What is hydroxyzine most similar to?: A Comparative Look at Antihistamines

October 10, 2025 •

4 min read

First-generation antihistamines, such as hydroxyzine, have been in use since the 1950s to treat allergies and anxiety. This class of medication is frequently discussed in comparison with others, and if you're asking what is hydroxyzine most similar to, the answer often points directly to diphenhydramine (Benadryl) due to their overlapping sedative and anti-itch effects.

Quick Summary

Hydroxyzine, a prescription first-generation antihistamine, is most comparable to over-the-counter diphenhydramine (Benadryl) for its sedative and anti-itch properties. It differs from newer antihistamines and anti-anxiety drugs like benzodiazepines in its usage and side effect profile.

Key Points

Closest Relative: Hydroxyzine is most similar to diphenhydramine (Benadryl) as both are first-generation antihistamines with strong sedative effects.
Prescription vs. OTC: A key difference is that hydroxyzine is prescription-only, while diphenhydramine is available over-the-counter.
Anxiety Treatment: Only hydroxyzine is FDA-approved for treating anxiety, unlike Benadryl, which is not indicated for this use.
Metabolite Relationship: Hydroxyzine is the parent drug of cetirizine (Zyrtec), but hydroxyzine is much more sedating and is prescription-only.
Not a Benzodiazepine: For anxiety, hydroxyzine is a non-addictive alternative to benzodiazepines like Xanax, which have a high potential for dependence.
Longer Action: Hydroxyzine has a longer duration of action compared to diphenhydramine, meaning its sedative effects can last longer.
Multiple Uses: Beyond allergies and anxiety, hydroxyzine is also used as a sedative for procedures and to treat nausea.

Understanding Hydroxyzine

Hydroxyzine is a prescription-only first-generation antihistamine used to treat several conditions, including anxiety, insomnia, and itching from allergic reactions like hives. It belongs to a chemical class known as piperazines. While it is primarily known for its antihistamine effects, its strong sedative and anxiolytic (anxiety-reducing) properties are also key to its therapeutic use. This is because it readily crosses the blood-brain barrier to act on the central nervous system (CNS).

There are two main forms of hydroxyzine: hydroxyzine hydrochloride (brand name Atarax, though the brand is discontinued) and hydroxyzine pamoate (brand name Vistaril). Both versions contain the same active ingredient and have similar therapeutic uses, but they differ in their formulation and cost, with pamoate often being cheaper.

Hydroxyzine vs. Diphenhydramine (Benadryl)

When it comes to answering the question, 'What is hydroxyzine most similar to?', the most common answer is diphenhydramine, the active ingredient in Benadryl. Both are first-generation antihistamines that act by blocking the body's histamine receptors, which helps relieve allergic symptoms like itching and hives. Their shared ability to cause drowsiness is why both are also sometimes used for sedation or sleep.

However, there are significant differences:

Availability: Diphenhydramine is available over-the-counter, while hydroxyzine requires a prescription from a doctor.
Duration of Action: Hydroxyzine remains in the body for a longer period than diphenhydramine, meaning its effects, including drowsiness, can last longer.
Approved Uses: Only hydroxyzine is FDA-approved for treating anxiety. While diphenhydramine can cause sedation, it is not officially sanctioned for anxiety treatment. It is also more frequently used for cold symptoms, like a runny nose.

Hydroxyzine vs. Cetirizine (Zyrtec)

Cetirizine (Zyrtec) is another important antihistamine to compare with hydroxyzine. Interestingly, cetirizine is a metabolite of hydroxyzine, meaning the body breaks down hydroxyzine into cetirizine.

Key Differences between Hydroxyzine and Cetirizine

Generations: Hydroxyzine is a first-generation antihistamine, while cetirizine is a second-generation one.
Sedation: Cetirizine is significantly less sedating than hydroxyzine because it does not cross the blood-brain barrier as readily. This makes it a preferred option for daytime allergy relief.
Availability: Cetirizine is widely available over-the-counter for allergies, whereas hydroxyzine remains prescription-only.
Anxiety Treatment: Only hydroxyzine is used to treat anxiety, a use for which cetirizine is ineffective.

Hydroxyzine vs. Benzodiazepines (e.g., Xanax, Valium)

For anxiety treatment, hydroxyzine is often compared to benzodiazepines like alprazolam (Xanax) and diazepam (Valium), but they are fundamentally different drugs.

Comparison with Benzodiazepines

Drug Class: Hydroxyzine is an antihistamine, while benzodiazepines are CNS depressants that enhance the effect of the neurotransmitter GABA.
Risk of Dependence: A major distinction is the risk of dependence. Benzodiazepines are controlled substances with a high potential for addiction and withdrawal symptoms, even with short-term use. Hydroxyzine does not carry this risk.
Primary Mechanism: While both cause sedation, hydroxyzine's calming effect is due to its antihistaminic and serotonergic properties, whereas benzodiazepines work by increasing GABA activity.

Hydroxyzine vs. Similar Medications Comparison


Feature	Hydroxyzine	Diphenhydramine (Benadryl)	Cetirizine (Zyrtec)	Benzodiazepines (e.g., Xanax)
Drug Class	First-Generation Antihistamine	First-Generation Antihistamine	Second-Generation Antihistamine	Benzodiazepine (CNS Depressant)
Availability	Prescription only	Over-the-counter	Over-the-counter	Prescription only (Controlled Substance)
Sedation	High	High	Low (non-sedating at recommended doses)	High
Anxiety Treatment	Yes (FDA approved for short-term use)	No (sometimes used off-label)	No	Yes (FDA approved)
Allergy Treatment	Yes (effective for itching/hives)	Yes (effective for allergies)	Yes (effective for allergies/hives)	No
Risk of Dependence	No	No	No	Yes (High risk)
Mechanism of Action	Blocks histamine H1 and muscarinic receptors	Blocks histamine H1 and muscarinic receptors	Blocks peripheral histamine H1 receptors	Increases GABA activity
Duration	Longer half-life	Shorter half-life	Longer half-life	Short to intermediate half-life

Other Relevant Uses of Hydroxyzine

Hydroxyzine's applications extend beyond anxiety and simple allergies due to its unique pharmacology. Some of its other notable uses include:

Sedation for procedures: It is used as a sedative before and after general anesthesia to help patients relax.
Nausea and vomiting: It can be used to control nausea and vomiting, including symptoms related to motion sickness.
Alcohol withdrawal: It can be used to manage anxiety and tension associated with alcohol withdrawal.
Pruritus relief: Its strong antihistaminic effect makes it effective for severe itching (pruritus) caused by chronic conditions like eczema.

Potential Side Effects and Safety Considerations

As with any medication, hydroxyzine carries a risk of side effects, which are particularly important to consider given its strong CNS effects. The most common side effects include:

Drowsiness
Dry mouth
Headache
Dizziness

More serious side effects are possible, such as QT prolongation, a potentially dangerous heart rhythm problem, which warrants careful consideration for those with heart conditions. Due to anticholinergic effects, it should be used with caution in elderly patients, as it can increase the risk of confusion and falls. Hydroxyzine can also increase the sedative effects of alcohol and other CNS depressants.

Conclusion

When considering what is hydroxyzine most similar to, diphenhydramine (Benadryl) emerges as the closest relative due to their shared drug class and sedative properties. However, their differences in availability, duration, and approved uses are critical distinctions. For allergies, hydroxyzine shares a metabolite in cetirizine (Zyrtec), but is far more sedating and carries additional uses for anxiety. For anxiety, hydroxyzine offers a non-habit-forming alternative to benzodiazepines like Xanax or Valium, though its sedative profile and potential side effects require careful medical supervision. Ultimately, the best choice depends on the specific condition being treated, the desired effects, and the individual's overall health profile, making a consultation with a healthcare provider essential before use.

Frequently Asked Questions

No, hydroxyzine (e.g., Vistaril) and Benadryl (diphenhydramine) are not the same medication. They are both first-generation antihistamines, but hydroxyzine requires a prescription and is also approved for anxiety, while Benadryl is over-the-counter and not for anxiety treatment.

Both are quite sedating, but some reports indicate that hydroxyzine may produce a more potent sedative effect than Benadryl. The longer duration of action of hydroxyzine also means its drowsiness effects may last longer.

While both can treat anxiety and cause sedation, hydroxyzine and Xanax are not similar in their fundamental mechanism. Hydroxyzine is a non-addictive antihistamine, whereas Xanax is a benzodiazepine, a controlled substance with a high potential for dependence.

Cetirizine (Zyrtec) is actually a metabolite of hydroxyzine. However, cetirizine is a non-sedating second-generation antihistamine used only for allergies, whereas hydroxyzine is a sedating first-generation antihistamine also used for anxiety.

Hydroxyzine is prescribed for short-term anxiety treatment due to its sedative and anxiolytic properties, which arise from its effect on histamine and serotonin levels in the brain. It is often used as a temporary measure while other long-term anxiety medications take effect.

Hydroxyzine's sedative effects make it useful for occasional sleep disturbances, but it is not recommended for long-term insomnia. Its use for sleep should be supervised by a healthcare provider.

Both versions contain the same active ingredient and are used for similar conditions like anxiety and itching. The main differences are the salt compound used, the available dosage forms (pamoate is only in capsules), and the cost.