All antihistamines cross blood-brain barrier

Editor—With reference to the paper by Mann et al,¹ the dichotomy between antihistamines of the first and second generation was introduced to indicate a big pharmacological difference between these drugs. The second generation antihistamines were less soluble in lipid and thus less readily penetrated the blood-brain barrier. When given to people in therapeutic doses, terfenadine produced about 17% occupancy of histamine H₁ receptors in the frontal lobe whereas the first generation antihistamine chlorpheniramine produced about 77% occupancy.² In rats receptor binding increases with the dose of several first and second generation antihistamines until full receptor saturation occurs.³ Thus the “non-sedating” title of the second generation antihistamines refers to a low tendency to diminish central arousal when taken in therapeutic doses. There is no reason to believe, however, that all non-sedating antihistamines have exactly the same low tendency to cross the blood- brain barrier. The study by Mann et al illustrates this point.¹ Their prescription-event monitoring study showed that second generation antihistamines differ in their potential to produce sedation. The odds ratios for the incidence of sedation were 0.63 for fexofenadine, 2.79 for acrivastine, and 3.53 for cetirizine compared with loratadine.

Although we share Mann et al's conclusion that fexofenadine and loratadine may be more appropriate for people working in safety critical jobs, we would like to add that any antihistamine may produce performance impairment if H₁ receptor occupancy exceeds a certain criterion. The antihistamine effects on performance have previously been measured in an actual driving test in normal traffic.⁴,⁵ The primary outcome variable of the test is standard deviation of lateral position, a measure of “weaving” or road tracking error. Results of these studies show that the extent to which second generation antihistamines affect driving varies with the drug, its dose, and its dosing regimen. Acrivastine, cetirizine, and mizolastine mildly affected driving performance when given at therapeutic doses. Ebastine, fexofenadine, loratadine, and terfenadine did not have clinically significant effects after recommended doses but had at least measurable effects after doses that were twice as high. Patients who have seasonal allergic rhinitis and urticaria often use higher doses.

We therefore believe that warnings about antihistamines' possible adverse effects on driving and other potentially dangerous activities should not be waived for the second generation drugs. Most patients are unlikely to experience untoward reactions affecting their driving safety, but if some will be affected all patients should receive an appropriate warning.