Non‐cardiac adverse effects of antihistamines (H₁‐receptor antagonists)

Abstract

Antihistamines, available without prescription in many countries, are generally considered to be safe medications; however, the old first-generation H1 antagonists commonly cause adverse central nervous system (CNS) effects, even when administered in usual doses. Patients may not be aware of these effects and do not necessarily develop tolerance to them. In contrast, the new, second-generation H1 antagonists are relatively free from adverse effects in the CNS, primarily because they do not cross the blood-brain barrier and block the important neurotransmitter function of histamine. Most of the H1 antagonists in current use are unlikely to cause cardiac toxicity. There is no evidence that H1 antagonists, which have been approved by regulatory agencies, have carcinogenic, tumour-promoting, or teratogenic effects in humans.

Effects of Antihistamines on Innate Immune Responses to Severe Bacterial Infection in Mice

“…Indeed, H1R-deficient mice did not show any differences in mortality and overall morbidity after CLP, indicating that histamine action via H1R is not critically involved in the host response in murine bacterial peritonitis. First-generation sedating antihistamines like diphenhydramine are known to effectively block H1R, but they can also have additional non-H1R-mediated effects, for example, they can block muscarinic cholinergic, α-adrenergic and serotonin receptors [22], offering possible off-target effects of these drugs. Blockade of H2R and H3/H4R resulted in comparable effects on morbidity as the first-generation H1R antagonist.…”

Combination Therapeutic Approach for Asthma and Allergic Rhinitis

“…Their propensity to occupy central nervous system H 1 -receptors varies from none for fexofenadine to 30 percent for cetirizine [37]. First-generation H 1 -antihistamines have antimuscarinic and -adrenergic blockade activity and may cause dose-related prolongation of the QT interval [38,39]. Even second generation antihistaminic drugs, Terfenadine and astemizole, have been withdrawn from the market because of QT interval prolongation side effect [40][41][42].…”

Clinical outcomes and adverse effect monitoring in allergic rhinitis

“…Additional clinically relevant concerns about CNS symptoms from first-generation H 1 -antihistamines are listed in Table I. A detailed description of measurement of the CNS effects of H 1 -antihistamines is given in Table II. [109][110][111][112][113][114][115] Because the sensitivity of objective tests used to measure CNS impairment after medication intake differs, a variety of tests are used, and both a positive control (sedating H 1 -antihistamine) and a negative control (placebo) are generally incorporated into the study design. By using a battery of selected subjective and objective tests and a prospective, randomized, double-blind, placebo-controlled, crossover study design, statistically significant and clinically relevant differences between a sedating H 1 -antihistamine and a nonsedating H 1 -antihistamine can be demonstrated in studies involving as few as 6 participants.…”