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Sedation with “non-sedating” antihistamines: four prescription-event monitoring studies in general practiceCommentary: Reporting of adverse events is worth the effort

BMJ 2000; 320 doi: (Published 29 April 2000) Cite this as: BMJ 2000;320:1184

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All sedating and 'non-sedating' antihistamines cross the blood-brain barrier.

The dichotomy between 1st and 2nd generation antihistamines was
introduced in 1983 at about the time of the European registration of two
drugs: terfenadine and astemizole. The distinction was drawn by the drugs'
manufactures to indicate a major pharmacological difference between these
drugs and their predecessors. The 2nd generation antihistamines were less
soluble in lipid and thus less readily penetrated the blood brain barrier.

When given to man in oral therapeutic doses terfenadine produced about 17%
H1 receptor occupancy in the frontal lobe whereas the 1st generation
antihistamine chlorpheneramine produced about 77% occupancy1. In rats, it
was shown for several 1st and 2nd generation antihistamines that receptor
binding continues to increase with the dose until full receptor saturation
occurs2. Thus the 'non-sedating' title of the 2nd generation
antihistamines refers to a low tendency to diminish CNS arousal when taken
in therapeutic doses. However there is no reason to believe that all 'non-
sedating' antihistamines possess exactly the same low tendency to cross
the blood brain barrier. The study by Mann et al 3 nicely illustrates this
point of view. Their prescription-event monitoring study demonstrated that
2nd 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

Though we share the authors' 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 traffic4,5. The primary outcome variable of
the test is standard deviation of lateral position (SDLP), a measure of
'weaving' or road tracking error. Results of these studies show that the
extend to which 2nd generation antihistamines affect SDLP varies with the
drug, its dose and dosing regimen. Several (acrivastine, cetirizine and
mizolastine) mildly affected driving performance when given at therapeutic
doses. Others (ebastine, fexofenadine, loratadine and terfenadine) did not
have significant effects after recommended doses but had at least
measurable effects after doses that were twice as high. Patients suffering
from seasonal allergic rhinitis and urticaria frequently 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 2nd generation drugs. It is unlikely that the majority
of patients will experience untoward reactions affecting their driving
safety, but if any fraction will, all patients should receive an
appropriate warning.

JG Ramaekers, Senior researcher and lecturer

A0 Vermeeren, Senior researcher and lecturer

Experimental Psychopharmacology Unit, Brain & Behaviour
Institute, Maastricht University, PO Box 616, 6200 MD Maastricht, The

1 Yanai K, Ryu JH, Watanabe T, Iwata R, Ido T, Sawai Y, Ito K, Itoh
M. Histamine H1 receptor occupancy in human brains after single oral doses
of histamine H1 antagonists measured by positron emission tomography. Br J
Pharmacology 1995; 116: 1649-1655

2 Rose C, Quache TT, Lorens C, Schwartz JC. Relationship between
occupation of cerebral H1 receptors and sedative properties of
antihistamines. Assessment in the case of terfenadine.
Arzneimittelforschung 1982; 32: 1171-1173

3 Mann RD, Pearce GL, Dunn N, Shakir S. sedation with "non-sedating"
anthistamines: four prescription-event monitoring studies in general
practice. BMJ 2000; 320: 1184-1186

4 O'Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving
performance in a standard test: a summary of Dutch experience, 1989-1994.
Allergy 1995; 50: 234-242

5 Vermeeren A, O'Hanlon JF. Fexofenadine's effects, alone and with
alcohol, on actual driving performance. J Allergy Clin Immunology 1998;
101: 306-311

Competing interests: No competing interests

20 May 2000
J G Ramaekers