What are the potential reactions between Diphenhydramine (Diphen) and Loratadine?

Diphenhydramine and Loratadine: Drug Interaction Profile

There are no clinically significant pharmacokinetic or pharmacodynamic interactions between diphenhydramine and loratadine, but combining them is generally unnecessary and potentially harmful due to additive anticholinergic effects and increased sedation risk from diphenhydramine. 1, 2

Mechanism and Interaction Potential

Pharmacologic Differences

• Diphenhydramine is a first-generation H1-antihistamine that readily crosses the blood-brain barrier due to its high lipophilicity, causing significant CNS depression, anticholinergic effects, and sedation. 3, 4
• Loratadine is a second-generation antihistamine with threefold greater affinity for peripheral versus central H1-receptors, with insignificant brain penetration and no sedation at recommended doses. 1, 5
• Animal studies demonstrate loratadine has no EEG depressant activity even at doses 170 times higher than its therapeutic dose, while diphenhydramine depresses EEG at doses only 0.6-2.0 times its peripheral antihistamine dose. 6

Direct Interaction Evidence

• No documented pharmacokinetic interactions exist between these agents—they are metabolized through different pathways and do not interfere with each other's clearance. 5, 6
• The primary concern is additive anticholinergic burden when combining diphenhydramine with any other medication, though loratadine itself has minimal anticholinergic properties. 1, 2

Clinical Performance and Safety Concerns

Cognitive and Psychomotor Impairment

• Diphenhydramine causes significant deficits in divided attention, working memory, vigilance, and speed compared to loratadine, which performs identically to placebo on comprehensive psychometric testing. 3, 4
• Subjects taking diphenhydramine report greater fatigue, sleepiness, lower motivation, and poorer self-rated performance quality that persists through day 3 of treatment. 3
• These performance deficits create potential hazards in occupations requiring vigilance and may decrease work productivity. 4

Anticholinergic Effects

• Diphenhydramine should be avoided in older adults and postoperative patients due to increased delirium risk, urinary retention, dry mouth, blurred vision, constipation, and impaired judgment. 1, 7
• The American Geriatrics Society identifies diphenhydramine as an inappropriate medication that induces delirium postoperatively in older adults. 1
• Anticholinergic effects are particularly problematic in patients with bladder neck obstruction, glaucoma, or existing urinary difficulties. 1, 7

Clinical Recommendations

When Combination Might Occur

• There is no therapeutic rationale for combining these agents—both are H1-antihistamines treating the same symptoms through the same mechanism. 1, 8
• If a patient is already taking loratadine for allergic rhinitis and receives diphenhydramine (e.g., as an adjunct antiemetic or for acute allergic reaction in the ED), monitor for excessive sedation and anticholinergic effects. 1, 2

Preferred Approach

• Second-generation antihistamines like loratadine are generally preferred over diphenhydramine for allergic rhinitis treatment due to superior safety profile. 1
• For acute allergic reactions where sedation is a concern, newer antihistamines (cetirizine or fexofenadine) provide similar efficacy to diphenhydramine with less sedation, despite slightly higher cost ($0.52-2.39 more per dose). 8
• Cetirizine has the fastest onset of action among newer antihistamines if rapid effect is needed. 8

Special Populations at Risk

• Avoid diphenhydramine in older adults, young children, and patients with cardiac arrhythmia, hypertension, bladder neck obstruction, glaucoma, or hyperthyroidism. 1
• Diphenhydramine's hypnotic effect is increased when combined with alcohol, benzodiazepines, or opioid narcotics—exercise extreme caution if loratadine patient receives these agents. 2
• The 4-6 hour duration of diphenhydramine often exceeds the time needed for symptom control, potentially extending recovery time. 2

Monitoring If Combination Occurs

• Watch for paradoxical agitation (particularly in children and adolescents), excessive sedation, hypotension, urinary retention, and anticholinergic crisis. 2
• Assess for impaired driving ability and workplace safety concerns, as diphenhydramine effects persist well into the next day even when taken at bedtime. 4