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 names	Periactin, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682541
License data	US DailyMed: Cyproheptadine
Pregnancy category	AU: A
Routes of administration	Oral
ATC code	R06AX02 (WHO)
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 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
IUPAC name 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine
CAS Number	129-03-3 Y 969-33-5 (hydrochloride)
PubChem CID	2913
IUPHAR/BPS	277
DrugBank	DB00434 Y
ChemSpider	2810 Y
UNII	2YHB6175DO
KEGG	D07765 Y
ChEBI	CHEBI:4046 Y
ChEMBL	ChEMBL516 Y
CompTox Dashboard (EPA)	DTXSID8022872
ECHA InfoCard	100.004.482
Chemical and physical data
Formula	C21H21N
Molar mass	287.406 g·mol−1
3D model (JSmol)	Interactive image
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 Y Key:JJCFRYNCJDLXIK-UHFFFAOYSA-N Y
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It was patented in 1959 and came into medical use in 1961.^[5] In 2022, it was the 293rd most commonly prescribed medication in the United States, with more than 400,000 prescriptions.^[6][7]

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).^[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]

• 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:
  • Hepatitis
  • Jaundice
  • Liver failure^[26]
  • 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

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][29]

Site	Ki (nM)[a]	Action[b]	Species	Ref.
5-HT1A	50–59	↓	Human
5-HT1B	1600		Human
5-HT1D	670		Human
5-HT1E	1500		Human
5-HT2A	0.46–3.0	↓	Human
5-HT2B	1.5–2.6	↓	Human
5-HT2C	2.2–18	↓	Human
5-HT3	235		Human
5-HT4	ND		Human
5-HT5A	57		Human
5-HT6	96–150		Human
5-HT7	30–126		Human
D1	10–117		Human
D2	74–112	↓	Human
D3	8		Human
D4	120		Human
D5	60		Human
α1A	45		Human
α1B	>10000		Human
α2A	330		Human
α2B	220		Human
α2C	160		Human
β1	>10000		Human
β2	>10000		Human
H1	0.06–2.3	↓	Human
H2	4.8		Human
H3	>10,000		Human
H4	202–>10,000		Human
M1	12	↓	Human
M2	7	↓	Human
M3	12	↓	Human
M4	8	↓	Human
M5	11.8	↓	Human
I1 receptor	204		Human
σ1 receptor	>10000		Guinea pig
σ2 receptor	750		Rat
SERTTooltip Serotonin transporter	>10000		Human
NETTooltip Norepinephrine transporter	290–2550		Human
DATTooltip Dopamine transporter	4100		Human
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.^[30] However, it is possible that blockade of 5-HT₁ receptors may also contribute to its effectiveness in serotonin syndrome.^[31] 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).^[32] The dose of cyproheptadine recommended to ensure blockade of the 5-HT₂ receptors for serotonin syndrome is 20 to 30 mg.^[30] Besides its activity at neurotransmitter targets, cyproheptadine has been reported to possess weak antiandrogenic activity.^[33]

Pharmacokinetics

Cyproheptadine is well-absorbed following oral ingestion, with peak plasma levels occurring after 1 to 3 hours.^[34] 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.^[35] 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.^[36]

There have been some trials to see if cyproheptadine could reduce sexual dysfunction caused by selective serotonin reuptake inhibitor (SSRI) and antipsychotic medications.^[37]

Cyproheptadine has been studied for the treatment of post-traumatic stress disorder.^[36]

Veterinary use

Cyproheptadine is used in cats as an appetite stimulant^{[38][39]: 1371} and as an adjunct in the treatment of asthma.^[40] Possible adverse effects include excitement and aggressive behavior.^[41] The elimination half-life of cyproheptadine in cats is 12 hours.^[40]

Cyproheptadine is a second line treatment for pituitary pars intermedia dysfunction in horses.^[42][43]