Antihistamines fall into two main groups: older “first-generation” drugs that tend to cause drowsiness, and newer “second-generation” options that generally don’t. Most of the popular choices are available over the counter, and they come in pills, nasal sprays, and eye drops. Here’s a breakdown of the common options and how they compare.
How Antihistamines Work
When your body encounters an allergen like pollen or pet dander, immune cells release a chemical called histamine. Histamine latches onto receptors in your nose, eyes, skin, and throat, triggering the sneezing, itching, runny nose, and hives you associate with allergies. Antihistamines block those receptors so histamine can’t activate them. The result is fewer symptoms, or milder ones.
The antihistamines most people think of target what are called H1 receptors, which are responsible for allergy symptoms. A separate category targets H2 receptors in the stomach lining, reducing acid production. These are different medications used for different problems, and both are covered below.
Second-Generation Antihistamines
These are the ones most people reach for today. They barely cross into the brain, which means they’re far less likely to make you drowsy. They also last longer, with half-lives of 12 to 24 hours, so a single daily dose covers most people all day. The most widely used options, all available without a prescription, include:
- Cetirizine (Zyrtec): Switched to OTC status in 2007. Effective and widely used, though it causes mild drowsiness in a small percentage of people. In sedation testing, cetirizine showed measurable impairment in about 1 out of every 5 tests, making it the most sedating of the second-generation group.
- Levocetirizine (Xyzal): A refined version of cetirizine that became available OTC in 2017. Dosed once daily.
- Loratadine (Claritin): One of the first second-generation antihistamines to go OTC, back in 2002. Its half-life ranges from 8 to 24 hours. In sedation testing it showed impairment in roughly 1 out of 4 tests, slightly more than fexofenadine.
- Desloratadine (Clarinex): The active breakdown product of loratadine, with a similar duration. Available by prescription.
- Fexofenadine (Allegra): Switched to OTC in 2011. In comprehensive sedation testing across 31 measures, fexofenadine showed zero impairment, making it the least sedating antihistamine studied.
If staying alert matters to you, fexofenadine is the standout. Cetirizine, while technically second-generation, sits in a gray zone where some people notice slight drowsiness.
First-Generation Antihistamines
These older medications cross easily into the brain, which is why they cause noticeable drowsiness, slower reaction times, and impaired focus. They also wear off faster, typically lasting only 4 to 6 hours, so you may need multiple doses per day. They remain widely available and inexpensive. Common ones include:
- Diphenhydramine (Benadryl): Probably the most recognized antihistamine. Very effective for allergic reactions but heavily sedating. In testing, it impaired performance on 55 out of 57 measures. It’s the active ingredient in many OTC sleep aids for exactly this reason.
- Chlorpheniramine (Chlor-Trimeton): Found in many cold and allergy combination products. Less sedating than diphenhydramine but still significantly impairing compared to newer options.
- Doxylamine (Unisom SleepTabs): Marketed primarily as a sleep aid due to heavy sedation.
- Dimenhydrinate (Dramamine): Used mainly for motion sickness rather than allergies.
- Meclizine (Bonine): Another motion sickness treatment, sometimes used for vertigo.
- Hydroxyzine (Vistaril, Atarax): Prescription only. Often used for anxiety and itching, particularly hives.
Beyond drowsiness, first-generation antihistamines have anticholinergic effects. In practical terms, that means dry mouth, constipation, difficulty urinating, and excessive drying of mucous membranes. Older adults are especially vulnerable to these side effects, and these medications can cause confusion or agitation in people with dementia.
Nasal Sprays and Eye Drops
Not all antihistamines come as pills. Topical versions deliver the drug directly where you need it, which can mean faster relief for localized symptoms with less absorption into the rest of your body.
For nasal congestion and sneezing, antihistamine nasal sprays include azelastine (Astepro) and olopatadine. Azelastine is one of the few antihistamines available in both nasal and oral forms in some countries. For itchy, watery eyes, antihistamine eye drops include ketotifen (sold as Alaway and Zaditor) and olopatadine (Pataday). Ketotifen switched to OTC status in 2006.
H2 Antihistamines for Stomach Acid
A completely separate class of antihistamines blocks histamine receptors in the stomach rather than in the nose and eyes. These are called H2 blockers, and they reduce acid production. Three are currently available in the U.S., both over the counter and by prescription: famotidine (Pepcid), cimetidine (Tagamet), and nizatidine. They’re approved for heartburn, gastroesophageal reflux disease (GERD), and stomach or intestinal ulcers. They’re also sometimes used off-label for hives that don’t respond well to standard allergy antihistamines alone.
Choosing Between Them
For seasonal or year-round allergies, a second-generation antihistamine taken once daily is the standard starting point. If you need to drive, operate machinery, or stay sharp at work, fexofenadine carries the lowest sedation risk. Cetirizine and loratadine are effective alternatives, though cetirizine may cause mild drowsiness in some people.
First-generation antihistamines still have a role for acute allergic reactions where sedation isn’t a concern, or when you actually want the drowsiness, like using diphenhydramine as a sleep aid. For symptoms concentrated in your nose or eyes, a targeted spray or drop can work well on its own or alongside an oral antihistamine.
Combination products that pair an antihistamine with a decongestant (like Zyrtec-D, Claritin-D, or Allegra-D) add a nasal decongestant for stuffiness that antihistamines alone don’t fully address. These are typically kept behind the pharmacy counter but don’t require a prescription.