Hydroxyzine: Effect as a sedating antihistamine

Hydroxyzine (brand names Atarax and generics) is a first-generation H1 antihistamine with pronounced sedating and anxiolytic effects. Unlike modern, non-sedating antihistamines, hydroxyzine crosses the blood brain barrier and exerts central effects. In Germany, hydroxyzine has been used for decades in allergy, dermatology, and psychiatry, primarily for pruritus (itching), generalized anxiety disorder, and sleep induction. Since 2015, there have been additional safety warnings regarding QT prolongation, resulting in more targeted use with cardiac risk assessment.

Hydroxyzine is prescription-only and is offered in several dosage forms: tablets of 25 mg, drops, syrup for children, and in some countries as an injection. An important feature is that hydroxyzine is partially metabolized to cetirizine, a modern, non-sedating antihistamine. In clinical practice, hydroxyzine is used primarily when the central depressant component is desired, such as in pruritus with sleep disturbances or in anxiety.

Mechanism of action

Hydroxyzine is a piperazine derivative and competitively blocks H1 histamine receptors in the periphery and central nervous system. This blockade prevents histamine-induced effects such as itching, bronchoconstriction, vasodilation, and increased permeability. Because hydroxyzine is lipophilic and crosses the blood brain barrier well, it blocks central H1 receptors and causes sedation, anxiolysis, and partial antiemetic effects.

In addition to H1 blockade, hydroxyzine has anticholinergic, antiserotonergic, and antialpha adrenergic properties that contribute to sedative and anxiolytic effects, but also cause typical side effects such as dry mouth, accommodation disorders, and orthostatic hypotension. Effects on the limbic system contribute to the anxiolytic component, making hydroxyzine an alternative to benzodiazepines in generalized anxiety disorder without their addiction potential.

Pharmacokinetically, hydroxyzine is rapidly absorbed following oral administration with onset of action within 15 to 30 minutes and peak effect after 2 hours. The elimination half-life is approximately 14 to 25 hours, allowing for administration one to three times daily. Hydroxyzine is hepatically metabolized via CYP3A4 and aldehyde oxidase. The main metabolite, cetirizine, has antihistamine activity with significantly lower central component and a half-life of approximately 10 hours.

Indications

• Pruritus of various causes, especially in chronic urticaria, atopic dermatitis, pruritus associated with liver disease, or paraneoplastic itching
• Generalized anxiety disorder, often as an alternative to benzodiazepines due to lower addiction potential
• Sleep induction in anxiety and restlessness, short-term sleep induction in chronic pruritus with sleep disturbance
• Premedication in anesthesia, for sedation and anxiolysis before surgery
• Antiemetic therapy for nausea, vomiting, motion sickness, in specific indications
• Adjunctive therapy in alcohol or opioid withdrawal, in specialized settings

Hydroxyzine is not suitable for long-term use as a sleep medication. Use is short to medium-term; with chronic pruritus or anxiety disorder, longer-term use may be appropriate in individual cases.

Dosage and administration

Pruritus in adults: 25 mg three to four times daily, maximum daily dose 100 mg per day. In elderly patients maximum daily dose 50 mg.

Generalized anxiety disorder in adults: 12.5 to 25 mg three times daily, maximum daily dose 100 mg.

Sleep induction: 25 to 50 mg approximately half an hour before bedtime.

Premedication: 50 to 100 mg one to two hours before surgery.

Pediatric: 1 to 2 mg per kg per day divided into multiple single doses, maximum 50 mg per day in children under 40 kg, 100 mg per day from 40 kg.

Administration: Take tablets or drops with water, regardless of meals. For sleep induction take in the evening; for pruritus or anxiety distribute throughout the day.

Renal impairment: in moderate impairment dose reduction (50 percent of standard dose), in severe impairment use with caution. Hepatic impairment: consider dose reduction due to metabolite accumulation.

Important: due to QT prolongation, maximum dose 100 mg per day in adults, 50 mg in elderly patients and 2 mg per kg in children.

Side effects

Very common: Tiredness, drowsiness, sedation. This effect can be pronounced especially at the start of therapy.

Common: Dry mouth, headache, blurred vision, accommodation disorder, dizziness, nausea, constipation, tremor, concentration difficulties, paradoxical insomnia.

Uncommon to rare: Skin rash, itching, tachycardia, hypotension, urinary retention, confusion, hallucinations (especially in elderly patients), seizures (at overdose), hepatotoxicity.

Very rare: QT prolongation with risk of Torsade de Pointes, severe skin reactions such as Stevens Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), allergic reactions including anaphylaxis.

Note: in elderly patients, increased risk of anticholinergic side effects, cognitive impairment, and fall risk. Hydroxyzine is listed on the PRISCUS list (potentially inappropriate medication for elderly patients).

Drug interactions

• Other central depressants (benzodiazepines, opioids, alcohol, antipsychotics): additive sedation and respiratory depression. Combine with caution.
• Anticholinergics (atropine, tricyclic antidepressants, antiparkinson agents): additive anticholinergic effect. Confusion and urinary retention increased.
• Substances with QT prolonging effect (Class Ia and III antiarrhythmics, macrolides, fluoroquinolones, antipsychotics, methadone): contraindicated or use with strict caution.
• CYP3A4 inhibitors (ketoconazole, erythromycin, ritonavir): increased hydroxyzine levels.
• MAO inhibitors: prolonged and intensified effect of hydroxyzine.
• Antihypertensives: additive hypotension.

Special precautions

Pregnancy: not recommended, especially in the first trimester. If absolutely necessary, use the lowest effective dose for the shortest duration. Breastfeeding: passes into breast milk, sedation possible in infants. Use only with strict indication, possibly with breastfeeding pause or alternative.

Children: approved from 12 months, however QT risk must be considered. Do not use as a sleep medication without medical indication.

Elderly patients: caution regarding anticholinergic side effects, cognitive impairment, fall risk, and QT prolongation. Maximum daily dose 50 mg.

Contraindications: known hypersensitivity to hydroxyzine or cetirizine, congenital Long QT syndrome, concurrent use with QT prolonging substances, severe renal impairment, severe dementia with anticholinergic sensitivity, narrow-angle glaucoma, prostatic hyperplasia with residual urine.

Before use: history of cardiac disease, syncope, family history of sudden cardiac death. If at risk, ECG to assess QT interval. Check concomitant medications.

During therapy: in at-risk patients ECG monitoring, clinical monitoring for efficacy and side effects.

Lifestyle: no alcohol during therapy, safe behavior due to sedation. With chronic use, regular medical reevaluation of indication.

Ability to drive: Hydroxyzine can significantly impair reaction capacity. For the first days and after dose adjustments, do not drive or operate heavy machinery. With stable progression, individual assessment with treating physician.

You might also be interested in

• Cetirizine, active metabolite of hydroxyzine
• Diphenhydramine, another sedating antihistamine
• Promethazine, sedating phenothiazine antihistamine
• Loratadine, non-sedating antihistamine
• Lorazepam, benzodiazepine anxiolytic

Frequently asked questions

Sources

• Gelbe Liste, Hydroxyzine active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• German Society for Allergology and Clinical Immunology (DGAKI)
• German Society for Psychiatry, Psychotherapy and Neurology
• AWMF Guidelines on pruritus and anxiety disorders