Introduction
Hydroxyzine is a first-generation antihistamine with additional anxiolytic, sedative, and antiemetic properties. Originally developed in the 1950s, it remains widely used in clinical practice for various indications. It is available as hydroxyzine hydrochloride (oral tablets and capsules) and hydroxyzine pamoate (oral suspension), with the pamoate salt being less soluble and potentially associated with reduced gastrointestinal side effects.
Mechanism of Action
Hydroxyzine primarily acts as a potent antagonist at histamine H₁ receptors, producing antihistaminic effects. Its anxiolytic and sedative properties are attributed to:
- Suppression of activity in key subcortical regions of the central nervous system
- Additional anticholinergic effects through muscarinic receptor blockade
- Moderate antagonism of serotonin receptors (5-HT₂A)
- Some evidence suggests effects on other neurotransmitter systems, though these are less well-characterized
The drug does not significantly affect GABA receptors, distinguishing it from benzodiazepines.
Indications
FDA-approved indications:- Management of anxiety disorders and tension
- Preoperative and postoperative adjunctive sedation
- Pruritus associated with allergic conditions
- Antiemetic therapy
- Insomnia (particularly anxiety-related)
- Adjunctive treatment in opioid withdrawal protocols
- Treatment of nausea and vomiting in palliative care
- Acute agitation in emergency settings
Dosage and Administration
Adults:- Anxiety: 50-100 mg PO QID (max 600 mg/day in divided doses)
- Pruritus: 25 mg PO TID-QID
- Preoperative sedation: 50-100 mg IM
- Antiemetic: 25-100 mg IM
- Initiate with lower doses (25 mg PO BID-TID) due to increased sensitivity
- <6 years: 50 mg/day PO in divided doses
- ≥6 years: 50-100 mg/day PO in divided doses
- Use with caution; consider dose reduction
- Not recommended in severe hepatic impairment
Pharmacokinetics
Absorption: Rapidly absorbed from GI tract; peak plasma concentrations within 2 hours Distribution: Widely distributed throughout body tissues; crosses blood-brain barrier and placenta Protein binding: Approximately 93% Metabolism: Extensive hepatic metabolism via aromatic oxidation to active metabolite cetirizine (less sedating) Elimination: Half-life of 20-25 hours; primarily excreted in feces via biliary elimination Bioavailability: Oral bioavailability is approximately 80%Contraindications
- Hypersensitivity to hydroxyzine or any component of formulation
- Early pregnancy (first trimester)
- Prolonged QT interval or known risk factors for torsades de pointes
- Acute narrow-angle glaucoma
- Urinary retention
- Concurrent use with MAO inhibitors
Warnings and Precautions
Boxed Warning: None Important precautions:- CNS depression: May impair mental/physical abilities required for hazardous tasks
- QT prolongation: Monitor ECG in patients with cardiac risk factors
- Anticholinergic effects: Use cautiously in elderly patients (increased risk of confusion, dry mouth, constipation)
- Seizure threshold: May lower seizure threshold in susceptible patients
- Respiratory depression: Use caution in patients with respiratory conditions
- Pregnancy: Category C (risk cannot be ruled out)
- Lactation: Excreted in breast milk; not recommended during breastfeeding
Drug Interactions
Major interactions:- CNS depressants (alcohol, benzodiazepines, opioids): Additive sedation
- Anticholinergic agents: Enhanced anticholinergic effects
- QT-prolonging agents: Increased risk of torsades de pointes
- MAO inhibitors: Increased anticholinergic and sedative effects
- CYP2D6 inhibitors: May increase hydroxyzine concentrations
- Epinephrine: Hydroxyzine may reduce vasopressor effects
Adverse Effects
Common (≥1%):- Sedation/drowsiness (40-50%)
- Dry mouth (20-30%)
- Headache (10-15%)
- Dizziness (5-10%)
- QT prolongation and torsades de pointes
- Seizures
- Severe hypotension
- Anaphylaxis
- Acute dystonic reactions
- Hepatitis (rare)
Monitoring Parameters
- Efficacy: Anxiety symptoms, pruritus severity, nausea/vomiting frequency
- Safety: Mental status changes, sedation level
- Cardiac: ECG monitoring in patients with risk factors for QT prolongation
- Anticholinergic effects: Mouth dryness, urinary retention, constipation
- Hepatic function: Periodically in long-term use
- Withdrawal symptoms: After prolonged high-dose therapy
Patient Education
- Take exactly as prescribed; do not increase dose without consultation
- Avoid alcohol and other CNS depressants
- Be cautious when driving or operating machinery
- Rise slowly from sitting/lying position to prevent dizziness
- Report palpitations, fainting, or difficulty urinating
- Use sugar-free lozenges or gum for dry mouth
- Do not stop abruptly after long-term use
- Inform all healthcare providers of hydroxyzine use
References
1. FDA Prescribing Information: Vistaril (hydroxyzine pamoate) and Atarax (hydroxyzine hydrochloride) 2. Katzung BG, et al. Basic & Clinical Pharmacology. 15th ed. 2021 3. Lexicomp Online: Hydroxyzine Monograph 4. Clinical Pharmacology [database online]. Tampa, FL: Elsevier 5. Patel TP, et al. The role of antihistamines in anxiety disorders: A systematic review of the literature. Expert Opin Pharmacother. 2017 6. Zeller S, et al. Systematic review of the efficacy and safety of hydroxyzine for the treatment of generalized anxiety disorder. J Psychiatr Pract. 2018 7. Church MK, et al. The role of histamine in human allergic disease. J Allergy Clin Immunol. 2020
This monograph is intended for educational purposes only and should not replace clinical judgment. Always consult appropriate references and prescribing information before making treatment decisions.