Hydroxyzine

Introduction Overview

Generic Name

hydroxyzine

Brand Name

ANX, Vistaril, Atarax, Vistaril IM, Hyzine, Vistaject-50, Rezine

Dosage Form

Oral tablets, oral capsules, oral suspension (liquid), intramuscular injection

Drug Class

Antihistamines; Miscellaneous anxiolytics, sedatives and hypnotics

Pharmacokinetics

Absorption:
Hydroxyzine is well absorbed from the gastrointestinal tract following oral administration. The onset of action typically occurs within 15 to 30 minutes, reflecting rapid absorption. The drug's bioavailability may be influenced by factors such as food intake and gastric pH, though these effects are generally minimal. Peak plasma concentrations are usually achieved within 2 hours post-dose. The oral suspension requires thorough shaking prior to dosing to ensure accurate dosing and optimal absorption.

Distribution:
Once absorbed, hydroxyzine is widely distributed throughout the body tissues, including the central nervous system, which underpins its sedative properties. It is known to cross the blood-brain barrier effectively. Hydroxyzine exhibits moderate plasma protein binding, approximately 70-75%, mainly to albumin. The volume of distribution is relatively large, indicating extensive tissue binding which contributes to its prolonged duration of action. Special patient populations, such as those with impaired plasma protein levels, may experience altered drug distribution.

Metabolism:
Hydroxyzine undergoes hepatic metabolism predominantly via the cytochrome P450 enzyme system, including CYP3A4 and CYP2D6 isoenzymes. It is metabolized mainly into cetirizine, which itself has antihistaminic activity but reduced sedative effects. The metabolic pathways involve oxidative reactions, dealkylation, and other phase I metabolic processes, while minimal phase II conjugations occur. Genetic polymorphisms affecting CYP450 enzymes can lead to inter-individual variability in metabolism and therapeutic response.

Elimination:
The elimination half-life of hydroxyzine in adults is approximately 20 hours, though it may range from 14 to 25 hours depending on individual factors such as age, hepatic and renal function. The drug and its metabolites are primarily excreted via the kidneys with renal clearance playing a significant role. About 70% of the dose is eliminated in urine mostly as metabolites, and around 14-30% is excreted via feces. Impaired renal or hepatic function can prolong elimination half-life, requiring dosing adjustments. It takes approximately 5 half-lives, or about 100 hours, for hydroxyzine to be almost completely cleared from the system.

Dosage Forms

Available Dosage Forms:
- Oral capsules: 10 mg, 25 mg, 50 mg
- Oral tablets: 25 mg, 50 mg, 100 mg
- Oral suspension (liquid): 10 mg/5 mL
- Intramuscular injection (commonly Vistaril IM): available in 25 mg/mL and 50 mg/mL concentrations

Dosages for Adults and Adolescents:
- Anxiety and tension: typically 50-100 mg orally up to four times daily. Max daily doses usually do not exceed 400 mg.
- Pruritus due to allergic conditions: 25 mg three to four times daily.
- Sedation adjunct during anesthesia: doses vary based on clinical context, often 50-100 mg intramuscularly preoperatively.
- Oral suspension dosing is weight-based for pediatric patients, and careful measurement with supplied syringe or medicine cup is essential.

Specific Patient Populations:
- Elderly patients: lower doses are recommended due to increased sensitivity and risk of confusion or sedation.
- Renal impairment: dose adjustments may be necessary to avoid accumulation and toxicity.
- Pregnant or breastfeeding women: hydroxyzine use is generally contraindicated or should be carefully weighed against potential risks, given possible teratogenicity and uncertain excretion in breast milk.
- Pediatric use: oral suspension allows for precise dosing; however, safety and efficacy in children under six years must be determined by a healthcare provider.
- Short-term use only: recommended treatment duration for anxiety should not exceed 4 months to minimize risk of adverse effects.

Mechanism Of Action

Hydroxyzine exerts its primary pharmacological effects through antagonism of peripheral and central histamine H1 receptors. By competitively inhibiting these receptors, hydroxyzine prevents the actions of endogenous histamine, thus alleviating symptoms of allergic reactions such as pruritus, urticaria, and skin irritation. This blockade reduces capillary permeability and suppresses vasodilation and sensory nerve stimulation mediated by histamine.

Additionally, hydroxyzine possesses significant central nervous system depressant activity. This is attributed not only to its antihistaminic properties but also its action on various neurotransmitter systems including cholinergic, serotonergic, and dopaminergic pathways, contributing to anxiolytic and sedative effects. The drug's sedative mechanism is believed to involve the inhibition of histaminergic neurons in the central nervous system, leading to decreased arousal and anxiolysis.

Hydroxyzine also exhibits anticholinergic properties, which contribute to its drying effects on mucous membranes and may influence side effect profiles such as dry mouth and urinary retention. Compared to other first-generation antihistamines, hydroxyzine’s anxiolytic efficacy distinguishes it, making it useful in managing anxiety and tension states as an adjunct or alternative to benzodiazepines.

Clinical trials and pharmacodynamic studies support hydroxyzine’s use in preoperative sedation and management of anxiety disorders, highlighting its dual role in histamine receptor antagonism and voluntary CNS depression. Its metabolite, cetirizine, retains antihistaminic effects but lacks significant sedative properties, underscoring hydroxyzine’s unique clinical niche. The mechanism is comparable but distinct from benzodiazepines, reflecting a different receptor target profile and side effect spectrum.

Pharmacological Actions

Competitive antagonism of peripheral and central H1 histamine receptors leading to anti-allergic effects
Central nervous system depressant effects producing sedation and anxiolysis
Anticholinergic activity contributing to mucosal drying and reduced secretions
Reduction of pruritus and urticaria symptoms through histamine blockade
Prevention of histamine-induced vasodilation and capillary permeability
Diminishing CNS arousal by inhibiting histaminergic neurotransmission
Used as a premedicant in anesthesia for its sedative and antiemetic properties
Modulation of serotonergic and dopaminergic pathways influencing anxiety relief
Exertion of antiemetic effects possibly through central and peripheral mechanisms
Metabolized to cetirizine, a selective peripheral H1 antagonist with reduced sedation

Therapeutic Or Clinical Uses

Treatment of anxiety and tension disorders as a short-term anxiolytic
Management of pruritus and allergic skin manifestations such as urticaria and contact dermatitis
Sedative premedication prior to and during surgical procedures to reduce anxiety
Adjunctive therapy postoperatively for sedation and nausea control
Relief of itching associated with allergic reactions including poison ivy and insect bites
Reduces histamine-mediated symptoms in allergic conditions
Used off-label for nausea and vomiting associated with various conditions
Alternative anxiolytic for patients intolerant or contraindicated to benzodiazepines
Palliative treatment of generalized pruritus related to chronic medical conditions
Short-term management of sleep disturbances related to anxiety
Pediatric use for symptomatic relief of allergies with appropriate dosing and monitoring
Adjunct in the treatment of allergic urticaria and atopic dermatitis
Prevention of motion sickness in veterinary applications (not detailed here but known)
Supports sedation in emergency medical settings where rapid onset is required

Side Or Adverse Effects

Drowsiness and sedation, the most common adverse effect
Dry mouth due to anticholinergic effects
Headache of varying intensity
Skin rash and, rarely, severe hypersensitivity reactions including Stevens-Johnson syndrome
Confusion and cognitive impairment, especially in elderly patients
Tachycardia or palpitations, signaling potential cardiac effects
Extrapyramidal symptoms such as tremors, dystonia, or restless movements in rare cases
Hypotension and dizziness, especially on standing (orthostatic hypotension)
Nausea and gastrointestinal discomfort
Rare cases of seizures or convulsions, particularly in overdose
Increased risk of QT interval prolongation and cardiac arrhythmias
Potential for paradoxical excitation or nervousness in some individuals
Allergic reactions including urticaria, angioedema, or anaphylaxis
Blurred vision and urinary retention due to anticholinergic side effects
Risk of respiratory depression when combined with other CNS depressants

Precautions

Use with caution in patients with pre-existing heart disease, especially those with long QT syndrome
Avoid use in patients with known allergy to hydroxyzine or related antihistamines such as cetirizine or levocetirizine
Screen for electrolyte imbalances before initiating therapy, as these may precipitate arrhythmias
Exercise caution in patients with glaucoma due to potential worsening from anticholinergic effects
Monitor elderly patients closely for increased sedation or confusion
Avoid use in patients with bladder obstruction or urinary retention
Avoid concomitant use with other CNS depressants without medical supervision
Pregnant or breastfeeding women should consult healthcare providers due to potential teratogenic effects and unknown breast milk excretion
Hydroxyzine should not be used long-term (>4 months) due to lack of safety data
Advise patients to avoid activities requiring alertness, such as driving or operating machinery, especially during initiation
Be alert for signs of severe skin reactions and discontinue if rash or blistering develops
Use caution in patients with impaired hepatic or renal function due to altered pharmacokinetics
Assess for potential drug interactions that may increase risk of cardiac or CNS adverse effects
Patients with a personal or family history of seizures require careful monitoring
Hydroxyzine may exacerbate anticholinergic burden when used with other medications

Warnings

Hydroxyzine may cause birth defects; avoid use during pregnancy unless clearly needed
Can cause serious heart problems including QT prolongation and arrhythmias, especially when used with other QT-prolonging drugs
May impair cognitive and motor functions; caution advised when performing tasks requiring alertness
Risk of severe hypersensitivity and skin reactions necessitates immediate discontinuation if symptoms occur
Using alcohol with hydroxyzine increases risk of sedation and respiratory depression
Discontinue immediately if seizures, tremors, or restless muscle movements develop
Not recommended for long-term use due to potential cognitive risks and limited safety data
Potential for additive CNS depression when combined with other sedatives, opioids, or anesthetics
Increased risk of adverse effects in older adults, including falls due to sedation and hypotension
Can potentiate anticholinergic effects leading to serious complications in susceptible individuals
Use with caution in patients with a history of prolonged QT interval or cardiac arrhythmias
Hydroxyzine overdose can cause severe CNS depression and requires urgent medical intervention
Careful assessment advised before prescribing to patients with a history of substance use disorder
Pregnancy category C; benefits must outweigh risks
Not to be given to children without medical advice due to risk of paradoxical CNS excitation

Contraindication

Known hypersensitivity to hydroxyzine or any component of the formulation
Allergy to cetirizine or levocetirizine due to cross-reactivity
Patients with congenital or acquired long QT syndrome
Individuals with a history of severe cardiac arrhythmias
Concurrent use with other drugs known to prolong the QT interval without appropriate monitoring
Patients with severe respiratory depression or compromised respiratory function
Known bladder obstruction or severe urinary retention
Glaucoma, especially narrow-angle type with increased risk of worsening
Children below specified age limits without medical supervision
Pregnant women unless benefits clearly outweigh risks
Patients with severe hepatic or renal impairment where dosage adjustment is not possible
Individuals with history of epileptic seizures without careful monitoring
Use is contraindicated in patients with known hypersensitivity reactions to any first-generation antihistamines
Concurrent use with monoamine oxidase inhibitors (MAOIs) is generally avoided
Patients who have experienced prior severe anticholinergic reactions to similar drugs

Drug Interactions

Additive CNS depressant effects with benzodiazepines, opioids, sedatives, and hypnotics
Increased risk of QT interval prolongation when combined with antiarrhythmics, certain antibiotics (macrolides, fluoroquinolones), antipsychotics, and antidepressants
May increase sedation and respiratory depression when used with alcohol
Potential interaction with CYP3A4 and CYP2D6 inhibitors leading to elevated hydroxyzine levels
Additive anticholinergic effects with other anticholinergic medications causing increased dry mouth, urinary retention, and confusion
Concomitant use with MAO inhibitors may potentiate adverse CNS effects
May interact with medications affecting electrolyte balance, increasing risk for cardiac arrhythmias
Coadministration with muscle relaxants can exacerbate sedation and respiratory depression
Interaction with seizure medications may alter seizure threshold or hydroxyzine plasma levels
Drugs affecting hepatic metabolism can modify hydroxyzine clearance and efficacy
Combining with narcotic pain medications enhances sedation risk
Concomitant use with other antihistamines can increase anticholinergic and sedation side effects
Herbal supplements such as valerian or kava may potentiate sedation when combined
Use with catecholamine depleting drugs may increase risk of hypotension
Interactions with cancer chemotherapeutic agents such as arsenic trioxide that prolong QT interval

Preparations Of The Drug

Oral capsules available in strengths of 10 mg, 25 mg, and 50 mg for flexible dosing
Oral tablets in 25 mg, 50 mg, and 100 mg allowing for titration based on clinical response
Oral suspension formulated as 10 mg per 5 mL for accurate pediatric dosing and easier administration
Intramuscular injection preparations, such as Vistaril IM, in 25 mg/mL and 50 mg/mL concentrations for rapid sedation and premedication
Combination formulations are not currently marketed
Formulations are supplied with dosing devices to ensure precise measurement for liquid forms
Available generically and under multiple brand names to enhance accessibility
Stable at room temperature, requiring protection from moisture and heat to maintain potency
Parenteral formulations used primarily in hospital or surgical settings due to injection route
Oral preparations formulated for good taste masking to improve pediatric compliance
Non-enteric coated tablets and capsules allowing prompt dissolution and absorption
Packaging includes safety features to prevent accidental ingestion, especially in pediatric forms
All formulations undergo rigorous quality control to meet pharmacopeial standards
FDA-approved monographs detail excipients and storage conditions for each formulation
Specialty compounding preparations may be available for off-label dosage adjustments under medical supervision