Gastrointestinal Side Effects: Hydroxyzine vs Diphenhydramine
Hydroxyzine has fewer gastrointestinal side effects than diphenhydramine. Both are first-generation antihistamines with anticholinergic properties, but diphenhydramine specifically lists epigastric discomfort as a documented adverse effect, while hydroxyzine does not have this same GI profile 1.
Evidence-Based Comparison
Diphenhydramine GI Effects
- Diphenhydramine causes epigastric discomfort as a recognized adverse effect when used for sedation and allergic conditions 1
- The anticholinergic properties of diphenhydramine contribute to dry mouth, constipation, and gastrointestinal symptoms 2, 3
- These GI effects are part of the broader anticholinergic syndrome associated with first-generation antihistamines 1
Hydroxyzine GI Effects
- Hydroxyzine with extended antiserotonergic activity may actually help gastrointestinal symptoms in certain conditions like mast cell activation syndrome 1
- Cyproheptadine (a related antihistamine with similar properties) is specifically noted to help GI symptoms due to its antiserotonergic effects 1
- In direct comparison studies, hydroxyzine-poisoned patients showed fewer antimuscarinic/anticholinergic findings overall compared to diphenhydramine-poisoned patients 4
Mechanistic Differences
The pharmacologic profiles explain the GI difference:
- Diphenhydramine has stronger anticholinergic effects that directly impact GI motility and secretion, leading to epigastric discomfort, dry mouth, and constipation 1, 3
- Hydroxyzine has additional antiserotonergic properties that may actually counteract some GI symptoms, particularly in conditions with serotonin-mediated GI distress 1
- Large-scale toxicology data confirms hydroxyzine produces fewer antimuscarinic findings than diphenhydramine across 17,265 vs 102,354 exposures respectively 4
Clinical Implications
Common Pitfalls to Avoid
- Do not assume all first-generation antihistamines have identical side effect profiles—hydroxyzine and diphenhydramine differ significantly in their anticholinergic burden 4, 5
- Both medications remain problematic in elderly patients due to cognitive effects and should generally be avoided in this population 1, 2
- Neither medication should be first-line for allergic conditions when second-generation antihistamines are available 5
When GI Considerations Matter Most
- For patients with pre-existing GI sensitivity or complaints, hydroxyzine would be the preferred first-generation antihistamine if one must be used 1, 4
- In mast cell disorders with GI symptoms, hydroxyzine's antiserotonergic properties may provide additional benefit beyond antihistamine effects 1
- Both medications cause sedation and cognitive impairment equally, so the choice should not be based on CNS effects alone 6, 5