SYMPOSIUM REPORT SUPPLEMENT Pharmacology of Antihistamines Diana S. Church, MD, and Martin K. Church, PhD, DSc compounds was to measure histamine-induced contractions Abstract: This article reviews the molecular biology of the inter- of pieces of muscle from experimental animals, usually action of histamine with its H -receptor and describes the concept 1 guinea-pig intestine, suspended in an organ bath. Candidate that H1-antihistamines are not receptor antagonists but are inverse agonists i.e. they produce the opposite effect on the receptor to hista- antihistaminic compounds were primarily modifications of those synthesized as cholinergic antagonists and are from mine. It then discourages the use of first-generation H1-antihistamines in clinical practice today for two main reasons. First, they are less diverse chemical entities, ethanolamines, ethylene diamines, alkylamines, piperazines, piperidines, and phenothiazines. It effective than second generation H1-antihistamines. Second, they have unwanted side effects, particularly central nervous system and is hardly surprising, therefore, that these first-generation an- anti-cholinergic effects, and have the potential for causing severe tihistamines had poor receptor selectivity and significant unwanted side effects. toxic reactions which are not shared by second-generation H1- antihistamines. There are many efficacious and safe second-gener- During this time, knowledge of the nature and diversity of receptors was rudimentary to say the least and it was only ation H1-antihistamines on the market for the treatment of allergic disease. Of the three drugs highlighted in this review, levocetirizine several decades later that the existence of more than one and fexofenadine are the most efficacious in humans in vivo. species of histamine receptor was discovered. This review However, levocetirizine may cause somnolence in susceptible indi- will concentrate on the histamine H1-receptor. Further details viduals while fexofenadine has a relatively short duration of action on the biology and clinical functions of histamine H2-, H3-, 6 requiring twice daily administration for full all round daily protec- and H4-receptors are the subject of a separate review. tion. While desloratadine is less efficacious, it has the advantages of rarely causing somnolence and having a long duration of action. Lastly, all H1-antihistamines have anti-inflammatory effects but it THE HISTAMINE H1-RECEPTOR requires regular daily dosing rather than dosing ‘on-demand’ for this The human histamine H1-receptor is a member of the effect to be clinically demonstrable. superfamily of G-protein coupled receptors. This superfamily represents at least 500 individual membrane proteins that Key Words: H1-antihistamines, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine share a common structural motif of 7 transmembrane ␣-he- 7,8 lical segments (Fig. 1A). The histamine H1-receptor gene (WAO Journal 2011; 4:S22–S27) encodes a 487 amino acid protein with a molecular mass of 9,10 55.8 kDa. The absence of introns in the H1-receptor gene indicates that only a single receptor protein is transcribed t is now more than a century since the discovery of hista- with no splice variants.10 mine,1 more than 70 years since the pioneering studies of I The histamine H -receptor, like other G-protein cou- Anne Marie Staub and Daniel Bovet led to the discovery of 1 pled receptors, may be viewed as “cellular switches,” which the first antihistamine2 and more than 60 years since the exist as an equilibrium between the inactive or “off” state and introduction into the clinic of antergan in 1942,3 followed by the active or “on” state.11 In the case of the histamine diphenhydramine in 19454 and chlorpheniramine, bromphe- niramine, and promethazine later the same decade. Medicinal H1-receptor, histamine cross-links sites on transmembrane chemistry was very different in those days compared with the domains III and V to stabilize the receptor in its active present day as elegantly described by Emanuel in his review conformation, thus causing the equilibrium to swing to the on 12 entitled “Histamine and the antiallergic antihistamines: a position (Fig. 1B). H1-antihistamines, which are not struc- history of their discoveries.”5 The usual way of testing novel turally related to histamine, do not antagonize the binding of histamine but bind to different sites on the receptor to produce the opposite effect. For example, cetirizine cross- From the University of Southampton School of Medicine, Southampton, UK; links sites on transmembrane domains IV and VI to stabilize Allergie-Centrum-Charite´/ECARF, Charite´-Universita¨tsmedizin, Berlin, Germany. the receptor in the inactive state and swing the equilibrium to 13 Correspondence to: Martin K. Church, PhD, DSc, Sir Henry Wellcome the off position (Fig. 1C). Thus, H1-antihistamines are not Laboratories, South Block 825, Southampton General Hospital, South- receptor antagonists but are inverse agonists in that they ampton SO16 6YD, United Kingdom. produce the opposite effect on the receptor to histamine.14 Telephone: 44 (0)23 8079 6149. Fax: 44(0)23 8070 4183. E-mail: mkc@ southampton.ac.uk. Consequently, the preferred term to define these drugs is Copyright © 2011 by World Allergy Organization “H1-antihistamines” rather than “histamine antagonists.” S22 WAO Journal ● March 2011, Supplement WAO Journal • March 2011, Supplement Pharmacology of Antihistamines onset of rapid eye movement sleep and reduce the duration of rapid eye movement sleep.19–21 The residual effects of poor sleep, including impairment of attention, vigilance, working memory, and sensory-motor performance, are still present the next morning.20,22 The detrimental central nervous system effects of first-generation H1-antihistamines on learning and examination performance in children and on impairment of the ability of adults to work, drive, and fly aircraft have been reviewed in detail in a recent review.23 The use of first-generation H1-antihistamines in young children has recently been brought into question. In the United States, reports of serious and often life-threatening adverse events of promethazine in children led to a “boxed warning” being added in 2004 to the labeling of prometha- zine. The warning included a contraindication for use in children younger than 2 years and a strengthened warning with regard to use in children 2 years of age or older.24 In February 2009, the Medicines and Healthcare products Reg- ulatory Agency (MHRA) in the United Kingdom25 advised that cough and cold remedies containing certain ingredients, FIGURE 1. A, Diagram of a histamine H1-receptor in a membrane showing the 7 transmembrane domains. Hista- including first-generation H1-antihistamines, should no lon- mine stimulates the receptor after its penetration into the ger be used in children younger than 6 years because the central core of the receptor. B, A surface view of an acti- balance of benefit and risks has not been shown to be vated receptor with histamine linking domains III and V. C, favorable. Reports submitted to regulators stated that more A surface view of an inactive receptor with cetirizine linking than 3000 people have reported adverse reactions to these domains IV and VI. drugs and that diphenhydramine and chlorpheniramine were mentioned in reports of 27 and 11 deaths, respectively.25 FIRST-GENERATION H -ANTIHISTAMINES 1 SECOND-GENERATION H -ANTIHISTAMINES Because first-generation H1-antihistamines derive from 1 the same chemical stem from which cholinergic muscarinic A major advance in antihistamine development oc- antagonists, tranquilizers, antipsychotics, and antihyperten- curred in the 1980s with the introduction of second-genera- 26 sive agents were also developed, they have poor receptor tion H1-antihistamines, which are minimally sedating or selectivity and often interact with receptors of other biolog- nonsedating because of their limited penetration of the blood- ically active amines causing antimuscarinic, anti–␣-adrener- brain barrier. In addition, these drugs are highly selective for gic, and antiserotonin effects. But perhaps their greatest the histamine H1-receptor and have no anticholinergic effects. drawback is their ability to cross the blood-brain barrier and When choosing an H1-antihistamine, patients seek at- interfere with histaminergic transmission. Histamine is an tributes that include good efficacy, a rapid onset of action, a important neuromediator in the human brain which contains long duration of action, and freedom from unwanted effects. approximately 64,000 histamine-producing neurones, located Although some of these attributes may be predicted from in the tuberomamillary nucleus. When activated, these neu- preclinical and pharmacokinetic studies, it is only in the clinical environment that they may be definitively estab- rones stimulate H1-receptors in all of the major parts of the cerebrum, cerebellum, posterior pituitary, and spinal cord15 lished. where they increase arousal in the circadian sleep/wake cycle, reinforce learning and memory, and have roles in fluid bal- Efficacy ance, suppression of feeding, control of body temperature, The efficacy of an H1-antihistamine is determined by 2 control of the cardiovascular system, and mediation of stress- factors: the affinity of the drug for H1-receptors (absolute triggered release of adrenocorticotrophic hormone and ␤- potency) and the concentration of the drug at the sites of the 16 endorphin from the pituitary gland. It is not surprising then H1-receptors.