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Hydroxyzine

Hydroxyzine molecule structureHydroxyzine molecule structure
2-[2-[4-(4-Chlorobenzhydryl)piperazin-1-yl]ethoxy]ethanol
Atarax, Vistaril, Hyzine, Rezine, Vistaject
Chemical Class
PiperazineDephenylmethane

Hydroxyzine is a first-generation antihistamine of the diphenylmethane and piperazine classes, first developed in 1956.citation needed Primarily prescribed for allergic conditions such as itchiness and urticaria, it also exhibits anxiolytic and sedative properties, making it useful for treating generalized anxiety disorder and insomnia. Hydroxyzine is additionally employed to reduce nausea1 and has been used to potentiate opioid analgesia while diminishing opioid-related side effects like itchiness.citation needed

Dosage & Duration

Dosage

Doses are population estimates that vary widely between individuals.

Moderate25-100 mg

Duration

Onset20-60 minutes
After Effects1-8 hours
Total3-5 hours
Half-life
14-25 hours

Subjective Effects

Legacy content. A statistically backed ontology from Mindstate Design Labs is coming soon.

The experience is dominated by sedation, with subjective sleepiness closely tracking the degree of central histamine receptor blockade. Onset occurs within roughly 15 to 60 minutes and effects last around four to six hours, with the calming quality often described as a general settling rather than any distinct alteration of perception. Reported sedation is most pronounced on first exposure and diminishes markedly over the following five to seven days of repeated use. Anxiolysis and reduced nausea accompany the sedative state.

Physical

Deep sleepiness, dizziness, and reduced coordination are the principal physical effects, alongside dry mouth and headache. Overdose is characterised chiefly by extreme sedation.

Sedation

Uncomfortable

Headache

Cognitive

The overall character is calming and anxiety-reducing, though confusion has been reported, particularly at higher doses or alongside other sedating drugs. Hallucinations and cognitive decline are documented but uncommon, appearing mainly in overdose or when combined with other central nervous system depressants.

Impairment

Auditory

Multisensory

Reagent Testing

Expected colorimetric results for common reagent tests. Colors show reaction change over 1–2 minutes.

Marquis(MQ)
No reaction
No reaction
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Pharmacology

Pharmacodynamics

Hydroxyzine is a potent and selective histamine H1 receptor inverse agonist, meaning it actively dampens receptor activity rather than simply blocking it.citation needed This inverse agonism underlies its antihistamine effects and sedative properties. Unlike many other first-generation antihistamines, hydroxyzine has lower affinity for muscarinic acetylcholine receptors, resulting in a reduced risk of anticholinergic side effects. Hydroxyzine also acts more weakly as an antagonist at serotonin 5-HT2A receptors, dopamine D2 receptors, and α1-adrenergic receptors. The comparably weak antiserotonergic activity likely contributes to its usefulness as an anxiolytic, as other antihistamines lacking such properties have not demonstrated efficacy for anxiety. Hydroxyzine readily crosses the blood-brain barrier; a positron emission tomography study found that a single 30 mg dose achieved 67.6% occupancy of brain H1 receptors, with subjective sleepiness correlating well with receptor occupancy. Hydroxyzine also functions as an inhibitor of acid sphingomyelinase.2

Pharmacokinetics

Hydroxyzine is rapidly absorbed from the gastrointestinal tract following oral administration, reaching peak plasma concentrations approximately 2 hours after dosing.3 The absolute bioavailability has not been determined due to the unavailability of intravenous formulations. Hydroxyzine is metabolized in the liver primarily by CYP3A4 and CYP3A5.citation needed The main metabolite, comprising approximately 45-60% of an oral dose, is the second-generation antihistamine cetirizine, formed through oxidation of the alcohol moiety to a carboxylic acid. Additional metabolites include an N-dealkylated metabolite (norchlorcyclizine) and an O-dealkylated metabolite with a plasma half-life of 59 hours. The elimination half-life averages approximately 20 hours in adults, 7.1 hours in children, and 29 hours in elderly patients. Higher concentrations are found in the skin than in plasma. Approximately 70% of cetirizine is excreted unchanged in the urine.

Interactions

Caution

Use caution

These combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.

1,2-BenzodiazepineAbametapirAbataceptAcalabrutinibAcebutolol
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Tolerance

Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.

Full Tolerance
Tolerance to the central nervous system effects, particularly sedation, can develop rapidly with continuous use.citation needed Studies indicate that subjective sedation levels decrease markedly over 5-7 days of use, likely due to CNS receptor desensitization. This rapid tolerance development is why hydroxyzine is typically prescribed only for short-term or as-needed use when employed as a sleep aid.
Cross Tolerance

Other antihistamine sleep aids, First-generation antihistamines

Harm Potential

Addiction & Dependence

Psychological

Low

Hydroxyzine has low abuse potential due to its lack of euphoric effects. It is not a controlled substance and is not typically associated with compulsive use patterns.

Physical

Low

Physical dependence is not commonly reported with hydroxyzine use. It does not produce significant withdrawal syndromes characteristic of other sedative classes.

Toxicity

Cardiovascular

Hydroxyzine can prolong the QT/QTc interval, with rare postmarketing reports of Torsade de Pointes, cardiac arrest, and sudden death;citation needed caution is advised in individuals with pre-existing risk factors for QTc prolongation.

Central Nervous System

Long-term prescription use over years can lead to tardive dyskinesia,citation needed with anecdotal reports of movement disorders appearing after periods as short as 7.5 months; symptoms include continual head rolling, lip licking, and other athetoid movements.

Reproductive/Developmental

Administration of large amounts during early pregnancy has been associated with fetal abnormalities in animal studies, including hypogonadism at doses significantly above human therapeutic ranges.

Psychosis Risk

Hallucinations and confusion have been observed in rare cases,citation needed attributed mostly to overdosage or in patients being treated for neuropsychological disorders.

Seizure Risk

Convulsions may occur in overdose situations4 but are not commonly associated with therapeutic use.

History & Culture

Hydroxyzine is a first-generation antihistamine of the diphenylmethane and piperazine classes. It was first developed in 1955citation needed and subsequently manufactured by Union Chimique Belge in 1956. That same year, it was approved for sale in the United States by…

Legality

By Country

Prescription3
United States flagUnited StatesPrescription only
Canada flagCanadaPrescription only
Turkey flagTurkeyPrescription only
Not scheduled1
Thailand flagThailandOver the counter

References

Source Pages

  1. DrugBank
  2. Wikipedia

Citations

  1. Hydroxyzine Hydrochloride Injection, USP - DailyMed (setid: 8af7e5ce-d9d9-44cc-9f2f-4ddbc89e758a). U.S. National Library of Medicine, DailyMed (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8af7e5ce-d9d9-44cc-9f2f-4ddbc89e758a1
  2. Identification of Novel Functional Inhibitors of Acid Sphingomyelinase. (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3166082/1
  3. Atarax (Hydroxyzine Hydrochloride) Data Sheet. GlaxoSmithKline (2013). https://www.e-lactancia.org/media/papers/Hydroxyzine-DS-Glaxo-SK2013.pdf1
  4. Hydroxyzine Pamoate Capsules USP — DailyMed Label. U.S. National Library of Medicine / DailyMed (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53d3540a-667d-474e-9994-aed08b3b160412
  5. ATARAX: FDA-Approved Drugs – NDA 010392. DrugFuture (FDA data) (n.d.). https://www.drugfuture.com/fda/drugview/0103921
  6. Cetirizine – StatPearls. StatPearls Publishing / NCBI Bookshelf (n.d.). https://www.ncbi.nlm.nih.gov/books/NBK549776/1
  7. ATARAX — Drug Product Database, Health Canada (DIN 00024694). Health Canada (n.d.). https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=31612
  8. HISTAN (Hydroxyzine HCl oral solution) — Thai FDA Drug Registration (1A 127/66). Thai Food and Drug Administration (อย.) (n.d.). https://pertento.fda.moph.go.th/FDA_SEARCH_DRUG/SEARCH_DRUG/pop-up_drug.aspx?Newcode_U=U1DR1A1022660012711C1
  9. ATARAX FILM TABLET 25 mg 30 tablet — ilacdata.com (Turkish pharmaceutical database). ilacdata.com (n.d.). http://www.ilacdata.com/ilac.asp?ilac=103412
  10. Atarax (hydroxyzine hydrochloride) tablet and syrup — DailyMed (setid 7eaf5043-5c73-47af-904b-8e1fae02af2e). U.S. National Library of Medicine (DailyMed) (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7eaf5043-5c73-47af-904b-8e1fae02af2e12

Further Reading

  1. Drugs.com: Hydroxyzine
  2. Drugs.com: Hydroxyzine-Oxycodone Interaction
  3. Drugs.com: Hydroxyzine-Xanax Interaction
  4. FDA: Vistaril (hydroxyzine pamoate) Label
  5. GoodRx: Hydroxyzine Side Effects
  6. Mayo Clinic: Hydroxyzine (Oral Route)
  7. Medical News Today: Hydroxyzine Interactions
  8. NCBI: Co-Administration of Subeffective Doses of Diazepam and Hydroxyzine
  9. PubMed: Potentiation of Pain Relief with Hydroxyzine
  10. Real Life Pharmacology: Hydroxyzine Pharmacology
  11. ScienceDirect: Hydroxyzine Overview
  12. Talkiatry: Hydroxyzine vs Xanax
  13. WebMD: Hydroxyzine (Atarax, Vistaril)

Article Status

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