Mechanism of action
Hydroxyzine is a piperazine-derivative first-generation antihistamine that acts as a competitive antagonist at peripheral and central H1 histamine receptors. By blocking H1 receptors, it prevents histamine-mediated vasodilation, increased vascular permeability, and pruritus.
The anxiolytic and sedative effects are mediated through CNS depression, likely involving antagonism at central H1 receptors and modulation of serotonergic pathways. Hydroxyzine has been shown to have affinity for serotonin receptors, which may contribute to its anxiolytic properties. Unlike benzodiazepines, hydroxyzine does not act on GABA receptors and does not carry the same risk of dependence or tolerance.
Hydroxyzine also exhibits anticholinergic effects by blocking muscarinic acetylcholine receptors, leading to dry mouth, urinary retention, and other antimuscarinic symptoms. It has weak analgesic properties and can potentiate the effects of opioids and other CNS depressants.
The antiemetic effect is attributed to central anticholinergic activity and antagonism at the chemoreceptor trigger zone. Hydroxyzine's sedative properties make it useful for preoperative sedation and as an adjunct to anesthesia.
- Hydroxyzine is a first-generation H1 antihistamine with anxiolytic, antipruritic, and sedative properties
- Major metabolite is cetirizine (a second-generation antihistamine with less CNS penetration)
- Can prolong the QT interval and increase risk of torsades de pointes
- Contraindicated in early pregnancy due to potential teratogenic effects
- Not a controlled substance and does not cause physical dependence (safer than benzodiazepines for anxiety)
- Strong anticholinergic effects: dry mouth, urinary retention, confusion (especially in elderly)
- Appears on Beers Criteria as potentially inappropriate in patients ≥65 years
- Must be discontinued before allergy skin testing to avoid false negatives
Indications
Hydroxyzine is FDA-approved for the following conditions:
- Anxiety disorders: Short-term management of anxiety and tension associated with psychoneurosis, and as an adjunct in organic disease states where anxiety is manifested
- Pruritus: Symptomatic relief of pruritus due to allergic conditions such as chronic urticaria, atopic dermatitis, and contact dermatitis
- Sedation: Preoperative and postoperative sedation when used as premedication or following anesthesia
- Antiemetic: As an adjunct to control nausea and vomiting, excluding nausea and vomiting of pregnancy
Off-label uses
- Insomnia (short-term)
- Alcohol withdrawal symptoms
- Adjunct in management of opioid withdrawal
- Pruritus associated with various dermatologic conditions
Hydroxyzine is particularly useful in patients where benzodiazepines are contraindicated or where the risk of substance abuse is a concern, as it lacks abuse potential and does not cause physical dependence.
Pharmacokinetics
Absorption: Hydroxyzine is rapidly absorbed from the gastrointestinal tract following oral administration. Peak plasma concentrations are reached within 2 to 3 hours. Food does not significantly affect absorption.
Distribution: The drug is widely distributed throughout the body with a large volume of distribution. Hydroxyzine crosses the blood-brain barrier, accounting for its CNS effects. It also crosses the placenta and is excreted in breast milk.
Metabolism: Hydroxyzine undergoes extensive hepatic metabolism via cytochrome P450 enzymes, primarily CYP3A4 and CYP3A5. The major metabolite is cetirizine (Zyrtec), a second-generation antihistamine with reduced CNS penetration. Other metabolites have minimal pharmacologic activity.
Excretion: Metabolites are excreted primarily in urine. The elimination half-life of hydroxyzine is approximately 20 hours in adults but may be prolonged in elderly patients and those with hepatic impairment. Renal impairment does not significantly affect clearance.
Special populations: Dosage adjustment is recommended in elderly patients due to increased sensitivity to anticholinergic effects and prolonged half-life. Use cautiously in hepatic impairment.
Adverse effects
Hydroxyzine is generally well tolerated, but several adverse effects warrant attention:
Common adverse effects
- Sedation and drowsiness: Most common, dose-dependent; typically diminishes with continued use
- Dry mouth: Due to anticholinergic activity
- Dizziness: Related to CNS depression
- Headache
Anticholinergic effects
- Blurred vision
- Urinary retention
- Constipation
- Confusion (especially in elderly)
Cardiovascular effects
- QT interval prolongation: Hydroxyzine has been associated with dose-dependent QT prolongation, which can predispose to torsades de pointes, a potentially fatal ventricular arrhythmia. Risk is increased with higher doses, electrolyte abnormalities, concomitant QT-prolonging drugs, and pre-existing cardiac conditions.
- Hypotension (rare)
- Tachycardia
Neurologic effects
- Tremor
- Seizures (rare, usually with overdose)
- Extrapyramidal symptoms (very rare)
Hypersensitivity reactions
- Rash
- Urticaria
- Anaphylaxis (rare)
Other effects
- Gastrointestinal upset
- Fatigue
- Weakness
Black box warning: None currently, but the European Medicines Agency has recommended that hydroxyzine be used at the lowest effective dose for the shortest duration due to QT prolongation risk.
Overdose can cause severe CNS depression, seizures, anticholinergic toxicity, and cardiovascular collapse. Treatment is supportive.
Contraindications and warnings
Absolute contraindications
- Known hypersensitivity to hydroxyzine, cetirizine, or any piperazine derivatives
- Early pregnancy (first trimester): Hydroxyzine has been associated with fetal harm in some studies and is generally avoided in pregnancy
- Prolonged QT interval: Patients with congenital long QT syndrome or acquired QT prolongation
- Recent myocardial infarction
- Concurrent use with other medications known to significantly prolong the QT interval
Relative contraindications and warnings
- Elderly patients: Increased risk of anticholinergic effects including confusion, sedation, falls, and urinary retention. Hydroxyzine appears on the Beers Criteria as a potentially inappropriate medication in older adults.
- Hepatic impairment: Dose reduction recommended due to decreased metabolism
- Renal impairment: Use with caution; the active metabolite cetirizine is renally excreted
- Cardiovascular disease: Risk of arrhythmias, hypotension
- Electrolyte abnormalities: Hypokalemia, hypomagnesemia increase risk of QT prolongation
- Narrow-angle glaucoma: Anticholinergic effects may precipitate acute angle closure
- Prostatic hypertrophy or urinary obstruction: Risk of urinary retention
- Seizure disorders: May lower seizure threshold
- Asthma or COPD: Anticholinergic drying of secretions may worsen respiratory status
Pregnancy and lactation
Pregnancy: Hydroxyzine is associated with an increased risk of congenital malformations when used in the first trimester. It should be avoided during early pregnancy. If use is necessary later in pregnancy, the benefits must clearly outweigh risks.
Lactation: Hydroxyzine is excreted in breast milk. Due to potential sedation and other adverse effects in the nursing infant, breastfeeding is not recommended during treatment.
Activities requiring alertness
Patients should be warned against driving, operating machinery, or engaging in activities requiring mental alertness until they know how hydroxyzine affects them, as it causes significant sedation.
Drug interactions
Hydroxyzine has multiple clinically significant drug interactions:
CNS depressants
Effect: Additive CNS depression leading to increased sedation, respiratory depression, and impaired psychomotor function.
Examples:
- Benzodiazepines
- Opioids
- Barbiturates
- Alcohol
- Other sedating antihistamines
- Sedative-hypnotics
- General anesthetics
Management: Use together with caution; reduce doses of one or both agents. Warn patients about the danger of concurrent alcohol use.
QT-prolonging agents
Effect: Additive QT prolongation with increased risk of torsades de pointes.
Examples:
- Class IA antiarrhythmics (quinidine, procainamide)
- Class III antiarrhythmics (amiodarone, sotalol)
- Macrolide antibiotics (erythromycin, clarithromycin)
- Fluoroquinolones (moxifloxacin)
- Antipsychotics (haloperidol, ziprasidone, quetiapine)
- Ondansetron
- Methadone
Management: Avoid combination if possible. If use is necessary, monitor ECG and electrolytes.
Anticholinergic agents
Effect: Additive anticholinergic effects.
Examples:
- Tricyclic antidepressants
- Antipsychotics
- Antiparkinson agents (benztropine)
- Antispasmodics
- Other antihistamines
Management: Use with caution, especially in elderly. Monitor for urinary retention, constipation, confusion, and dry mouth.
CYP3A4 inhibitors and inducers
CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, grapefruit juice): May increase hydroxyzine levels, enhancing effects and toxicity.
CYP3A4 inducers (rifampin, phenytoin, carbamazepine, St. John's wort): May decrease hydroxyzine levels, reducing efficacy.
Management: Monitor for changes in efficacy or adverse effects; adjust dose as needed.
Other interactions
- MAO inhibitors: May prolong and intensify anticholinergic effects; use with caution
- Epinephrine: Hydroxyzine may reverse the vasopressor effect of epinephrine
- Anticonvulsants: Hydroxyzine may interfere with seizure control
Clinical pearls
- Hydroxyzine vs. cetirizine: Hydroxyzine is the parent compound and a first-generation antihistamine that crosses the blood-brain barrier, causing significant sedation. Cetirizine (Zyrtec) is its active metabolite and a second-generation antihistamine with minimal CNS penetration and less sedation, making it preferred for chronic allergic conditions.
- Two salt forms: Hydroxyzine is available as hydroxyzine hydrochloride (Atarax) and hydroxyzine pamoate (Vistaril). Both have equivalent efficacy; the pamoate form is used primarily for anxiety, while hydrochloride is marketed more for pruritus, though both salts are effective for both indications.
- Non-addictive anxiolytic: Unlike benzodiazepines, hydroxyzine does not cause physical dependence, tolerance, or withdrawal. This makes it a safer option for patients with substance use disorders or those requiring long-term anxiolytic therapy, though efficacy for chronic anxiety is limited.
- ECG monitoring: Given the QT prolongation risk, consider baseline ECG in patients with risk factors (cardiac disease, electrolyte abnormalities, elderly, concomitant QT-prolonging drugs). Correct electrolyte abnormalities before initiating therapy.
- Beers Criteria: Hydroxyzine is listed as potentially inappropriate in patients ≥65 years due to high anticholinergic burden and risk of confusion, falls, and cognitive impairment. Consider alternatives in elderly populations.
- Rapid onset: Anxiolytic and antipruritic effects typically begin within 15 to 30 minutes, making hydroxyzine useful for acute symptom management.
- Preoperative use: Hydroxyzine is often used for preoperative anxiolysis and sedation. It also reduces opioid requirements postoperatively through its opioid-sparing effect.
- Not a controlled substance: Hydroxyzine is not scheduled under the Controlled Substances Act, making it easier to prescribe than benzodiazepines.
- Avoid abrupt discontinuation of CNS depressants: If hydroxyzine has been used with other CNS depressants, taper combinations carefully to avoid withdrawal syndromes from the other agents.
- Interferes with allergy testing: Like all antihistamines, hydroxyzine can suppress skin test reactivity. Discontinue at least 3 to 7 days before allergy testing.
Practice questions
1. A 68-year-old woman with a history of atrial fibrillation on amiodarone presents to her primary care physician with complaints of chronic itching due to eczema. She has tried topical corticosteroids with minimal relief. Her physician prescribes hydroxyzine for symptomatic relief. Three days later, she presents to the emergency department with palpitations. An ECG shows a prolonged QT interval and polymorphic ventricular tachycardia consistent with torsades de pointes. Which of the following best explains this patient's presentation?
2. A 72-year-old man with benign prostatic hyperplasia is started on hydroxyzine for generalized anxiety disorder by his psychiatrist. Two days later, he presents to the emergency department with suprapubic pain, inability to void for 8 hours, and a palpable bladder on examination. A bladder scan shows 800 mL of urine. Which property of hydroxyzine is most directly responsible for this presentation?
3. A 45-year-old woman with chronic idiopathic urticaria has been taking hydroxyzine 25 mg at bedtime for the past 3 years with good control of her symptoms. She visits her allergist for evaluation of new-onset seasonal allergic rhinitis. Skin prick testing is performed with common environmental allergens. Results show no wheal or flare reaction to any allergen, including positive controls. What is the most likely explanation for these results?
Frequently asked questions
How does hydroxyzine work?
Hydroxyzine works by blocking H1 histamine receptors in both the periphery and the central nervous system. This reduces allergic symptoms like itching and also produces anxiolytic and sedative effects through CNS depression. It also has anticholinergic properties that contribute to side effects like dry mouth and sedation. Unlike benzodiazepines, it does not act on GABA receptors and does not cause dependence.
What are the side effects of hydroxyzine?
The most common side effects of hydroxyzine are sedation, drowsiness, dry mouth, and dizziness. Anticholinergic effects include blurred vision, urinary retention, and constipation. A serious cardiovascular side effect is QT interval prolongation, which can lead to dangerous arrhythmias like torsades de pointes. Elderly patients are at higher risk for confusion, falls, and cognitive impairment. Hypersensitivity reactions are rare but can occur.
Is hydroxyzine a controlled substance?
No, hydroxyzine is not a controlled substance under the Controlled Substances Act. Unlike benzodiazepines, hydroxyzine does not have abuse potential and does not cause physical dependence or withdrawal symptoms. This makes it easier to prescribe and a safer option for patients with a history of substance use disorders who need treatment for anxiety or pruritus.
Can you take hydroxyzine during pregnancy?
Hydroxyzine should be avoided during pregnancy, especially in the first trimester, as it has been associated with an increased risk of congenital malformations and fetal harm in some studies. If use is necessary later in pregnancy, the benefits must clearly outweigh the risks, and it should only be used under close medical supervision. Alternative treatments for anxiety and pruritus should be considered in pregnant patients.
Hydroxyzine vs cetirizine — what is the difference?
Hydroxyzine is a first-generation antihistamine that crosses the blood-brain barrier, causing significant sedation and anticholinergic effects, and is used for anxiety, pruritus, and sedation. Cetirizine is the active metabolite of hydroxyzine and a second-generation antihistamine with minimal CNS penetration, resulting in much less sedation. Cetirizine is preferred for chronic allergic conditions like allergic rhinitis, while hydroxyzine is used when sedation is desired or for short-term anxiety management.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: N05BB01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.