Cyproheptadine

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

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
  • AU: S3 (Pharmacist only)
  • CA: OTC
  • UK: General sales list (GSL, OTC)
  • US: ℞-only
  • In general: Over-the-counter (OTC)
Pharmacokinetic data
Protein binding96 to 99%
MetabolismHepatic,[2][3] mostly CYP3A4 mediated.
Elimination half-life8.6 hours[4]
ExcretionFaecal (2–20%; of which, 34% as unchanged drug) and renal (40%; none as unchanged drug)[2][3]
Identifiers
IUPAC name
  • 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 InfoCard100.004.482
Chemical and physical data
FormulaC21H21N
Molar mass287.406 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 Y
  • Key:JJCFRYNCJDLXIK-UHFFFAOYSA-N Y
  (verify)

It was patented in 1959 and came into medical use in 1961.[5]

Medical uses
Periactin (cyproheptadine) 4 mg tablets
Cyproheptadine's 3D molecular structure represented as Space-filling model

Cyproheptadine is used to treat allergic reactions (specifically hay fever).[6] The evidence for its use for this purpose indicates its effectiveness but second generation antihistamines such as ketotifen and loratadine have shown equal results with fewer side effects.[7]

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.[7][8] 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.[9]

Cyproheptadine is sometimes used off-label to improve akathisia in people on antipsychotic medications.[10]

It is used off-label to treat various dermatological conditions, including psychogenic itch[11] drug-induced hyperhidrosis (excessive sweating),[12] and prevention of blister formation for some people with epidermolysis bullosa simplex.[13]

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.[14][15][16][17]

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.[18][19]

Cyproheptadine has sedative effects and can be used to treat insomnia similarly to other centrally-acting antihistamines.[20][21][22][23] The recommended dose for this use is 4 to 8 mg.[21]

Adverse effects

Adverse effects include:[2][3]

  • 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
  • Diaphoresis
  • 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:
  • Epigastric distress
  • Anorexia
  • Nausea
  • Vomiting
  • Diarrhea
  • Anticholinergic side effects such as:
    • 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
  • 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.[2][3]

Pharmacology

Pharmacodynamics
Cyproheptadine[25]
Site Ki (nM)[lower-alpha 1] Action[lower-alpha 2] Species Ref.
H10.06↓Human
H2NDND
H3>10,000Human
H4202Human
M112↓Human
M27↓Human
M312↓Human
M48↓Human
M511.8↓Human
5-HT1A59↓Human
5-HT2A1.67↓Human
5-HT2B1.54↓Human
5-HT2C2.23↓Human
5-HT3228Mouse
5-HT6142Human
5-HT7123Human
D1117Human
D2112↓Human
D38Human
SERT4,100Rat
NET290Rat
DATNDND
  1. The smaller the equilibrium constant, the more strongly the drug binds to the site.
    • ↑ 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.[26] However, it is possible that blockade of 5-HT1 receptors may also contribute to its effectiveness in serotonin syndrome.[27] 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).[28] The dose of cyproheptadine recommended to ensure blockade of the 5-HT2 receptors for serotonin syndrome is 20 to 30 mg.[26] Besides its activity at neurotransmitter targets, cyproheptadine has been reported to possess weak antiandrogenic activity.[29]

Pharmacokinetics

Cyproheptadine is well-absorbed following oral ingestion, with peak plasma levels occurring after 1 to 3 hours.[30] 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.[31] 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.[32]

There have been some trials to see if cyproheptadine could reduce sexual dysfunction caused by SSRI and antipsychotic medications.[33]

Cyproheptadine has been studied for the treatment of posttraumatic stress disorder.[32]

Veterinary use

Cyproheptadine is used in cats as an appetite stimulant[34][35]: 1371  and as an adjunct in the treatment of asthma.[36] Possible adverse effects include excitement and aggressive behavior.[37] The elimination half-life of cyproheptadine in cats is 12 hours.[36]

Cyproheptadine is a second line treatment for pituitary pars intermedia dysfunction in horses.[38][39]

References
  1. "Cyproheptadine". Dictionary.com Unabridged (Online). n.d.
  2. "CYPROHEPTADINE HYDROCHLORIDE tablet [Boscogen, Inc.]" (PDF). DailyMed. Boscogen, Inc. November 2010. Retrieved 26 October 2013.
  3. "PRODUCT INFORMATION PERIACTIN® (cyproheptadine hydrochloride)" (PDF). Aspen Pharmacare Australia. Aspen Pharmacare Australia Pty Ltd. 17 November 2011. Archived from the original (PDF) on 29 October 2013. Retrieved 26 October 2013.
  4. 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. S2CID 20196551.
  5. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 547. ISBN 9783527607495.
  6. MedlinePlus Drug Information: Cyproheptadine
  7. 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. S2CID 21185048.
  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. S2CID 34703034.
  9. 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.
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  13. So, Jodi Y.; Teng, Joyce (1993). "Epidermolysis Bullosa Simplex". GeneReviews®. University of Washington, Seattle. PMID 20301543.
  14. Ciproheptadina, estimulante del apetito (Cyproheptadine, appetite stimulant)
  15. "Bioplex NF". Archived from the original on 2018-04-18. Retrieved 2018-04-18.
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