Cyproheptadine

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Cyproheptadine
Cyproheptadine.svg
Cyproheptadine-Spartan-PM3-3D-balls.png
Clinical data
Pronunciation /ˌsaɪproʊˈhɛptədiːn/ [1]
Trade names Periactin, others
AHFS/Drugs.com Monograph
MedlinePlus a682541
License data
Pregnancy
category
  • AU:A
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 96 to 99%
Metabolism Liver, [2] [3] mostly CYP3A4 mediated.
Elimination half-life 8.6 hours [4]
Excretion Faecal (2–20%; of which, 34% as unchanged drug) and renal (40%; none as unchanged drug) [2] [3]
Identifiers
  • 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.482 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H21N
Molar mass 287.406 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 Yes check.svgY
  • Key:JJCFRYNCJDLXIK-UHFFFAOYSA-N Yes check.svgY
   (verify)

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

Contents

It was patented in 1959 and came into medical use in 1961. [5] In 2021, it was the 280th most commonly prescribed medication in the United States, with more than 800,000 prescriptions. [6] [7]

Medical uses

Periactin (cyproheptadine) 4 mg tablets Periactin.jpg
Periactin (cyproheptadine) 4 mg tablets
Cyproheptadine's 3D molecular structure represented as space-filling model Cyproheptadine3Dan.gif
Cyproheptadine's 3D molecular structure represented as space-filling model

Cyproheptadine is used to treat allergic reactions (specifically hay fever). [8] There is evidence supporting its use for allergies, but second generation antihistamines such as ketotifen and loratadine have shown equal results with fewer side effects. [9]

It is also used as a preventive treatment against migraine. In a 2013 study the frequency of migraine was dramatically reduced in patients within 7 to 10 days after starting treatment. The average frequency of migraine attacks in these patients before administration was 8.7 times per month, this was decreased to 3.1 times per month at 3 months after the start of treatment. [9] [10] This use is on the label in the UK and some other countries.

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. [11]

Cyproheptadine is sometimes used off-label to improve akathisia in people on antipsychotic medications. [12]

It is used off-label to treat various dermatological conditions, including psychogenic itch, [13] drug-induced hyperhidrosis (excessive sweating), [14] and prevention of blister formation for some people with epidermolysis bullosa simplex. [15]

One of the effects of the drug is increased appetite and weight gain, which has led to its use (off-label in the USA) for this purpose in children who are wasting as well as people with cystic fibrosis. [16] [17] [18] [19]

It is also 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. [20] [21]

Cyproheptadine has sedative effects and can be used to treat insomnia similarly to other centrally-acting antihistamines. [22] [23] [24] [25] The recommended dose for this use is 4 to 8 mg. [23]

Adverse effects

Adverse effects include: [2] [3]

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. [2] [3]

Pharmacology

Pharmacodynamics

Cyproheptadine [27] [28]
SiteKi (nM) [a] Action [b] SpeciesRef.
5-HT1A 50–59↓Human
5-HT1B 1600Human
5-HT1D 670Human
5-HT1E 1500Human
5-HT2A 1.7–1.9↓Human
5-HT2B 1.5–2.6↓Human
5-HT2C 2.2–18↓Human
5-HT3 235Human
5-HT4 NDHuman
5-HT5A 57Human
5-HT6 96–142Human
5-HT7 30–123Human
D1 10–117Human
D2 74–112↓Human
D3 8Human
D4 120Human
D5 60Human
α1A 45Human
α1B >10000Human
α2A 330Human
α2B 220Human
α2C 160Human
β1 >10000Human
β2 >10000Human
H1 0.06–2.3↓Human
H2 4.8Human
H3 >10,000Human
H4 202Human
M1 12↓Human
M2 7↓Human
M3 12↓Human
M4 8↓Human
M5 11.8↓Human
I1 receptor 204Human
σ1 receptor >10000Guinea pig
σ2 receptor 750Rat
SERT Tooltip Serotonin transporter>10000Human
NET Tooltip Norepinephrine transporter2550Human
DAT Tooltip Dopamine transporter4100Human
  1. ↑ The smaller the equilibrium constant, the more strongly the drug binds to the site.
  2. ↑
    • ↑ Agonist
    • ↓ Antagonist

Cyproheptadine is a very potent antihistamine or inverse agonist 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. This is thought to underlie its effectiveness in the treatment of serotonin syndrome. [29] However, it is possible that blockade of 5-HT1 receptors may also contribute to its effectiveness in serotonin syndrome. [30] Cyproheptadine has been reported to block 85% of 5-HT2 receptors in the human brain at a dose of 4 mg three times per day (12 mg/day total) and to block 95% of 5-HT2 receptors in the human brain at a dose of 6 mg three times per day (18 mg/day total) as measured with positron emission tomography (PET). [31] The dose of cyproheptadine recommended to ensure blockade of the 5-HT2 receptors for serotonin syndrome is 20 to 30 mg. [29] Besides its activity at neurotransmitter targets, cyproheptadine has been reported to possess weak antiandrogenic activity. [32]

Pharmacokinetics

Cyproheptadine is well-absorbed following oral ingestion, with peak plasma levels occurring after 1 to 3 hours. [33] Its terminal half-life when taken orally is approximately 8 hours. [4]

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 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. [34] 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. [35]

There have been some trials to see if cyproheptadine could reduce sexual dysfunction caused by SSRI and antipsychotic medications. [36]

Cyproheptadine has been studied for the treatment of post-traumatic stress disorder. [35]

Veterinary use

Cyproheptadine is used in cats as an appetite stimulant [37] [38] : 1371  and as an adjunct in the treatment of asthma. [39] Possible adverse effects include excitement and aggressive behavior. [40] The elimination half-life of cyproheptadine in cats is 12 hours. [39]

Cyproheptadine is a second line treatment for pituitary pars intermedia dysfunction in horses. [41] [42]

Related Research Articles

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<span class="mw-page-title-main">Haloperidol</span> Typical antipsychotic medication

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References

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  6. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
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  38. ↑ Gupta RC, ed. (2012). Veterinary Toxicology : Basic and Clinical Principles (2 ed.). Amsterdam Boston: Academic Press. pp. xii+1438. ISBN   978-0-12-385926-6. OCLC   794491298.
  39. 1 2 Dowling PM (8 February 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   978-0-911910-50-6. Retrieved on 26 October 2008.
  40. ↑ Dowling PM (8 February 2005). "Drugs Affecting Appetite". In Kahn CM, Line S, Aiello SE (eds.). The Merck Veterinary Manual (9th ed.). John Wiley & Sons. ISBN   978-0-911910-50-6. Retrieved on 26 October 2008.
  41. ↑ 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.
  42. ↑ Kritchevsky JE (July 2019). "Hirsutism Associated with Adenomas of the Pars Intermedia". Merck Vet Manual. Retrieved 24 April 2011.
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