5-HT₂ Receptor

Cyproheptadine, a 5-HT2A receptor antagonist, has been shown to counteract serotonin-induced platelet aggregation caused by ADP both in vitro and in vivo, indicating that it has antiplatelet and thromboprotective properties.

Absorption, Distribution and Excretion
A single study examining the difference in absorption of orally administered versus sublingually administered cyproheptadine in five healthy males demonstrated a mean Cmax of 30.0 mcg/L and 4.0 mcg/L, respectively, and a mean AUC of 209 mcg.h/L and 25 mcg.h/L, respectively. The Tmax of orally and sublingually administered cyproheptadine was 4 hours and 9.6 hours, respectively.
Approximately 2-20% of the radioactivity from an orally administered radio-labeled dose of cyproheptadine is excreted in the feces, of which approximately 34% is unchanged parent drug (less than 5.7% of the total dose). At least 40% of radioactivity is recovered in the urine.
H1 antagonists are eliminated more rapidly by children than by adults and more slowly in those with severe liver disease. /H1 Receptor Antagonists/
The H1 antagonists are well absorbed from the gastrointestinal tract. Following oral administration, peak plasma concentrations are achieved in 2 to 3 hours ... . /H1 Receptor Antagonists/
To investigate the pharmacokinetics of cyproheptadine (CPH) and its metabolites, the plasma concn and urinary excretion of CPH and its detectable metabolites were determined after iv admin of parent or synthesized metabolites to rats. The plasma CPH concn time course was subjected to biexponential calculation following the iv admin of CPH, producing the temporal and low plasma concn of desmethylcyproheptadine (DMCPH) and the sustained plasma concn of desmethylcyproheptadine epoxide (DMCPHepo). DMCPH was also eliminated according to the biexponential equation, after iv admin of performed DMCPH, forming DMCPHepo in plasma. On the other hand, no detectable DMCPHepo was found in plasma after the iv admin of cyproheptadine epoxide (CPHepo). All cmpd administered had large distribution volumes and were most entirely excreted as DMCPHepo in urine; this excretion continued for a long time. However, the urinary excretion pattern of DMCPHepo after CPHepo was different from those after CPH and MCPH. The mean residence times of the epoxidized metabolites estimated from the urinary data were much longer than those from the plasma concn data, suggesting either a gradual reflux of the metabolites from a tissue depot into systemic circulation under those plasma concn close of detection limit, or one interaction which delays excretion into the urine. This study suggests that both metabolic pathways of CPH, through DMCPH nd CPHepo, to DMCPHepo are possible, but that the demethylation largely occurs prior to epoxidation; also that the extensive and persistent distribution of DMCPHepo to tissues may relate to the toxicity of CPH reported in rats.
Twelve diphenhydramine and cyproheptadine derivatives were synthesized and screened for Hl-receptor antagonist activity at the isolated guinea pig ileum and for H2-receptor antagonist activity at the isolated guinea pig right atrium. The cmpd showed high Hl- and H2-receptor antagonist activity. The incorporation of the diphenhydramine and cyproheptadine components provided high affinity to Hl-receptors. All compounds elicited a dual mode of competitive and noncompetitive antagonism. The nitroethenediamines with 4-fluoro-4-methyl-substituted diphenhydramine as the Hl-receptor antagonist moiety displayed the most potent Hl- and H2-receptor antagonist effects.
The blood brain barrier transport system for Hl-antagonists was studied using primary cultured bovine brain capillary endothelial cells to study the effects of five H1-antagonists (azelastine, ketotifen, cyproheptadine, emedastine, and cetirizine) on the uptake of radiolabeled mepyramine (pyrilamine). The uptake of mepyramine was inhibited by various H1-antagonists. Ketotifen competitively inhibited mepyramine uptake, and lipophilic basic drugs significantly inhibited mepyramine uptake. The results indicated that H1-antagonists are transported across the blood brain barrier via a carrier mediated transport system common to lipophilic basic drugs.

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Metabolism / Metabolites
The principal metabolite found in human urine has been identified as a quaternary ammonium glucuronide conjugate of cyproheptadine.
In humans, the metabolism of a number of tertiary amine containing pharmacological agents to quaternary ammonium linked glucuronides, catalyzed by UDP-glucuronosyltransferase (UGT), represents a unique and important metabolic pathway for these compounds. A full length cDNA encoding human UGTl.4 (the so-called minor human bilirubin UGT) was inserted into the expression vector pREP9 and transfected into human embryonic kidney 293 cells, and stable transfectants were obtained after geneticin selection. As expected, the expressed protein had low catalytic activity toward bilirubin. However, expressed human UGTl.4 protein exhibited glucuronidation activity toward tertiary amine substrates, such as imipramine, cyproheptadine, tripelennamine, and chlorpromazine, which form quaternary ammonium linked glucuronides. Carcinogenic primary amines (beta-naphthylamine, benzidine, and 4-aminobiphenyl) also reacted with the expressed UGTl.4 protein at rates approximately 10-fold higher than the rates for quaternary ammonium glucuronide formation. Although a number of other UGT gene products are capable of catalyzing the glucuronidation of primary amine substrates, expressed human UGTl.4 protein is the only UGT isoform that has been shown to conjugate tertiary amine substrates, forming quaternary ammonium linked glucuronides.
Cyproheptadine has known human metabolites that include Cyproheptadine N-glucuronide.
Hepatic (cytochrome P-450 system) and some renal.
Route of Elimination: After a single 4 mg oral dose of14C-labelled cyproheptadine HCl in normal subjects, given as tablets 2% to 20% of the radioactivity was excreted in the stools. At least 40% of the administered radioactivity was excreted in the urine.

Toxicity Summary
Cyproheptadine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding. Cyproheptadine also competes with serotonin at receptor sites in smooth muscle in the intestines and other locations. Antagonism of serotonin on the appetite center of the hypothalamus may account for Cyproheptadine's ability to stimulate appetite.

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Hepatotoxicity
Unlike most first generation antihistamines, cyproheptadine has been associated with several instances of clinically apparent liver injury. The few cases that have been described had a time to onset of 1 to 6 weeks and a cholestatic or mixed pattern of liver enzyme elevations. Immunoallergic and autoimmune features were not present and most patients recovered rapidly without residual. Acute liver failure due to cyproheptadine has not been described.
Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Unless it is intentionally being used to lower maternal serum prolactin levels, cyproheptadine should be avoided during lactation because it may interfere with lactation, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. The nonsedating antihistamines are preferred alternatives.
◉ Effects in Breastfed Infants
Relevant published information on cyproheptadine was not found as of the revision date. In one telephone follow-up study, mothers reported irritability and colicky symptoms 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention and none of the infants were exposed to cyproheptadine.
◉ Effects on Lactation and Breastmilk
Cyproheptadine 16 to 24 mg daily lowers serum prolactin in the treatment of amenorrhea-galactorrhea syndrome because of its antiserotonin activity. Additionally, antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of cyproheptadine has the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Interactions
Concurrent use may potentiate the CNS depressant effects of either these medications /alcohol or other CNS depression-producing medications/ or antihistamines; also, concurrent use of maprotiline or tricyclic antidepressants may potentiate the anticholinergic effects of either antihistamines or these medications. /Antihistamines/
Anticholinergic effects may be potentiated when these medications /anticholinergics or other medications with anticholinergic activity/ are used concurrently with antihistamines; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. /Antihistamines/
Concurrent use of monoamine oxidase (MAO) inhibitors with antihistamines may prolong the intensify the anticholinergic and CNS depressant effects of antihistamines; concurrent use is not recommended. /Antihistamines/
Concurrent use /of ototoxic medications/ with antihistamines may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo. /Antihistamines/
For more Interactions (Complete) data for CYPROHEPTADINE (12 total), please visit the HSDB record page.

[1]. J Anal Toxicol . 1998 Jan-Feb;22(1):72-4.

[2]. PLoS One . 2014 Jan 23;9(1):e87026.

Cyproheptadine is the product resulting from the formal oxidative coupling of position 5 of 5H-dibenzo[a,d]cycloheptene with position 4 of 1-methylpiperidine resulting in the formation of a double bond between the two fragments. It is a sedating antihistamine with antimuscarinic and calcium-channel blocking actions. It is used (particularly as the hydrochloride sesquihydrate) for the relief of allergic conditions including rhinitis, conjunctivitis due to inhalant allergens and foods, urticaria and angioedema, and in pruritic skin disorders. Unlike other antihistamines, it is also a seratonin receptor antagonist, making it useful in conditions such as vascular headache and anorexia. It has a role as a H1-receptor antagonist, a serotonergic antagonist, an antipruritic drug, an anti-allergic agent and a gastrointestinal drug. It is a member of piperidines and a tertiary amine.
Cyproheptadine is a potent competitive antagonist of both serotonin and histamine receptors. It is used primarily to treat allergic symptoms, though it is perhaps more notable for its use in appetite stimulation and its off-label use in the treatment of serotonin syndrome.
Cyproheptadine is a first generation antihistamine used in the treatment of allergic rhinitis and urticaria and as an appetite stimulant. Cyproheptadine has been linked to rare instances of clinically apparent liver injury.
Cyproheptadine is only found in individuals that have used or taken this drug. It is a serotonin antagonist and a histamine H1 blocker used as antipruritic, appetite stimulant, antiallergic, and for the post-gastrectomy dumping syndrome, etc. Cyproheptadine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding. Cyproheptadine also competes with serotonin at receptor sites in smooth muscle in the intestines and other locations. Antagonism of serotonin on the appetite center of the hypothalamus may account for Cyproheptadine's ability to stimulate appetite.
A serotonin antagonist and a histamine H1 blocker used as antipruritic, appetite stimulant, antiallergic, and for the post-gastrectomy dumping syndrome, etc.
See also: Cyproheptadine Hydrochloride (has salt form).

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Drug Indication
In the US, prescription cyproheptadine is indicated for the treatment of various allergic symptomatologies - including dermatographia, rhinitis, conjunctivitis, and urticaria - as well as adjunctive therapy in the management of anaphylaxis following treatment with epinephrine. In Canada, cyproheptadine is available over-the-counter and is indicated for the treatment of pruritus and for appetite stimulation. In Australia, cyproheptadine is additionally indicated for the treatment vascular headaches. Cyproheptadine is also used off-label for the treatment of serotonin syndrome.

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Mechanism of Action
Cyproheptadine appears to exert its antihistamine and antiserotonin effects by competing with free histamine and serotonin for binding at their respective receptors. Antagonism of serotonin on the appetite center of the hypothalamus may account for cyproheptadine's ability to stimulate the appetite.
CYPROHEPTADINE...IS A SEROTONIN & HISTAMINE ANTAGONIST...
... It is an effective H1 blocker. Cyproheptadine also has prominent 5-H blocking activity on smooth muscle by virtue of its binding to 5-HT2A receptors. ... It has weak anticholinergic activity and possess mild central depressant properties.

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Therapeutic Uses
Anti-Allergic Agents; Antipruritics; Gastrointestinal Agents; Histamine H1 Antagonists; Serotonin Antagonists
IT IS EFFECTIVE FOR...PREVENTION OF REACTIONS TO BLOOD OR PLASMA IN PT WITH KNOWN HISTORY OF SUCH REACTIONS, DERMOGRAPHISM, & AS THERAPY FOR ANAPHYLACTIC REACTIONS ADJUNCTIVE TO EPINEPHRINE & OTHER STANDARD MEASURES AFTER ACUTE MANIFESTATIONS HAVE BEEN CONTROLLED. /HCL/
IT IS PROBABLY EFFECTIVE IN MILD, LOCAL REACTIONS TO INSECT BITES, PHYSICAL ALLERGY, & MINOR DRUG & SERUM REACTIONS CHARACTERIZED BY PRURITUS. IT IS POSSIBLY EFFECTIVE IN PRURITUS OF...CONTACT DERMATITIS & PRURITUS OF CHICKEN POX. /HCL/
CYPROHEPTADINE...HAS BEEN REPORTED TO BE EFFECTIVE IN SOME PATIENTS /IN THE PROPHYLAXIS OF MIGRAINE/, BUT RESULTS OF CONTROLLED STUDIES HAVE DEMONSTRATED THAT IT IS ONLY SLIGHTLY BETTER THAN A PLACEBO.
For more Therapeutic Uses (Complete) data for CYPROHEPTADINE (16 total), please visit the HSDB record page.

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Drug Warnings
PERSONS TAKING ANTIHISTAMINES SHOULD BE ALERTED TO THEIR SEDATIVE EFFECTS & SHOULD BE CAUTIONED NOT TO DRIVE AN AUTOMOBILE, FLY AN AIRPLANE, OR OPERATE HAZARDOUS MACHINERY WHILE ON SUCH MEDICATION. /ANTIHISTAMINES/
Potential Adverse Effects On Fetus: No problems in animal studies. Controlled studies not done in humans. Potential Side Effects On Breast-Fed Infant: Not known if secreted. FDA Category: B (B = Studies in laboratory animals have not demonstrated a fetal risk, but there are no controlled studies in pregnant women; or animal studies have shown an adverse effect (other than a decrease in fertility), but controlled studies in pregnant women have not demonstrated a risk to the fetus in the first trimester and there is no evidence of a risk in later trimesters.) /from Table II/
Side effects of cyproheptadine include those common to other H1 antagonist, such as drowsiness. Weight gain and increased growth in children have been observed and been attributed to an interference with regulation of the secretion growth hormone.
Small amounts of antihistamines are distributed into breast milk; use is not recommended in nursing mothers because of the risk of adverse effects, such as unusual excitement or irritability, in infants. /Antihistamines/
For more Drug Warnings (Complete) data for CYPROHEPTADINE (8 total), please visit the HSDB record page.

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Pharmacodynamics
Cyproheptadine has been observed to antagonize several pharmacodynamic effects of serotonin in laboratory animals, including bronchoconstriction and vasodepression, and has demonstrated similar efficacy in antagonizing histamine-mediated effects. The reason for its efficacy in preventing anaphylactic shock has not been elucidated, but appears to be related to its anti-serotonergic effects.

C21H22CLN

323.86

323.144

969-33-5

Cyproheptadine hydrochloride sesquihydrate; 41354-29-4; Cyproheptadine; 129-03-3

2913

White to off-white solid powder

440.1ºC at 760mmHg

112.3-113.3
112.3-113.3 °C
215 - 217 °C

194.5ºC

5.437

0

1

0

22

423

0

C1C=CC=C2/C(=C3\CCN(C)CC\3)/C3=CC=CC=C3C=CC=12.Cl

ZPMVNZLARAEGHB-UHFFFAOYSA-N

InChI=1S/C21H21N.ClH/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;1H

1-methyl-4-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaenylidene)piperidine;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.72 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)