543.
  15. ^ Chinuck, R; Dewar, J; Baldwin, DR; Hendron, E (27 July 2014). "Appetite stimulants for people with cystic fibrosis". The Cochrane database of systematic reviews (7): CD008190. doi:10.1002/14651858.CD008190.pub2. PMID 25064192.
  16. ^ Iqbal, MM; Basil, MJ; Kaplan, J; Iqbal, MT (November 2012). "Overview of serotonin syndrome". Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists. 24 (4): 310–8. PMID 23145389.
  17. ^ Chertoff, Jason (8 July 2014). "Cyproheptadine-Induced Acute Liver Failure". ACG Case Reports Journal. 1 (4). doi:10.14309/crj.2014.56. PMC 4286888.
  18. ^ 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. Archived from the original on 8 November 2013. Retrieved 26 October 2013. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  19. ^ Lindsay Murray; Frank Daly; David McCoubrie; Mike Cadogan (15 January 2011). Toxicology Handbook. Elsevier Australia. p. 388. ISBN 978-0-7295-3939-5. Retrieved 27 November 2011.
  20. ^ Buoli, M; Altamura, AC (March 2015). "May non-antipsychotic drugs improve cognition of schizophrenia patients?". Pharmacopsychiatry. 48 (2): 41–50. doi:10.1055/s-0034-1396801. PMID 25584772.
  21. ^ a b Dabaghzadeh, F; Khalili, H; Ghaeli, P; Dashti-Khavidaki, S (December 2012). "Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz". Expert opinion on pharmacotherapy. 13 (18): 2613–24. doi:10.1517/14656566.2012.742887. PMID 23140169.
  22. ^ Nunes, LV; Moreira, HC; Razzouk, D; Nunes, SO; Mari Jde, J (2012). "Strategies for the treatment of antipsychotic-induced sexual dysfunction and/or hyperprolactinemia among patients of the schizophrenia spectrum: a review". Journal of sex & marital therapy. 38 (3): 281–301. doi:10.1080/0092623X.2011.606883. PMID 22533871.
  23. ^ Agnew, W; Korman, R (September 2014). "Pharmacological appetite stimulation: rational choices in the inappetent cat". Journal of feline medicine and surgery. 16 (9): 749–56. doi:10.1177/1098612X14545273. PMID 25146662.
  24. ^ a b Dowling PM (February 8, 2005). "Systemic Therapy of Airway Disease: Cyproheptadine". In Kahn CM, Line S, Aiello SE (eds.). The Merck Veterinary Manual (9th ed.). John Wiley & Sons. ISBN 0-911910-50-6. {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help) Retrieved on October 26, 2008.
  25. ^ Dowling PM (February 8, 2005). "Drugs Affecting Appetite". In Kahn CM, Line S, Aiello SE (eds.). The Merck Veterinary Manual (9th ed.). John Wiley & Sons. ISBN 0-911910-50-6. {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help) Retrieved on October 26, 2008.
  26. ^ Durham, AE (April 2017). "Therapeutics for Equine Endocrine Disorders". The Veterinary clinics of North America. Equine practice. 33 (1): 127–139. doi:10.1016/j.cveq.2016.11.003. PMID 28190613.
  27. ^ Merck Vet Manual. "Hirsutism Associated with Adenomas of the Pars Intermedia". Retrieved April 24, 2011.
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