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Hydroxyzine
Clinical data
Pronunciation/haɪˈdrɒksɪziːn/
Trade namesAtarax,[1] Vistaril,[2] others
Other namesUCB-4492
AHFS/Drugs.comMonograph
MedlinePlusa682866
License data
Dependence
liability		None[3]
Routes of
administration		By mouth, intramuscular
Drug classFirst-generation antihistamine[4]
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityHigh
Protein binding93%
MetabolismLiver
MetabolitesCetirizine, others
Elimination half-lifeAdults: 20.0 hours[5][6]
Elderly: 29.3 hours[7]
Children: 7.1 hours[5]
ExcretionUrine, feces
Identifiers
  • (±)-2-(2-{4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl}ethoxy)ethanol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.630 Edit this at Wikidata
Chemical and physical data
FormulaC21H27ClN2O2
Molar mass374.91 g·mol−1
3D model (JSmol)
  • Clc1ccc(cc1)C(c2ccccc2)N3CCN(CC3)CCOCCO
  • InChI=1S/C21H27ClN2O2/c22-20-8-6-19(7-9-20)21(18-4-2-1-3-5-18)24-12-10-23(11-13-24)14-16-26-17-15-25/h1-9,21,25H,10-17H2 checkY
  • Key:ZQDWXGKKHFNSQK-UHFFFAOYSA-N checkY
  (verify)

Hydroxyzine, sold under the brand names Atarax and Vistaril among others, is an antihistamine medication.[8] It is used in the treatment of itchiness, anxiety, insomnia, and nausea (including that due to motion sickness).[8] It is used either by mouth or injection into a muscle.[8]

Hydroxyzine works by blocking the effects of histamine.[9] It is a first-generation antihistamine in the piperazine family of chemicals.[8][4] Common side effects include sleepiness, headache, and dry mouth.[8][9] Serious side effects may include QT prolongation.[9] It is unclear if use during pregnancy or breastfeeding is safe.[8]

It was first made by Union Chimique Belge in 1956 and was approved for sale by Pfizer in the United States later that year.[8][10] In 2023, it was the 39th most commonly prescribed medication in the United States, with more than 15 million prescriptions.[11][12]

Medical uses

[edit]

Hydroxyzine is used in the treatment of itchiness, anxiety, and nausea due to motion sickness.[8]

A systematic review concluded that hydroxyzine outperforms placebo in treating generalized anxiety disorder. Insufficient data were available to compare the drug with benzodiazepines and buspirone.[13]

Hydroxyzine can also be used for the treatment of allergic conditions, such as chronic urticaria, atopic or contact dermatoses, and histamine-mediated pruritus.[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 for premedication as a sedative has no effects on tropane alkaloids, such as atropine, but may, following general anesthesia, potentiate meperidine and barbiturates, and use in pre-anesthetic adjunctive therapy should 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 the central nervous system (CNS) effects of hydroxyzine can develop in as little as a few days.[18][non-primary source needed] A major systematic review and network meta-analysis of medications for the treatment of insomnia published 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

[edit]

Hydroxyzine is contraindicated for subcutaneous or intra-articular administration.[21]

The administration of hydroxyzine in large amounts by ingestion or intramuscular administration during the onset of pregnancy can cause fetal abnormalities. When administered to pregnant rats, mice, and rabbits, hydroxyzine caused abnormalities such as hypogonadism with 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, the US Food and Drug Administration (FDA) has introduced contraindication guidelines regarding hydroxyzine.[22] Use by those at risk for or showing previous signs of hypersensitivity is also contraindicated.[22]

Other contraindications include the administration of hydroxyzine alongside depressants and other compounds that affect the central 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 to tardive dyskinesia after years of use, but effects related to dyskinesia have also anecdotally been reported after periods of 7.5 months,[23] such as continual head rolling, lip licking, and other forms of athetoid movement. In certain cases, elderly patients' previous interactions with phenothiazine derivatives or pre-existing neuroleptic treatment 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

[edit]
Two packages of Atarax, a brand name for hydroxyzine, in Suomi. Four foil packages of pills sit in front of two boxes, one labeled as having 25 pills and the other labeled for 100.
Atarax

Several reactions have been noted in manufacturer guidelines—deep sleep, incoordination, sedation, and dizziness have been reported in children and adults, as well as others such as hypotension, tinnitus, and headaches.[24][medical citation needed] Gastrointestinal effects have also been observed, as well as less serious effects such as dryness of the mouth and constipation caused by the mild antimuscarinic properties of hydroxyzine.[24][medical citation needed]

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 hallucinogenic 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 the reticular 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 as lithium or ethanol.[26]

Hydroxyzine exhibits anxiolytic and sedative 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 acute hypnotic, reducing sleep 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.[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

[edit]

Pharmacodynamics

[edit]
Hydroxyzine[30]
Site Ki (nM) Species Ref
5-HT2A 170 (IC50Tooltip Half-maximal inhibitory concentration) 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]
mAChTooltip Muscarinic acetylcholine receptor 4600
10000+
10000+ (IC50)
6310 (pA2)
3800		 Human
Mouse
Rat
Guinea pig
Bovine		 [37]
[32]
[31]
[38]
[36]
VDCCTooltip Voltage-dependent calcium channel 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 predominant mechanism of action is as a potent and selective histamine H1 receptor inverse agonist.[39][40] This action is responsible for its antihistamine and sedative effects.[39][40] Unlike many other first-generation antihistamines, hydroxyzine has a lower affinity for the muscarinic acetylcholine receptors, and in accordance, has a lower risk of anticholinergic side effects.[36][40][41][42] In addition to its antihistamine activity, hydroxyzine has also been shown to act more weakly as an antagonist of the serotonin 5-HT2A receptor, the dopamine D2 receptor, and the α1-adrenergic receptor.[31][39] Similarly to the atypical antipsychotics, the comparably weak antiserotonergic effects of hydroxyzine likely underlie its usefulness as an anxiolytic.[43] Other antihistamines without such properties have not been found to be effective in the treatment of anxiety.[44]

Hydroxyzine crosses the blood–brain barrier easily and exerts effects in the central nervous system.[39] A positron emission tomography (PET) study found that brain occupancy of the H1 receptor was 67.6% for a single 30 mg dose of hydroxyzine.[45] In addition, subjective sleepiness correlated well with the brain H1 receptor occupancy.[45] PET studies with antihistamines have found that brain H1 receptor occupancy of more than 50% is associated with a high prevalence of somnolence and cognitive decline, whereas brain H1 receptor occupancy of less than 20% is considered to be non-sedative.[46]

Hydroxyzine also acts as a functional inhibitor of acid sphingomyelinase.[47]

Pharmacokinetics

[edit]

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 by alcohol 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 an N-dealkylated metabolite and an O-dealkylated 1/16 metabolite with a plasma half-life of 59 hours. These pathways are mediated principally by CYP3A4 and CYP3A5.[48][49] The N-dealykylated metabolite, norchlorcyclizine, bears some structural similarities to trazodone, 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 its elimination half-life is 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

[edit]

Hydroxyzine is a member of the diphenylmethylpiperazine class of antihistamines.[medical citation needed]

Hydroxyzine is supplied mainly as a dihydrochloride salt (hydroxyzine hydrochloride) but also to a lesser extent as an embonate salt (hydroxyzine pamoate).[56][57][58] The molecular weights of 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

[edit]

Analogues of hydroxyzine include buclizine, cetirizine, cinnarizine, cyclizine, etodroxizine, meclizine, and pipoxizine among others.[60]

Society and culture

[edit]

Brand names

[edit]

Hydroxyzine preparations require a doctor's prescription. The drug is available in two formulations, the pamoate and the dihydrochloride or hydrochloride salts. 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

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Hydroxyzine

View on Grokipedia
from Grokipedia
Hydroxyzine is a first-generation antihistamine medication approved by the U.S. Food and Drug Administration in 1956, primarily used to treat symptoms of anxiety and tension associated with psychoneurosis or organic disease states, pruritus due to allergic conditions such as chronic urticaria and atopic or contact dermatoses, and as a sedative for premedication or following general anesthesia.[1][2][3] As a member of the piperazine class of antihistamines, hydroxyzine works by blocking the action of histamine—a substance in the body that causes allergic symptoms—and by decreasing activity in the brain to produce sedative and anxiolytic effects, though it is not a cortical depressant and its precise mechanism may involve suppression of activity in subcortical regions of the central nervous system.[4][3] It is available in various dosage forms, including oral capsules (25 mg and 50 mg), tablets (10 mg, 25 mg, 50 mg, and 100 mg), syrup, oral suspension (25 mg/5 mL), and intramuscular injection, with typical adult dosing ranging from 25–100 mg three to four times daily depending on the indication.[1][5][3] Common side effects include drowsiness, dry mouth, dizziness, and headache, which are generally mild and transient, while more serious adverse reactions may involve seizures, involuntary motor activity, or cardiac arrhythmias, particularly in cases of overdose or when combined with other central nervous system depressants like alcohol.[4][5][3] Hydroxyzine is contraindicated in early pregnancy due to potential risks and in patients with hypersensitivity to the drug or its components; it is not recommended for nursing mothers or individuals over 65 years old without careful consideration, as it may cause significant drowsiness impairing activities such as driving.[4][5][3] It has no established association with hepatotoxicity or clinically apparent liver injury and is sometimes used to manage pruritus in patients with liver disease.[1]

Medical uses

Indications

Hydroxyzine is primarily indicated for the management of pruritus associated with allergic conditions, including chronic urticaria, atopic dermatitis, and contact dermatitis, as well as histamine-mediated pruritus.[6] It provides symptomatic relief of anxiety and tension linked to psychoneuroses and serves as an adjunct in organic disease states where anxiety is prominent, including for acute anxiety.[7] Hydroxyzine pamoate (brand name Vistaril), a sedating antihistamine, has an onset of action of 15-30 minutes and is considered less potent than benzodiazepines such as Xanax (alprazolam) but effective for milder to moderate anxiety symptoms; it is a safer alternative to benzodiazepines for anxiety relief due to its lack of addiction risk, non-benzodiazepine classification, and association with fewer long-term problems, in contrast to Xanax which carries a high potential for addiction, dependence, and respiratory depression effects.[8][9] In surgical settings, hydroxyzine acts as a preoperative and postoperative adjunct to induce sedation and reduce the need for opioids.[6] It is also used to manage agitation during acute alcohol withdrawal.[1] Additional applications include the treatment of nausea and vomiting, excluding cases related to pregnancy, and the prevention of motion sickness.[10] In veterinary medicine, hydroxyzine is employed off-label in dogs and cats for allergic reactions, atopic dermatitis, pruritus, anxiety, and motion sickness, with typical oral dosages of 1-2 mg/kg administered every 6-12 hours.[11] Evidence supports hydroxyzine's efficacy in select off-label uses; a 2023 systematic review indicated it reduces sleep onset latency and improves overall sleep quality as a short-term option for insomnia in adults.[12] Hydroxyzine pamoate (brand name Vistaril), a sedating antihistamine, is used off-label as a sleep aid in children with ADHD, particularly for insomnia associated with stimulant medications, anxiety, or hyperactivity; it is considered a safer alternative to stronger hypnotics such as benzodiazepines due to a lower risk of dependence and adverse effects in pediatric populations.[13][6][14] A 2021 multicenter observational study found that hydroxyzine administration was associated with lower mortality rates among hospitalized COVID-19 patients.[15] Furthermore, a 2025 retrospective study demonstrated that intravenous hydroxyzine monotherapy was comparable to haloperidol in managing delirium symptoms, offering a potential alternative with sedative benefits.[16] Hydroxyzine is not a standard or approved treatment for restless legs syndrome (RLS). Antihistamines including hydroxyzine can exacerbate or worsen RLS symptoms, potentially due to effects on the dopamine system. While rare case reports have described symptomatic improvement in specific familial RLS cases, this is not supported by broader evidence or guidelines, which advise avoiding such medications in RLS patients.[17][18][19]

Dosage and administration

Hydroxyzine is administered orally or intramuscularly, with dosing tailored to the indication, patient age, and response. For anxiety and tension in adults, the recommended oral dose is 50 to 100 mg up to four times daily.[20] For pruritus due to allergic conditions, adults typically receive 25 mg orally three to four times daily.[20] In children under 6 years of age, the oral dose is 50 mg daily in divided doses for either indication; for children 6 years and older, it is 50 to 100 mg daily in divided doses.[20] For off-label use in treating insomnia, the common dosage range is 25–100 mg orally at bedtime. Higher doses (50–100 mg) may be used for stronger sedation but increase the risk of next-day grogginess.[5][21][22][23] Hydroxyzine is not recommended for children under 6 months of age due to limited safety data in this population.[24] For preoperative sedation, adults may receive 25 to 100 mg intramuscularly, while children are dosed at 0.6 mg/kg orally or 1 mg/kg intramuscularly.[20] Intramuscular administration should not be used subcutaneously or intravenously, as it may cause tissue irritation.[25] When initiating treatment intramuscularly, subsequent doses can transition to oral administration.[20] Hydroxyzine is available as the hydrochloride salt in capsules, tablets, and syrup formulations, and as the pamoate salt in capsules and oral suspension.[26] Oral administration produces clinical effects within 15 to 30 minutes, with a duration of action of 4 to 6 hours.[7] Dosage adjustments are recommended when co-administered with central nervous system depressants, reducing the dose by up to 50% to avoid additive effects.[20] In elderly patients, dosing should start at the lower end of the range due to potential declines in hepatic and renal function, with close monitoring.[20] In veterinary medicine, hydroxyzine is used off-label for allergies in dogs and cats at 1 to 2 mg/kg orally every 12 hours.[11] For acute reactions, up to 2 mg/kg may be given intramuscularly.[27]

Safety profile

Contraindications

Hydroxyzine is contraindicated in patients with known hypersensitivity to hydroxyzine or any of its components, including cetirizine hydrochloride or levocetirizine hydrochloride.[28] The drug is contraindicated during early pregnancy (first trimester) due to potential fetal harm, as evidenced by teratogenic effects observed in animal reproduction studies at doses substantially above the human therapeutic range, with inadequate clinical data available to assess risk in humans.[28] However, studies in over 200 pregnant women show no increased risk of birth defects. In later trimesters, use may be justified if potential benefits outweigh risks.[29] Hydroxyzine is contraindicated in individuals with a known prolonged QT interval, as it can exacerbate this condition and increase the risk of torsades de pointes, particularly in combination with other QT-prolonging agents.[28] Hydroxyzine should be used with caution in patients with asthma, where its anticholinergic properties may thicken bronchial secretions and hinder clearance, potentially worsening respiratory distress.[30] Hydroxyzine is not recommended for use in nursing mothers, as the drug and its active metabolite cetirizine pass into breast milk and may cause sedation or other effects in the breastfed infant.[31] In special populations, hydroxyzine should be used with caution in neonates and premature infants due to heightened risk of central nervous system depression and limited safety data.[4] It should also be used with caution or avoided in patients with narrow-angle glaucoma, as the anticholinergic effects can precipitate an acute increase in intraocular pressure.[32]

Drug interactions

Hydroxyzine exhibits significant interactions with central nervous system (CNS) depressants, including alcohol, opioids (such as narcotics), barbiturates, and benzodiazepines, leading to additive sedative effects like enhanced drowsiness, dizziness, and impaired concentration.[33] When co-administered, the dosage of the CNS depressant should be reduced to mitigate these risks, and alcohol should be avoided entirely due to its potentiation of hydroxyzine's CNS-depressant properties.[33][34] Concomitant use of hydroxyzine with QT interval-prolonging drugs, such as quinidine, pimozide, cisapride, erythromycin, or ketoconazole, increases the risk of QT prolongation and potentially life-threatening arrhythmias like torsade de pointes.[33][35] Post-marketing reports have documented cases of QT prolongation associated with hydroxyzine, particularly in the presence of arrhythmogenic agents or electrolyte imbalances, necessitating ECG monitoring and caution in patients with cardiac risk factors.[33] Hydroxyzine, which possesses anticholinergic properties, can enhance the effects of other anticholinergic agents like atropine, resulting in intensified symptoms such as dry mouth, constipation, urinary retention, and blurred vision.[35][36] Patients receiving both should be monitored for exacerbated anticholinergic adverse effects, with dose adjustments considered as needed.[37] In emergency situations like anaphylaxis or overdose, hydroxyzine inhibits the vasopressor (blood pressure-raising) effect of epinephrine, rendering it ineffective; norepinephrine should be used as an alternative vasopressor.[33][3] Monoamine oxidase inhibitors (MAOIs) may potentiate the anticholinergic effects of hydroxyzine, prolonging and intensifying symptoms like dry mouth and constipation.[38] Corticosteroids, such as prednisone, do not have a direct pharmacokinetic interaction with hydroxyzine but may contribute to additive sedation when used together, warranting caution in dosing.[39][36]

Adverse effects

Hydroxyzine is associated with a range of adverse effects, primarily due to its antihistaminic and anticholinergic properties. The most common effects are mild and include drowsiness, which occurs in a substantial proportion of users and may diminish with continued administration or dose reduction; dry mouth; dizziness; and headache. Drowsiness is particularly prominent with higher doses (50–100 mg) used for sleep or sedation, potentially leading to next-day grogginess. These effects are typically transient and resolve without intervention in many cases.[6][40][22][23] In pediatric populations, including children with attention-deficit/hyperactivity disorder (ADHD) using hydroxyzine pamoate off-label as a sleep aid for stimulant-induced insomnia, the drug is generally well-tolerated at appropriate doses but carries risks of excessive sedation, behavioral changes, and limited long-term safety data. It may be considered a lower-risk alternative to stronger hypnotics like benzodiazepines due to reduced potential for dependence, though close monitoring is required and it is not first-line therapy.[41][42] Serious adverse effects, though less frequent, can include central nervous system disturbances such as confusion, particularly in vulnerable populations; tremors; seizures, which are rare and usually occur at high doses; and cardiac complications like QT interval prolongation, which may lead to torsade de pointes and ventricular arrhythmias. Hypersensitivity reactions, including rash, urticaria, pruritus, or anaphylaxis, have also been reported post-marketing. Cardiac effects warrant ECG monitoring in patients with risk factors, as hydroxyzine carries a documented increased risk of QT prolongation compared to non-use. Additionally, hydroxyzine may exacerbate restless legs syndrome (RLS) in patients with the condition, potentially due to its weak dopamine D2 receptor antagonism.[6][40][43][44][45] Although hydroxyzine is sometimes described as having fewer long-term problems compared to benzodiazepines like alprazolam due to its lack of addiction potential, its use for anxiety is generally recommended for short-term treatment only, typically less than 4 months. Long-term daily use is considered off-label, as no extensive studies have confirmed its safety beyond this timeframe. Prolonged exposure to its anticholinergic properties raises concerns, particularly in older adults, including a potential increased risk of dementia and reports of brain fog or cognitive impairment. Tolerance to its sedative effects can also develop relatively quickly, reducing efficacy over time. Hydroxyzine has a moderate interaction with benzodiazepines such as alprazolam (Xanax). Concurrent use can amplify central nervous system depressant effects, leading to increased drowsiness, dizziness, confusion, difficulty concentrating, and impaired coordination or judgment. Patients, especially the elderly, should be monitored closely, avoid alcohol, and refrain from activities requiring mental alertness until effects are known. While the combination may be used cautiously under medical supervision in certain cases, it is not first-line, and guidelines often prefer SSRIs/SNRIs for ongoing anxiety management with benzodiazepines or antihistamines reserved for short-term or as-needed relief. In cases of overdose, symptoms often involve severe central nervous system depression, manifesting as hypersedation, stupor, nausea, vomiting, seizures, and hypotension. Treatment is supportive and includes gastric lavage or activated charcoal to reduce absorption, intravenous fluids for hypotension, benzodiazepines for seizure control, and continuous ECG monitoring for arrhythmias; no specific antidote exists, and hemodialysis is unlikely to be beneficial.[6][40][46] Elderly patients face heightened risks from hydroxyzine due to age-related reductions in clearance and increased sensitivity to its anticholinergic and sedative effects, leading to greater incidences of confusion, falls, delirium, and cognitive impairment. Anticholinergic effects, such as dry mouth and constipation, contribute to an elevated burden in this group, with cumulative exposure linked to adverse outcomes like dementia. Recent guidelines, including the 2023 American Geriatrics Society Beers Criteria, strongly recommend avoiding hydroxyzine in older adults owing to these risks.[40][47][48] The overall incidence of anticholinergic effects with hydroxyzine is estimated at 10-20% in clinical settings, while cardiac events remain rare but require vigilance in at-risk individuals. Drowsiness affects up to 40% of patients, positioning it as the predominant adverse reaction across studies of sedating antihistamines.[49]

Pharmacology

Pharmacodynamics

Hydroxyzine is a first-generation antihistamine that acts primarily as a potent inverse agonist at the histamine H1 receptor, competitively binding to H1 receptor sites on effector cells and thereby suppressing histamine-mediated responses such as edema, flare, and pruritus associated with allergic conditions like urticaria and itching.[50][7] This blockade inhibits the physiological effects of histamine, including bronchoconstriction and increased vascular permeability, contributing to its antipruritic and antiallergic properties. The affinity of hydroxyzine for the human H1 receptor is high, with a reported Ki value of approximately 2 nM.[45] In the central nervous system (CNS), hydroxyzine exerts sedative and anxiolytic effects primarily through suppression of activity at subcortical levels, without significant cortical depression.[50] These actions are mediated by its H1 receptor antagonism in the brain, leading to reduced arousal and promotion of relaxation. Additionally, hydroxyzine displays weak antagonism at serotonin 5-HT2A receptors (Ki ≈ 50 nM) and dopamine D2 receptors (Ki ≈ 378 nM), which may contribute to its antiemetic effects and mild antipsychotic-like properties in certain contexts.[45] This dopamine D2 receptor antagonism may contribute to the exacerbation of restless legs syndrome (RLS) observed in some patients.[51] Hydroxyzine also possesses anticholinergic activity through blockade of muscarinic acetylcholine receptors, with moderate affinity (Ki ≈ 3.8 μM), resulting in effects such as dry mouth, enhanced sedation, and inhibition of the pressor response to epinephrine.[52] This muscarinic antagonism further supports its antiemetic and antispasmodic actions by interfering with acetylcholine-mediated pathways. At higher doses, hydroxyzine exhibits local anesthetic properties, likely due to sodium channel blockade, which can provide mild analgesia in topical or injectable applications.[53] Hydroxyzine does not significantly inhibit monoamine oxidase (MAO), showing only weak competitive inhibition of MAO-B (Ki ≈ 38 μM) and negligible activity at MAO-A.[54]

Pharmacokinetics

Hydroxyzine is rapidly absorbed from the gastrointestinal tract following oral administration, with a bioavailability of approximately 72% and peak plasma concentrations achieved within 2 hours.[55] Intramuscular administration results in faster onset of effects, typically within 15 to 30 minutes.[56] Food may delay the rate of absorption without affecting the overall extent.[7] The drug is widely distributed throughout the body, with a volume of distribution of about 16 L/kg, reflecting extensive tissue penetration.[50] Due to its lipophilic nature, hydroxyzine readily crosses the blood-brain barrier, contributing to its central nervous system effects.[7] Hydroxyzine binds to plasma proteins, primarily albumin.[7] Hydroxyzine undergoes hepatic metabolism primarily via cytochrome P450 enzymes CYP3A4 and CYP3A5, with the major active metabolite being cetirizine, which retains antihistaminic activity but is less sedating.[50] Cetirizine has an elimination half-life of 8 to 10 hours.[57] Elimination occurs mainly through renal excretion of unchanged cetirizine and other metabolites, accounting for approximately 70% of the dose in urine, with about 10-13% eliminated in feces.[58] The terminal half-life of hydroxyzine is around 20 hours in adults, though it is prolonged to about 29 hours in the elderly and further extended in patients with renal impairment.[7] With repeated dosing at therapeutic intervals, hydroxyzine does not accumulate significantly due to its elimination profile.[7] In cases of renal impairment, dosing adjustments may be necessary to account for reduced clearance.[7]

Chemistry

Physicochemical properties

Hydroxyzine is a piperazine derivative with the chemical formula C21H27ClN2O2 for the free base and C21H29Cl3N2O2 for the dihydrochloride salt commonly used in pharmaceuticals.[50][20] The molecular weight is 374.91 g/mol for the free base and 447.83 g/mol for the dihydrochloride salt.[50][20] Its IUPAC name is 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]ethanol, featuring a central piperazine ring substituted with a (4-chlorophenyl)(phenyl)methyl group and a 2-(2-hydroxyethoxy)ethyl chain. Hydroxyzine contains one chiral center and is administered as a racemic mixture.[59] The dihydrochloride salt appears as a white, odorless crystalline powder with a melting point of approximately 200°C, decomposing at higher temperatures.[20][60] It exhibits high solubility in water (very soluble) and is freely soluble in alcohols such as methanol and ethanol (95%), though solubility decreases in less polar solvents.[20][60] The compound has pKa values of approximately 2.0 and 7.4, reflecting the basicity of its piperazine nitrogens, which contributes to its salt formation and ionization behavior in physiological environments.[61] Hydroxyzine dihydrochloride is chemically stable under standard ambient conditions, including room temperature storage, but it should be protected from intense ultraviolet light to prevent degradation.[50] The pamoate salt form, used in some sustained-release formulations, is notably less soluble in water compared to the hydrochloride, enabling prolonged absorption profiles.[62] Structurally, hydroxyzine is related to other piperazine-based antihistamines, including cetirizine (a carboxylic acid metabolite classified as a second-generation agent), cyclizine (an antiemetic), and buclizine (another antiemetic with similar substitutions).[50]

Synthesis

Hydroxyzine is primarily synthesized through an alkylation reaction involving the key intermediate 1-(4-chlorobenzhydryl)piperazine, which is prepared by reacting 4-chlorobenzhydryl chloride with excess piperazine in a nucleophilic substitution under basic conditions, typically using a solvent like ethanol or acetonitrile and a base such as potassium carbonate to facilitate the attachment of the piperazine ring to the chlorobenzhydryl moiety.[63][64] This intermediate is then alkylated with 2-(2-chloroethoxy)ethanol in the presence of a base like potassium carbonate and a phase-transfer catalyst such as tetrabutylammonium bromide, often in an aqueous medium at elevated temperatures around 80°C, to introduce the 2-(2-hydroxyethoxy)ethyl side chain on the piperazine nitrogen, yielding hydroxyzine as the free base with high purity (up to 99% by HPLC).[64][50] An alternative synthetic route involves first forming 1-[2-(2-hydroxyethoxy)ethyl]piperazine by alkylating piperazine with 2-(2-chloroethoxy)ethanol under similar basic conditions, followed by reaction of this substituted piperazine with 4-chlorobenzhydryl chloride or bromide to attach the diphenylmethyl group, providing another pathway to the hydroxyzine free base.[50][65] This approach, detailed in early patents, allows flexibility in sequencing the substitutions and has been used in various process optimizations. The free base of hydroxyzine is subsequently converted to its pharmaceutically relevant salts; the hydrochloride salt is obtained by neutralization with hydrochloric acid, typically dissolving the base in a twofold molar excess of HCl followed by evaporation to dryness, while the pamoate salt is formed by reaction with pamoic acid in a suitable solvent like methanol or water to produce the insoluble embonate for oral suspension formulations.[50][62] Hydroxyzine was first synthesized in 1955 by scientists at Union Chimique Belge (UCB), with subsequent industrial scale-up enabling commercial production under patents filed shortly thereafter.[50]

History

Development

Hydroxyzine was first synthesized in 1955 by chemists at Union Chimique Belge (UCB), a Belgian pharmaceutical company, as part of a research program focused on developing new antihistamines.[50] The compound, chemically a piperazine derivative, emerged from efforts to create agents with enhanced antihistaminic activity, building on earlier piperazine-based antihistamines such as meclizine, with the goal of providing sedation without the respiratory depression associated with barbiturates.[1] In preclinical testing, hydroxyzine was identified for its potent antihistaminic, sedative, and anticholinergic properties. Animal studies, including those in rodents, confirmed its efficacy in allergy models by blocking histamine-induced responses and demonstrated sedative effects through reduced locomotor activity and prolonged barbiturate-induced sleep.[66] Further experiments, such as cardiovascular assessments in animal models, evaluated its safety profile, showing minimal impact on vital functions at therapeutic doses.[67] Early clinical trials began in 1956 across Europe, targeting conditions like pruritus and anxiety. These studies, including preliminary evaluations in dermatological therapy and psychosomatic affections, reported effective relief of itching and tension with a favorable safety margin, including lower abuse potential compared to barbiturates due to its non-narcotic mechanism.[68][69][70] Key milestones included the filing of a patent by UCB inventor Henri Morren in 1957 (issued in the US in 1959), securing intellectual property for the compound and its synthesis methods. Initial marketing followed shortly thereafter, with hydroxyzine introduced as Atarax for allergic conditions and Vistaril for anxiety management, marking its transition from research to clinical use.[71][72]

Regulatory history

Atarax (hydroxyzine hydrochloride) and Vistaril (hydroxyzine pamoate) were approved by the U.S. Food and Drug Administration (FDA) in 1957 for marketing by Pfizer, initially for the treatment of anxiety and pruritus associated with allergic conditions.[73][74] In April 2024, the FDA determined that Vistaril (hydroxyzine pamoate) oral suspension, 25 mg/5 mL, was not withdrawn from sale for reasons of safety or effectiveness, thereby permitting the approval of abbreviated new drug applications (ANDAs) for generic versions of this formulation.[74] In the European Union, the European Medicines Agency (EMA) initiated a referral procedure in February 2015 following assessments by the Pharmacovigilance Risk Assessment Committee (PRAC), which confirmed hydroxyzine's association with QT interval prolongation and torsade de pointes, leading to restrictions on its use in patients with known risk factors for these cardiac events.[75] As a result, hydroxyzine-containing medicines were updated to include contraindications and warnings, and it maintains prescription-only (Rx-only) status across EU member states.[76] Hydroxyzine has been approved and marketed in Canada since 1956, with the Drug Identification Number (DIN) 00646059 assigned to the 10 mg hydroxyzine hydrochloride capsule formulation.[77] In Australia, it is classified as a Schedule 4 (S4) prescription-only medicine under the Poisons Standard. In the United Kingdom, hydroxyzine has held Prescription Only Medicine (POM) status since its introduction in the late 1950s. Labeling updates have addressed emerging safety concerns. In June 2016, Health Canada conducted a safety review concluding that hydroxyzine can cause QT interval prolongation, prompting recommendations to avoid use in patients with cardiac risk factors and updates to product monographs.[77] As of February 2025, U.S. product labels were revised to reinforce contraindications in early pregnancy due to potential fetal risks and to include warnings for elderly patients, advising lower starting doses to mitigate risks of confusion and oversedation.[78] Globally, hydroxyzine labels contraindicate its use in early pregnancy across major regulatory jurisdictions, based on evidence of placental transfer and potential teratogenic effects in animal studies, though human data remain limited.[79] No major withdrawals or bans have occurred, but ongoing monitoring for cardiac risks, including QT prolongation, is emphasized in international pharmacovigilance efforts.[75]

Society and culture

Brand names

In the United States, hydroxyzine is marketed under the brand names Atarax for the hydrochloride salt and Vistaril for the pamoate salt, though Atarax was discontinued in 2021 for business reasons while generic equivalents remain available.[80][81] Generic hydroxyzine hydrochloride has been available since the 1980s following the original FDA approval prior to 1982.[82] Internationally, hydroxyzine is sold under various brand names, including Atarax in countries such as the United Kingdom, European Union members like Slovenia and Cyprus, Lebanon, and Turkey; Orgatrax in India; and other examples like Anxol, Itran, and Quiess in select regions.[83][75][84] Hydroxyzine is available in multiple formulations, including capsules (25 mg, 50 mg, 100 mg), tablets (10 mg, 25 mg, 50 mg), oral syrup (10 mg/5 mL), and intramuscular injection (25 mg/mL, 50 mg/mL).[85] Generic versions of both the hydrochloride and pamoate forms are widely available globally.[86][83] In 2023, hydroxyzine ranked as the 39th most prescribed medication in the United States, with approximately 15.3 million prescriptions. The global hydroxyzine market is projected to grow at a compound annual growth rate (CAGR) of over 6% from 2024 to 2030, driven by increasing prevalence of allergic conditions.[87][88]

Legal status

Hydroxyzine is classified as a prescription-only medication in the United States, requiring a valid prescription from a licensed healthcare provider for dispensing, and it is not a controlled substance under the Drug Enforcement Administration (DEA) schedules, rendering it exempt from federal narcotic or controlled substance regulations.[20][89] In the European Union, hydroxyzine is also available exclusively by prescription, with additional restrictions implemented in 2015 by the European Medicines Agency (EMA) to mitigate risks of QT interval prolongation and torsade de pointes; these measures contraindicate its use in patients under 18 years of age except for premedication prior to anaesthesia, limit the maximum daily dose to 100 mg for adults and 50 mg for those over 65 years, and advise against use in individuals with known QT prolongation or predisposing conditions.[75][48] Internationally, hydroxyzine holds a prescription-only status in numerous countries, including Schedule S4 (prescription-only medicine) classification in Australia under the Therapeutic Goods Administration (TGA), prescription-only in Canada as regulated by Health Canada, and Prescription Only Medicine (POM) designation in the United Kingdom via the Medicines and Healthcare products Regulatory Agency (MHRA).[77][90] The drug is available in over 100 countries worldwide, consistently requiring a prescription for access and not approved for over-the-counter sale in any jurisdiction.[83] Hydroxyzine is not designated as a controlled substance under United Nations conventions on psychotropic substances or narcotics, reflecting its low potential for abuse, though it is occasionally monitored for misuse in contexts such as self-medication for anxiety or sedation.[91] For veterinary applications, hydroxyzine is used off-label in most regions without specific regulatory approval for animal use, permitted under veterinary oversight in the United States via the Animal Medicinal Drug Use Clarification Act (AMDUCA) for extra-label purposes within established guidelines, and similarly allowed in the European Union under the cascade principle for treatments unavailable in authorized veterinary products.[92]

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