REVIEW ARTICLE H1 Antihistamines Current Status and Future Directions F. Estelle R. Simons***þ§ and Keith J. Simons*§¶ increases release of histamine and other mediators from mast Abstract: In this review, we compare and contrast the clinical cells and basophils, up-regulates cellular adhesion molecule pharmacology, efficacy, and safety of first-generation H1 antihista- expression and chemotaxis of eosinophils and neutrophils, mines and second-generation H1 antihistamines. First-generation H1 up-regulates Th1 priming and Th1 cell proliferation and antihistamines cross the blood-brain barrier, and in usual doses, they interferon-F production, and down-regulates humoral immu- potentially cause sedation and impair cognitive function and psy- nity. Through the H receptor, it suppresses inflammatory and chomotor performance. These medications, some of which have 2 effector functions. Through the presynaptic H3 receptor on been in use for more than 6 decades, have never been optimally histaminergic and nonhistaminergic neurons in the central investigated. Second-generation H1 antihistamines such as cetirizine, and peripheral nervous systems, it is probably involved in desloratadine, fexofenadine, levocetirizine, and loratadine cross the control of neurogenic inflammation through mast cell blood-brain barrier to a significantly smaller extent than their pre- feedback loops. Through the H4 receptor, it facilitates some decessors. The clinical pharmacology, efficacy, and safety of these proinflammatory activities (Table 1).1 medications have been extensively studied. They are therefore the Targeted disruption of the H1 receptor gene in mice H1 antihistamines of choice in the treatment of allergic rhinitis, al- results in impairment of neurological functions such as lergic conjunctivitis, and urticaria. In the future, clinically advanta- memory, learning, and locomotion, and in aggressive geous H1 antihistamines developed with the aid of molecular behavior. In addition, mice that are H1 receptorYdeficient techniques might be available. have immunologic abnormalities, including impaired antigen- 1Y3 Key Words: H1 antihistamines, second-generation H1 specific B-cell and T-cell responses. antihistamines, nonsedating H1 antihistamines, allergic rhinitis, All 4 types of histamine receptors are heptahelical allergic conjunctivitis, urticaria, atopic dermatitis, cetirizine, transmembrane molecules that transduce extracellular signals, desloratadine, fexofenadine, levocetirizine, loratadine by way of G-proteins, to intracellular second messenger systems. Histamine receptors have constitutive activity, which Y (WAO Journal 2008;145 155) is defined as the ability to trigger downstream events, even in the absence of ligand binding. The active and inactive states istamine, a natural body constituent, is synthesized from of these receptors exist in equilibrium; at rest, the inactive HL-histidine exclusively by histidine decarboxylase, an state isomerizes with the active state and vice versa.2,3 enzyme expressed in central nervous system (CNS) neurons, gastric mucosa parietal cells, mast cells, basophils, and other H1 Antihistamines cells throughout the body. Histamine plays a major role in H antihistamines act as inverse agonists that combine human health, exerting its diverse effects through 4 or 1 with and stabilize the inactive conformation of the H1 recep- more types of receptors (Table 1). Through the H1 receptor, tor, shifting the equilibrium toward the inactive state. H1- histamine is involved in cell proliferation and differentiation, receptor polymorphisms have been described, although it is hematopoiesis, embryonic development, regeneration, and not yet clear how they influence the clinical response to H wound healing. It is a neurotransmitter, has anticonvulsant 1 antihistamines. Human H1 receptors have approximately 45% activity, and contributes to regulation of the sleep-waking homology with muscarinic receptors.2,3 cycle, energy and endocrine homeostasis, cognition and H antihistamines down-regulate allergic inflammation memory.1,2 1 through the H1 receptor, either directly or indirectly through Through all 4 known types of histamine receptors, nuclear factor-JB, an ubiquitous transcription factor, through histamine also plays an important role in immune modulation which they down-regulate antigen presentation, expression of and in acute and chronic allergic inflammation. Through the proinflammatory cytokines and cell adhesion molecules, and H1 receptor, it increases antigen-presenting cell capacity, chemotaxis. In addition, through their effects on calcium ion channel activity, H1 antihistamines decrease mediator release; however, this effect is only seen at high H1-antihistamine Received for publication April 7, 2008; accepted July 16, 2008. 2 From the Departments of *Pediatrics and Child Health, **Immunology, concentrations. ‡Canadian Institutes of Health Research National Training Program in Traditionally, H1 antihistamines have been classified into Allergy and Asthma, §Faculty of Medicine, and ¶Faculty of Pharmacy, 6 chemical groups: alkylamines, ethanolamines, ethylene- University of Manitoba, Winnipeg, Manitoba, Canada. Reprints: F. Estelle R. Simons, MD, FRCPC, 820 Sherbrook St, Winnipeg, diamines, phenothiazines, piperazines, and piperidines. Cur- Manitoba, Canada R3A 1R9. E-mail: [email protected]. rently, the most commonly used classification system is a Copyright * 2008 by World Allergy Organization functional one, in which H1 antihistamines are classified as WAO Journal & September 2008 145 146 Simons and Simons TABLE 1. Histamine Receptors H1 Receptor H2 Receptor H3 Receptor H4 Receptor Receptor expression Nerve cells, airway and vascular Nerve cells, airway and vascular High expression in histaminergic High expression on bone marrow smooth muscle, endothelial cells, smooth muscle, endothelial cells, neurons, eosinophils, DC, and peripheral hematopoietic epithelial cells, neutrophils, epithelial cells, neutrophils, monocytes; low expression in cells, eosinophils, neutrophils, eosinophils, monocytes/ eosinophils, monocytes, peripheral tissues DC, T cells, basophils, mast cells macrophages, DC, T and B cells, DC, T and B cells, hepatocytes, hepatocytes, chondrocytes chondrocytes Histamine function, j Pruritus, pain, vasodilation, j Gastric acid secretion, vascular j Pruritus (no mast cell j Pruritus (no mast cell general vascular permeability, permeability, hypotension, involvement), j nasal involvement), j nasal congestion; hypotension; flushing, flushing, headache, tachycardia, congestion; prevent excessive differentiation of myeloblasts headache, tachycardia, chronotropic and inotropic bronchoconstriction and promyelocytes bronchoconstriction, activity, bronchodilation, mucus stimulation of airway vagal production (airway) afferent nerves and cough receptors; , atrioventricular node conduction time Histamine function in j Release of histamine and other , Eosinophil and neutrophil Probably involved in control of j Calcium flux in human allergic inflammation mediators; j cellular adhesion chemotaxis; , IL-12 by dendritic neurogenic inflammation through eosinophils; j eosinophil and immune modulation molecule expression and cells; j IL-10 and development of local neuron-mast cell feedback chemotaxis; j IL-16 production chemotaxis of eosinophils and Th2 or tolerance-inducing loops; j proinflammatory activity (H2 receptor also involved) neutrophils; j antigen-presenting dendritic cells; j humoral and APC capacity cell capacity, costimulatory immunity; , cellular immunity; activity on B cells; j cellular suppresses Th2 cells and immunity (Th1), j autoimmu- cytokines; indirect role in allergy, nity; , humoral immunity and autoimmunity, malignancy, graft IgE production rejection Histamine function in Sleep/wakefulness, food intake, Neuroendocrine Presynaptic heteroreceptor; To be defined the CNS thermal regulation, emotions/ , histamine, dopamine, serotonin, * aggressive behavior, locomotion, noradrenaline, and acetylcholine WAO Journal 2008 World Allergy Organization memory, learning release APC indicates antigen-presenting cells; DC, dendritic cells; IgE, immunoglobulin E; IL, interleukin. Adapted from Simons and Akdis.3 & September 2008 WAO Journal & September 2008 H1 Antihistamines TABLE 2. H1 Antihistamines: Chemical and Functional Classification Functional Class Chemical Class First Generation Second Generation Alkylamines Brompheniramine, chlorpheniramine, Acrivastine* dimethindene,**,‡ pheniramine,‡ triprolidine* Piperazines Buclizine, cyclizine, hydroxyzine,* meclizine, oxatomide** Cetirizine,* levocetirizine* Piperidines Azatadine, cyproheptadine, diphenylpyraline, ketotifen‡ Astemizole,** bilastine,** desloratadine,* ebastine,** fexofenadine,* levocabastine,‡ loratadine,* mizolastine,** olopatadine,‡ rupatadine,** terfenadine*,** Ethanolamines Carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, V doxylamine, phenyltoloxamine** Ethylenediamines Antazoline, pyrilamine, tripelennamine V Phenothiazines Methdilazine, promethazine V Other Doxepin§ Azelastine,‡ emedastine,‡ epinastine‡ *Acrivastine is related tripolidine. Cetirizine is a metabolite of hydroxyzine, levocetirizine is an enantiomer of cetirizine, desloratadine is a metabolite of loratadine, and fexofenadine is a metabolite of terfenadine. **In the United States, these H1 antihistamines are not yet approved, have never been approved, or have had approval withdrawn. ‡ The H1 antihistamines azelastine, emedastine, epinastine, ketotifen, levocabastine, and olopatadine