Hydroxyzine,sold under the brand namesAtaraxandVistarilamong others, is anantihistaminemedication.[8]It is used in the treatment ofitchiness,anxiety,insomnia,andnausea(including that due tomotion sickness).[8]It is used eitherby mouthorinjection into a muscle.[8]
Hydroxyzine works by blocking the effects ofhistamine.[9]It is afirst-generation antihistaminein thepiperazinefamily of chemicals.[8][4]Common side effects includesleepiness,headache,anddry mouth.[8][9]Serious side effects may includeQT prolongation.[9]It is unclear if use during pregnancy or breastfeeding is safe.[8]
It was firstmadebyUnion Chimique Belgein 1956 and was approved for sale byPfizerin the United States later that year.[8][10]In 2022, it was the 46th most commonly prescribed medication in the United States, with more than 13million prescriptions.[11][12]
Medical uses
editHydroxyzine is used in the treatment ofitchiness,anxiety,andnauseadue tomotion sickness.[8]
Asystematic reviewconcluded that hydroxyzine outperformsplaceboin treating generalizedanxiety disorder.Insufficient data were available to compare the drug withbenzodiazepinesandbuspirone.[13]
Hydroxyzine can also be used for the treatment ofallergic conditions,such as chronicurticaria,atopicorcontact dermatoses,andhistamine-mediatedpruritus.[medical citation needed]These have also been confirmed in both recent and past studies to have no adverse effects on the liver, blood, nervous system, or urinary tract.[14][better source needed]
Use of hydroxyzine forpremedicationas a sedative has no effects ontropane alkaloids,such asatropine,but may, following general anesthesia, potentiatemeperidineandbarbiturates,and use in pre-anestheticadjunctive therapyshould be modified depending upon the state of the individual.[14]
Doses of hydroxyzine hydrochloride used for sleep range from 25 to 100 mg.[15][16][17]As with other antihistamine sleep aids, hydroxyzine is usually only prescribed for short term or "as-needed" use since tolerance to theCNS(central nervous system) effects of hydroxyzine can develop in as little as a few days.[18][non-primary source needed]A major systematic review andnetwork meta-analysisof medications for the treatment ofinsomniapublished in 2022 found little evidence to inform the use of hydroxyzine for insomnia.[19]A 2023 meta-review concludes that hydroxyzine is effective for inducing sleep onset but less effective for maintaining sleep for eight hours.[20]
Contraindications
editHydroxyzine is contraindicated forsubcutaneousorintra-articularadministration.[21]
The administration of hydroxyzine in large amounts by ingestion or intramuscular administration during the onset of pregnancy can causefetal abnormalities.When administered to pregnant rats, mice, and rabbits, hydroxyzine caused abnormalities such ashypogonadismwith doses significantly above that of the human therapeutic range.[22][better source needed]
In humans, a significant dose has not yet been established in studies, and, by default, theFood and Drug Administration(FDA) has introduced contraindication guidelines regarding hydroxyzine.[22]Use by those at risk for or showing previous signs ofhypersensitivityis also contraindicated.[22]
Other contraindications include the administration of hydroxyzine alongsidedepressantsand other compounds that affect thecentral nervous system;[22]if necessary, it should only be administered concomitantly in small doses.[22]If administered in small doses with other substances, as mentioned, then patients should refrain from using dangerous machinery, motor vehicles, or any other practice requiring absolute concentration, under safety laws.[22]
Studies have also been conducted which show that long-term prescription of hydroxyzine can lead totardive dyskinesiaafter years of use, but effects related todyskinesiahave also anecdotally been reported after periods of 7.5 months,[23]such as continual head rolling, lip licking, and other forms ofathetoidmovement. In certain cases, elderly patients' previous interactions withphenothiazinederivatives or pre-existingneuroleptictreatment may have contributed to dyskinesia at the administration of hydroxyzine due to hypersensitivity caused by prolonged treatment,[23]and therefore some contraindication is given for short-term administration of hydroxyzine to those with previous phenothiazine use.[23]
Side effects
editSeveral reactions have been noted in manufacturer guidelines—deep sleep, incoordination, sedation, calmness, and dizziness have been reported in children and adults, as well as others such ashypotension,tinnitus,and headaches.[24]Gastrointestinaleffects have also been observed, as well as less serious effects such as dryness of the mouth and constipation caused by the mildantimuscarinicproperties of hydroxyzine.[24]
Central nervous system effects such as hallucinations or confusion have been observed in rare cases, attributed mostly to overdosage.[25][24]Such properties have been attributed to hydroxyzine in several cases, particularly in patients treated for neuropsychological disorders, as well as in cases where overdoses have been observed. While there are reports of the "hallucinogenic" or "hypnotic" properties of hydroxyzine, several clinical data trials have not reported such side effects from the sole consumption of hydroxyzine, but rather, have described its overall calming effect described through the stimulation of areas within thereticular formation.The hallucinogenic or hypnotic properties have been described as being an additional effect from overall central nervous system suppression by other CNS agents, such aslithiumorethanol.[26]
Hydroxyzine exhibitsanxiolyticandsedativeproperties in many psychiatric patients. One study showed that patients reported very high levels of subjective sedation when first taking the drug, but that levels of reported sedation decreased markedly over 5–7 days, likely due to CNS receptor desensitization. Other studies have suggested that hydroxyzine acts as an acute hypnotic, reducingsleep onset latencyand increasing sleep duration — also showing that some drowsiness did occur. This was observed more in female patients, who also had greater hypnotic responses.[27]The use of sedating drugs alongside hydroxyzine can cause oversedation and confusion if administered at high doses—any form of hydroxyzine treatment alongside sedatives should be done under the supervision of a doctor.[28][25]
Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly.[29]
Pharmacology
editPharmacodynamics
edit| Site | Ki(nM) | Species | Ref |
|---|---|---|---|
| 5-HT2A | 170 (IC50) | Rat | [31] |
| 5-HT2C | ND | ND | ND |
| α1 | 460 (IC50) | Rat | [31] |
| D1 | 10000+ | Mouse | [32] |
| D2 | 378 560 (IC50) |
Mouse Rat |
[32] [31] |
| H1 | 2.0–19 6.4 100 (IC50) |
Human Bovine Rat |
[33][34][35] [36] [31] |
| H2 | ND | ND | ND |
| H3 | ND | ND | ND |
| H4 | 10000+ | Human | [34] |
| mACh | 4600 10000+ 10000+ (IC50) 6310 (pA2) 3800 |
Human Mouse Rat Guinea pig Bovine |
[37] [32] [31] [38] [36] |
| VDCC | 3400+ (IC50) | Rat | [31] |
| Values are Ki(nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. | |||
Hydroxyzine's predominantmechanism of actionis as apotentandselectivehistamineH1receptorinverse agonist.[39][40]This action is responsible for itsantihistamineandsedativeeffects.[39][40]Unlike many other first-generation antihistamines, hydroxyzine has a loweraffinityfor themuscarinic acetylcholine receptors,and in accordance, has a lower risk ofanticholinergicside effects.[36][40][41][42]In addition to its antihistamine activity, hydroxyzine has also been shown to act more weakly as anantagonistof theserotonin5-HT2Areceptor,thedopamineD2receptor,and theα1-adrenergic receptor.[31][39]Similarly to theatypical antipsychotics,the comparably weakantiserotonergiceffects of hydroxyzine likely underlie its usefulness as ananxiolytic.[43]Other antihistamines without such properties have not been found to be effective in the treatment ofanxiety.[44]
Hydroxyzine crosses theblood–brain barriereasily and exerts effects in thecentral nervous system.[39]Apositron emission tomography(PET) study found that brain occupancy of the H1receptor was 67.6% for a single 30 mg dose of hydroxyzine.[45]In addition, subjective sleepiness correlated well with the brain H1receptor occupancy.[45]PET studies with antihistamines have found that brain H1receptor occupancy of more than 50% is associated with a high prevalence ofsomnolenceandcognitive decline,whereas brain H1receptor occupancy of less than 20% is considered to be non-sedative.[46]
Hydroxyzine also acts as a functional inhibitor ofacid sphingomyelinase.[47]
Pharmacokinetics
editHydroxyzine can be administered orally or via intramuscular injection. When given orally, hydroxyzine is rapidly absorbed from the gastrointestinal tract. Hydroxyzine is rapidly absorbed and distributed with oral and intramuscular administration, and is metabolized in the liver; the main metabolite (45%),cetirizine,is formed through oxidation of the alcohol moiety to a carboxylic acid byalcohol dehydrogenase,and overall effects are observed within one hour of administration. Higher concentrations are found in the skin than in the plasma. Cetirizine, although less sedating, is non-dialyzableand possesses similar antihistamine properties. The other metabolites identified include aN-dealkylated metabolite, and anO-dealkylated 1/16 metabolite with a plasma half-life of 59 hours. These pathways are mediated principally byCYP3A4andCYP3A5.[48][49]The N-dealykylated metabolite, norchlorcyclizine, bears some structural similarities totrazodone,but it has not been established whether it is pharmacologically active.[50][51]In animals, hydroxyzine and its metabolites are excreted in feces primarily through biliary elimination.[52][53]In rats, less than 2% of the drug is excreted unchanged.[53]
The time to reach maximum concentration (Tmax) of hydroxyzine is about 2.0 hours in both adults and children and itselimination half-lifeis around 20.0 hours in adults (mean age 29.3 years) and 7.1 hours in children.[5][6]Its elimination half-life is shorter in children compared to adults.[5]In another study, the elimination half-life of hydroxyzine in elderly adults was 29.3 hours.[7]One study found that the elimination half-life of hydroxyzine in adults was as short as 3 hours, but this may have just been due to methodological limitations.[54]Although hydroxyzine has a long elimination half-life and acts, in-vivo, as an antihistamine for as long as 24 hours, the predominant CNS effects of hydroxyzine and other antihistamines with long half-lives seem to diminish after 8 hours.[55]
Administration in geriatrics differs from the administration of hydroxyzine in younger patients; according to the FDA, there have not been significant studies made (2004), which include population groups over 65, which provide a distinction between elderly aged patients and other younger groups. Hydroxyzine should be administered carefully in the elderly with consideration given to possible reduced elimination.[25][better source needed]
Chemistry
editHydroxyzine is a member of thediphenylmethylpiperazineclass of antihistamines.[medical citation needed]
Hydroxyzine is supplied mainly as adihydrochloridesalt(hydroxyzine hydrochloride) but also to a lesser extent as anembonatesalt (hydroxyzine pamoate).[56][57][58]Themolecular weightsof hydroxyzine, hydroxyzine dihydrochloride, and hydroxyzine pamoate are 374.9 g/mol, 447.8 g/mol, and 763.3 g/mol, respectively.[4]Due to their differences in molecular weight, 1 mg hydroxyzine dihydrochloride is equivalent to about 1.7 mg hydroxyzine pamoate.[59]
Analogues
editAnaloguesof hydroxyzine includebuclizine,cetirizine,cinnarizine,cyclizine,etodroxizine,meclizine,andpipoxizineamong others.
Society and culture
editBrand names
editHydroxyzinepreparationsrequire adoctor's prescription.The drug is available in twoformulations,thepamoateand thedihydrochlorideorhydrochloridesalts.Vistaril, Equipose, Masmoran, and Paxistil are preparations of the pamoate salt, while Atarax, Alamon, Aterax, Durrax, Tran-Q, Orgatrax, Quiess, and Tranquizine are of the hydrochloride salt.
See also
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