Cyproheptadine

Cyproheptadine

Systematic (IUPAC) name
4-(5H-dibenzo [a,d]cyclohepten-5-ylidene)-1-methylpiperidine hydrochloride
Clinical data
Trade names	Periactin
AHFS/Drugs.com	monograph
MedlinePlus	a682541
License data	US DailyMed: 54686520-506f-7765-7220-436f736d6963
Pregnancy category	AU: A US: B (No risk in non-human studies)
Routes of administration	Oral
Legal status
Legal status	AU: S3 (Pharmacist only) CA: OTC UK: OTC
Pharmacokinetic data
Protein binding	96 to 99%
Metabolism	Hepatic.[1][2] Mostly CYP3A4 meditated.
Biological half-life	8.6 hours[3]
Excretion	Faecal (2-20%; 34% of this as unchanged drug) and renal (40%; none as unchanged drug)[1][2]
Identifiers
CAS Number	129-03-3 969-33-5 (hydrochloride)
ATC code	R06AX02 (WHO)
PubChem	CID 2913
IUPHAR/BPS	277
DrugBank	DB00434
ChemSpider	2810
UNII	2YHB6175DO
KEGG	D07765
ChEBI	CHEBI:4046
ChEMBL	CHEMBL516
Chemical data
Formula	C21H21N
Molar mass	287.398 g/mol
SMILES c43\C(=C1/CCN(C)CC1)c2ccccc2\C=C/c3cccc4
InChI 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 Key:JJCFRYNCJDLXIK-UHFFFAOYSA-N
(verify)

Cyproheptadine (/ˌsaɪproʊˈhɛptədiːn/^[4][5]), sold under the brand name Periactin or Peritol, 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).^[6] It is also used to treat vasomotor mucosal edema, including vasomotor rhinitis and edema of the throat.
• It has shown effectiveness in the treatment of nightmares, including those related to post-traumatic stress disorder.^[7][8]
• It has been used in the management of moderate to severe cases of serotonin syndrome, a complex of symptoms associated with the use of serotonergic drugs,^[9] such as selective serotonin reuptake inhibitors and monoamine oxidase inhibitors),^[10][11][12] and in cases of high levels of serotonin in the blood resulting from a serotonin-producing carcinoid tumor.^[13][14]
• It can also be used as a preventive measure against migraine in children and adolescents.^{[15][16][17][18][19]} In Australia this is the only indication for which cyproheptadine is subsidised by the PBS.^[9]
• It can relieve SSRI-induced sexual dysfunction^[20] and drug-induced hyperhidrosis (excessive sweating).^[21]
• It is also used in the treatment of cyclical vomiting syndrome^[22]
• Use of the drug can stimulate the appetite and may lead to weight gain, which is helpful for underweight people.^[23]
• According to a small study, cyproheptadine hydrochloride has been found to improve sleep, calmness, and mood and energy levels, and to improve both negative and (sometimes even) positive psychotic symptoms in a subgroup of chronic schizophrenics who did not respond (either completely or sufficiently) to other therapies.^[24]
• Cyproheptadine may improve akathisia in patients on antipsychotic medications.^[25]
• In clinical trials in which cyproheptadine was used as an adjunct to antipsychotic treatment for patients with schizophrenia, an improvement in negative symptoms was seen.^[26]

Adverse effects

Adverse effects include^[1][2]

• 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

- Hepatic function abnormality

• 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

Research has shown a suppression of growth hormone with doses of 8–12 mg per day taken for 5 days.^[27]

Overdose

Supportive measures such as gastric lavage or induced emesis are usually 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.^[1][2]

Pharmacology

Cyproheptadine is known to be an antagonist (or inverse agonist depending on the site in question) of the receptors listed in the table below.

Receptor/Transporter Protein	Binding affinity (Ki[nM]) towards cloned human receptors unless otherwise specified[28]
SERT	4100 (RC)
NET	290 (RC)
5-HT1A	59
5-HT2A	1.67
5-HT2B	1.54
5-HT2C	2.23
5-HT3	228 (MN)
5-HT6	142
5-HT7	123.01
M1	12
M2	7
M3	12
M4	8
M5	11.8
D1	117
D2	112
D3	8
H1	0.06
H3	>10000
H4	201.5

Acronyms used:
RC - Cloned rat receptor.
MN - Mouse NG108-15 receptor.

Pharmacokinetics

Cyproheptadine is well-absorbed following oral ingestion, with peak plasma levels occurring after 1–3 hours.^[29] Its half-life when taken orally is approximately 8 hours.^[3]

Veterinary use

Cyproheptadine is used in cats as an appetite stimulant and as an adjunct in the treatment of asthma.^[30][31] Possible adverse effects include excitement and aggressive behavior.^[30] The elimination half-life of cyproheptadine in cats is 12 hours.^[31]

Cyproheptadine has been used successfully in treatment of pituitary pars intermedia dysfunction in horses.^[32]

See also

• Benzocycloheptenes
• Pizotifen
• Toll-like receptor 4 investigating probable antagonistic (antiinflammatory) property of several TCA based molecules
• Pimethixene

References

1. "CYPROHEPTADINE HYDROCHLORIDE tablet [Boscogen, Inc.]" (PDF). DailyMed. Boscogen, Inc. November 2010. Retrieved 26 October 2013.
2. "PRODUCT INFORMATION PERIACTIN® (cyproheptadine hydrochloride)" (PDF). Aspen Pharmacare Australia. Aspen Pharmacare Australia Pty Ltd. 17 November 2011. Retrieved 26 October 2013.
3. 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.
4. "Cyproheptadine". Dictionary.com Unabridged. Random House.
5. "Cyproheptadine". Merriam-Webster Dictionary.
6. MedlinePlus Drug Information: Cyproheptadine
7. Rijnders, R. J.P.; Laman, DM; Van Diujn, H (2000). "Cyproheptadine for Posttraumatic Nightmares". American Journal of Psychiatry 157 (9): 1524–a. doi:10.1176/appi.ajp.157.9.1524-a. PMID 10964879.
8. Gupta, S; Popli, A; Bathurst, E; Hennig, L; Droney, T; Keller, P (May 1998). "Efficacy of cyproheptadine for nightmares associated with posttraumatic stress disorder". Comprehensive Psychiatry 39 (3): 160–4. doi:10.1016/S0010-440X(98)90076-1. ISSN 0010-440X. PMID 9606583.
9. Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
10. Mills KC (October 1995). "Serotonin syndrome". American Family Physician 52 (5): 1475–82. PMID 7572570.
11. Gillman PK (1999). "The serotonin syndrome and its treatment". Journal of Psychopharmacology (Oxford, England) 13 (1): 100–9. doi:10.1177/026988119901300111. PMID 10221364.
12. Hall M, Buckley N (2003). "Serotonin syndrome". Australian Prescriber 26 (3): 62–3.
13. Berry EM, Maunder C, Wilson M (January 1974). "Carcinoid myopathy and treatment with cyproheptadine (Periactin)". Gut 15 (1): 34–8. doi:10.1136/gut.15.1.34. PMC 1412931. PMID 4274414.
14. Moertel, Charles G.; Kvols, LK; Rubin, J (1991). "A study of cyproheptadine in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome". Cancer 67 (1): 33–6. doi:10.1002/1097-0142(19910101)67:1<33::AID-CNCR2820670107>3.0.CO;2-E. PMID 1985720.
15. Wendy G Mitchell; et al. (2006). "Childhood Migraine Variants".
16. UVA Neurogram: Treatment of Pediatric Migraine
17. Netdoctor: Periactin
18. Migraines in Children and Adolescents
19. Klimek A (1979). "Cyproheptadine (Peritol) in the treatment of migraine and related headache". Ther Hung 27 (2): 93–4. PMID 494146.
20. Cohen AJ (June 1992). "Fluoxetine induced yawning and anorgasmia reversed by cyproheptadine treatment". The Journal of Clinical Psychiatry 53 (5): 174. PMID 1592848.
21. 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.
22. Andersen JM, Sugerman KS, Lockhart JR, Weinberg WA (December 1997). "Effective Prophylactic Therapy for Cyclic Vomiting Syndrome in Children Using Amitriptyline or Cyproheptadine". Pediatrics 100 (6): 977–981. doi:10.1542/peds.100.6.977. PMID 9374568.
23. Long-term trial of cyproheptadine as an appetite stimulant in cystic fibrosis | Wiley Online Library
24. "Cyproheptadine, Human Health Effects". Toxicology Data Network. 2003. Retrieved 8 November 2012.
25. Taylor, D; Paton, C; Shitij, K (2012). Maudsley Prescribing Guidelines in Psychiatry (11th ed.). West Sussex: Wiley-Blackwell. ISBN 978-0-47-097948-8.
26. Silver, H; Blacker, M; Weller, MPI; Lerer, B (February 1989). "Treatment of chronic schizophrenia with cyproheptadine". Biological Psychiatry 25 (4). doi:10.1016/0006-3223(89)90206-0.
27. Rosskamp RH, Haverkamp F, von Kalckreuth G (May 1990). "The effect of cyproheptadine on plasma growth hormone (GH) and on somatostatin response to GH-releasing hormone in man". Horm. Metab. Res. 22 (5): 295–7. doi:10.1055/s-2007-1004905. PMID 1971804.
28. Roth BL, Driscol J (12 January 2011). "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 26 October 2013.
29. 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.
30. 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. Retrieved on October 26, 2008.
31. 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. Retrieved on October 26, 2008.
32. Merck Vet Manual. "Hirsutism Associated with Adenomas of the Pars Intermedia". Retrieved April 24, 2011.