Dermatologic Therapy, Vol. 13, 2000, 327–336 Printed in the United States · All rights reserved Copyright © Blackwell Science 2000 DERMATOLOGIC THERAPY ISSN 1396-0296 327 Second- and third-generation antihistamines Anne K. Ellis & James H. Day Division of Allergy and Immunology, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada ABSTRACT: Chronic urticaria is mainly idiopathic in nature and can be difficult to treat. While less responsive to antihistamine therapy than acute urticaria, antihistamines still play a key role in the management of symptomatology. While many of the antihistamines still commonly used to treat urticaria are first generation H 1 antagonists (e.g., diphenhydramine, hydroxyzine), the more recently developed second-generation agents (e.g., loratadine, cetirizine) and their metabolites—the third- generation antihistamines (e.g., fexofenadine, norastemizole, descarboxyloratadine)—possess many of the desirable clinical effects of the first-generation agents with a more tolerable side effect profile. This review discusses the advantages and disadvantages of each of the various second- and third- generation agents available, and presents some of the data showing the differences among these agents in the treatment of chronic urticaria. KEYWORDS: chronic urticaria, first-generation antihistamines, second-generation antihistamines, third-generation antihistamines. Urticarial syndrome may be classified as acute, chronic, and physical. Acute urticaria is commonly IgE mediated and is usually rapidly responsive to antihistamines, while chronic urticaria is mainly idiopathic and less responsive. Physical urticaria variably respond to antihistamines depending on the type. Cold urticaria, for example, has quite spe- cific antihistamine requirements. Antihistamines have a role in simple urticarial vasculitis, while corticosteroids are usually required to manage moderate and severe forms. While many of the antihistamines still commonly used to treat urticaria are first-generation H 1 antagonists (e.g., diphen- hydramine, hydroxyzine), the more recently devel- oped second-generation agents (e.g., loratadine, cetirizine) and their metabolites—the third-gener- ation antihistamines (e.g., fexofenadine, norastem- izole, descarboxyloratadine)—possess many of the desirableclinical effects of the first-generation agents with a more tolerable side effect profile. Background Antihistamines are classified as H 1 , H 2 , and H 3 on the basis of their ability to block the specific ac- tions of histamine-receptor interactions in respon- sive tissue. H 1 receptor antagonists were first syn- thesized in the 1940s and consist of substitutions on the imidazole ring of histamine (1). A large number of H 1 antihistamines, including ethanol- amines, ethylenediamines, allylamines, phenothi- azines, and piperazines, were developed by vary- ing the substitutions on the ethylamine moiety (2). Pharmacology At low concentrations, antihistamines are revers- ible competitive antagonists of histamine at H 1 receptor sites. Antagonism results in decreased Address correspondence and reprint requests to James H. Day, MD, 1 Division of Allergy and Immunology, Kingston General Hospital, Kingston, ON K7L 2V7 Canada.