It was firstmade byUnion Chimique Belge in 1956 and was approved for sale byPfizer in the United States later that year.[11][13] In 2023, it was the 39th most commonly prescribed medication in the United States, with more than 15million prescriptions.[14][15]
Doses of hydroxyzine hydrochloride used for sleep range from 25 to 100 mg.[18][19][20] As with other antihistamine sleep aids, hydroxyzine is usually only prescribed for short term or "as-needed" use sincetolerance to thecentral nervous system (CNS) effects of hydroxyzine can develop in as little as a few days.[21][non-primary source needed] A major systematic review andnetwork meta-analysis of medications for the treatment ofinsomnia published in 2022 found little evidence to inform the use of hydroxyzine for insomnia.[22] A 2023 meta-review concludes that hydroxyzine is effective for inducingsleep onset but less effective for maintaining sleep for eight hours.[23]
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 ashypogonadism with doses significantly above that of the human therapeutic range.[25][better source needed]
In humans, a significant dose has not yet been established in studies, and, by default, the USFood and Drug Administration (FDA) has introduced contraindication guidelines regarding hydroxyzine.[25] Use by those at risk for or showing previous signs ofhypersensitivity is also contraindicated.[25]
Other contraindications include the administration of hydroxyzine alongsidedepressants and other compounds that affect thecentral nervous system;[25] if necessary, it should only be administered concomitantly in small doses.[25] 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.[25]
Studies have also been conducted which show that long-term prescription of hydroxyzine can lead totardive dyskinesia after years of use, but effects related todyskinesia have also anecdotally been reported after periods of 7.5 months,[26] such as continual head rolling, lip licking, and other forms ofathetoid movement. In certain cases, elderly patients' previous interactions withphenothiazine derivatives or pre-existingneuroleptic treatment may have contributed to dyskinesia at the administration of hydroxyzine due to hypersensitivity caused by prolonged treatment,[26] and therefore some contraindication is given for short-term administration of hydroxyzine to those with previous phenothiazine use.[26]
Central nervous system effects such ashallucinations orconfusion have been observed in rare cases, attributed mostly to overdosage.[28][27] 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 ofhallucinogenic effects from use 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 aslithium orethanol.[29]
Hydroxyzine exhibitsanxiolytic andsedative properties 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 acutehypnotic, reducingsleep onset latency and increasing sleep duration—also showing that some drowsiness did occur. This was observed more in female patients, who also had greater hypnotic responses.[30] 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.[31][28]
Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly.[32]
Hydroxyzine crosses theblood–brain barrier easily and exerts effects in thecentral nervous system.[42] Apositron emission tomography (PET) study found that brain occupancy of the H1 receptor was 67.6% for a single 30 mg dose of hydroxyzine.[48] In addition, subjective sleepiness correlated well with the brain H1 receptor occupancy.[48] PET studies with antihistamines have found that brain H1 receptor occupancy of more than 50% is associated with a high prevalence ofsomnolence andcognitive decline, whereas brain H1 receptor occupancy of less than 20% is considered to be non-sedative.[49]
Hydroxyzine can be administered orally or via intramuscular injection. In both cases it is rapidly absorbed and distributed. It is metabolized in the liver and the main metabolite (45%),cetirizine is formed through oxidation of the alcohol moiety to a carboxylic acid byalcohol dehydrogenase. 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-dialyzable and possesses similar antihistamine properties. Metabolites identified include anN-dealkylated metabolite and anO-dealkylated 1/16 metabolite with a plasma half-life of 59 hours. These pathways are mediated principally byCYP3A4 andCYP3A5.[51][52] The N-dealykylated metabolite, norchlorcyclizine, bears some structural similarities totrazodone, but it has not been established whether it is pharmacologically active.[53][54] In animals, hydroxyzine and its metabolites are excreted in feces primarily through biliary elimination.[55][56] In rats, less than 2% of the drug is excreted unchanged.[56]
The time to reach maximum concentration (Tmax) of hydroxyzine is about 2.0 hours in both adults and children and itselimination half-life is around 20.0 hours in adults (mean age 29.3 years) and 7.1 hours in children.[8][9] Its elimination half-life is shorter in children compared to adults.[8] In another study, the elimination half-life of hydroxyzine in elderly adults was 29.3 hours.[10] 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.[57] 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.[58]
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.[28][better source needed]
Hydroxyzine is supplied mainly as adihydrochloridesalt (hydroxyzine hydrochloride) but also to a lesser extent as anembonate salt (hydroxyzine pamoate).[59][60][61] Themolecular weights of hydroxyzine, hydroxyzine dihydrochloride, and hydroxyzine pamoate are 374.9 g/mol, 447.8 g/mol, and 763.3 g/mol, respectively.[7] Due to their differences in molecular weight, 1 mg hydroxyzine dihydrochloride is equivalent to about 1.7 mg hydroxyzine pamoate.[62]
Hydroxyzinepreparations require adoctor's prescription. The drug is available in twoformulations, thepamoate and thedihydrochloride orhydrochloridesalts. 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.
^abSimons KJ, Watson WT, Chen XY, Simons FE (January 1989). "Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly".Clinical Pharmacology and Therapeutics.45 (1):9–14.doi:10.1038/clpt.1989.2.PMID2562944.S2CID24571876.
^Matheson E, Hainer BL (July 2017). "Insomnia: Pharmacologic Therapy".American Family Physician.96 (1):29–35.PMID28671376.
^Lippmann S, Yusufzie K, Nawbary MW, Voronovitch L, Matsenko O (2003). "Problems with sleep: what should the doctor do?".Comprehensive Therapy.29 (1):18–27.doi:10.1007/s12019-003-0003-x.PMID12701339.S2CID1508856.
^Levander S, Ståhle-Bäckdahl M, Hägermark O (1 September 1991). "Peripheral antihistamine and central sedative effects of single and continuous oral doses of cetirizine and hydroxyzine".European Journal of Clinical Pharmacology.41 (5):435–439.doi:10.1007/BF00626365.PMID1684750.S2CID25249362.
^Alford C, Rombaut N, Jones J, Foley S, Idzikowski C, Hindmarch I (1992). "Acute effects of hydroxyzine on nocturnal sleep and sleep tendency the following day: A C-EEG study".Human Psychopharmacology.7 (1):25–35.doi:10.1002/hup.470070104.S2CID143580519.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved14 August 2017.
^abcdefgSnowman AM, Snyder SH (December 1990). "Cetirizine: actions on neurotransmitter receptors".The Journal of Allergy and Clinical Immunology.86 (6 Pt 2):1025–1028.doi:10.1016/S0091-6749(05)80248-9.PMID1979798.
^abLim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R (September 2005). "Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist".The Journal of Pharmacology and Experimental Therapeutics.314 (3):1310–1321.doi:10.1124/jpet.105.087965.PMID15947036.S2CID24248896.
^Anthes JC, Gilchrest H, Richard C, Eckel S, Hesk D, West RE, et al. (August 2002). "Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) receptor".European Journal of Pharmacology.449 (3):229–237.doi:10.1016/s0014-2999(02)02049-6.PMID12167464.
^Cusack B, Nelson A, Richelson E (May 1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds".Psychopharmacology.114 (4):559–565.doi:10.1007/bf02244985.PMID7855217.S2CID21236268.
^Orzechowski RF, Currie DS, Valancius CA (January 2005). "Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models".European Journal of Pharmacology.506 (3):257–264.doi:10.1016/j.ejphar.2004.11.006.PMID15627436.
^Lamberty Y, Gower AJ (September 2004). "Hydroxyzine prevents isolation-induced vocalization in guinea pig pups: comparison with chlorpheniramine and immepip".Pharmacology, Biochemistry, and Behavior.79 (1):119–124.doi:10.1016/j.pbb.2004.06.015.PMID15388291.S2CID23593514.
^abTashiro M, Kato M, Miyake M, Watanuki S, Funaki Y, Ishikawa Y, et al. (October 2009). "Dose dependency of brain histamine H(1) receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C]doxepin".Human Psychopharmacology.24 (7):540–548.doi:10.1002/hup.1051.PMID19697300.S2CID5596000.
^Yanai K, Tashiro M (January 2007). "The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies".Pharmacology & Therapeutics.113 (1):1–15.doi:10.1016/j.pharmthera.2006.06.008.PMID16890992.
^Foye WO, Lemke TL, Williams DA (2013).Foye's principles of medicinal chemistry (7th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.ISBN978-1-60913-345-0.OCLC748675182.
^Thavundayil JX, Hambalek R, Kin NM, Krishnan B, Lal S (1994). "Prolonged penile erections induced by hydroxyzine: possible mechanism of action".Neuropsychobiology.30 (1):4–6.doi:10.1159/000119126.PMID7969858.
^Malcolm MJ, Cody TE (January 1994). "Hydroxyzine and Possible Metabolites".Canadian Society of Forensic Science Journal.27 (2):87–92.doi:10.1080/00085030.1994.10757029.
