Xyzal (levocetirizine) is not an anticholinergic. It is a second-generation antihistamine that works by selectively blocking H1 histamine receptors, with minimal activity at the receptors that anticholinergic drugs target. Levocetirizine is roughly 600 times more selective for histamine receptors compared with a broad panel of other receptors and channels, including the muscarinic receptors responsible for anticholinergic effects.
How Xyzal Works Differently
Anticholinergic drugs block muscarinic receptors, which control functions like saliva production, bladder contraction, and pupil dilation. That’s why classic anticholinergic side effects include dry mouth, urinary retention, blurred vision, and confusion. First-generation antihistamines like diphenhydramine (Benadryl) and hydroxyzine bind to both histamine and muscarinic receptors, giving them significant anticholinergic activity on top of their allergy relief.
Xyzal takes a different approach. Levocetirizine binds to H1 histamine receptors with high affinity (a Ki value of 3 nM, which means it latches on tightly at very low concentrations) and has little meaningful binding at muscarinic receptors. The FDA prescribing information for Xyzal describes its effects as “mediated via selective inhibition of H1 receptors” and does not mention anticholinergic activity at all.
Why Second-Generation Antihistamines Cause Fewer Side Effects
Beyond receptor selectivity, second-generation antihistamines like levocetirizine have a structural advantage: they don’t easily cross into the brain. The blood-brain barrier contains a protein called P-glycoprotein that acts as an efflux pump, actively pushing these drugs back out of brain tissue. PET scan studies have confirmed that first-generation antihistamines penetrate the barrier readily and interfere with histamine signaling in the brain, causing drowsiness, cognitive impairment, and other central nervous system effects. Second-generation antihistamines get pumped back out before they can accumulate.
This is why Xyzal causes far less sedation than older antihistamines and why its anticholinergic-like side effects are uncommon. The prescribing information does list dry mouth and urinary retention as possible adverse reactions, but these occur at low rates and don’t reflect a true anticholinergic mechanism in the way that diphenhydramine or hydroxyzine would produce them.
What the Beers Criteria Say
The 2023 American Geriatrics Society Beers Criteria is a widely used list of medications that older adults should generally avoid, and it includes a specific table of drugs with strong anticholinergic properties. Levocetirizine is not on that list. The antihistamines that do appear are all first-generation: diphenhydramine, hydroxyzine, chlorpheniramine, doxylamine, promethazine, meclizine, and several others. This distinction matters because anticholinergic drugs are linked to increased fall risk, confusion, and cognitive decline in older adults.
Xyzal vs. Zyrtec: Anticholinergic Comparison
Xyzal is the purified active half (the “eutomer”) of cetirizine, the drug sold as Zyrtec. A standard 5 mg dose of levocetirizine delivers roughly the same antihistamine potency as 10 mg of cetirizine because levocetirizine has twice the binding affinity for H1 receptors. It also stays bound to the receptor longer, which contributes to its extended duration of action.
Neither cetirizine nor levocetirizine has meaningful anticholinergic activity. Cetirizine has long been associated with a low incidence of anticholinergic side effects like dry mouth, no cardiac adverse effects, and minimal sedation. Levocetirizine carries a similar or slightly improved profile because it strips away the inactive enantiomer that doesn’t contribute to allergy relief.
Safe Use With Anticholinergic-Sensitive Conditions
If you have a condition that worsens with anticholinergic drugs, like narrow-angle glaucoma or urinary retention from an enlarged prostate, the distinction between first- and second-generation antihistamines is important. The American Academy of Allergy, Asthma, and Immunology has stated that first-generation antihistamines should be avoided in patients with glaucoma, but that “higher generation antihistamines should generally not be a problem.” Levocetirizine falls squarely in that safer category.
That said, the fact that dry mouth and urinary retention appear on the side effect list, even at low rates, means that people who are especially sensitive to these effects should pay attention to how they respond. The risk is far lower than with a true anticholinergic, but it isn’t zero.