Review of H1 Antihistamines in the Treatment of ... - Ob.Gyn. News

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Antihistamines for CIUcompared. Moreover, there are no evidencebaseddata demonstrating statistical superiorityof one newer-generation agent over another inthe treatment of CIU. However, of the neweragents, those that are labelled nonsedating atrecommended doses (fexofenadine, loratadine,and desloratadine) should be selected overcetirizine. In cases where the physician judgesthat a higher-than-recommended dose should beprescribed, or when the patient is likely to take ahigher dose, the relative safety profile of theseagents demands detailed consideration.Cutis. 2005;76:118–126.How idiopathic is chronic idiopathic urticaria(CIU)? With the fast pace of scientific andmedical discovery, it is anomalous that diseaseswith no known cause remain. However,despite the fact that CIU is less well understoodthan many other diseases, recent findings havepartially illuminated this condition’s etiology.At least 2 subgroups of patients with CIU exist.One group is composed of 30% to 50% of patientswith CIU with autoimmune chronic urticariacaused by autoantibodies against either the highaffinityimmunoglobulin E (IgE) receptor FcRI or,less commonly, IgE. 1,2 Patients in this subgrouphave an increased likelihood of thyroid autoimmunity;thyroid autoantibodies, Hashimoto thyroiditis,and Graves disease are recognized as beingassociated with CIU. 3 Indeed, 27% of patientswith CIU have high-titre antithyroglobulin,antithyroid peroxidase autoantibodies, or both,and 19% have abnormal thyroid function. 3 However,the remaining 50% to 70% of patients withCIU are truly idiopathic, because there is noknown cause for the disease. 1In keeping with the illusive nature of CIU, theprevalence of the disease has not been firmly established.4 Most recent estimates suggest that 15% to20% of the US population experience at least oneepisode of urticaria in their lifetime, and up to 3%of the population are diagnosed with CIU. 5,6 Interestingly,middle-aged women are more likely toexperience the condition than other groups 7 ; also,women are approximately 3 times more likely thanmen to acquire any autoimmune disease duringtheir lifetime, 8 supporting the notion that CIU isoften an autoimmune disease.Quality of LifeThe impact of a disease extends beyond physical signsand symptoms; health-related quality of life (QOL)also should play a pivotal role in the evaluation ofthe effect of a disease or its treatment. Thisparameter is particularly pertinent to CIU, asevidenced by O’Donnell et al 9 whose analysis of adisease-specific, purpose-designed questionnaireand the Nottingham Health Profile demonstratedthat patients with chronic urticaria experiencedconsiderable disability, handicap, and reducedQOL. Part 1 of the health profile showed thatpatients were restricted in areas of mobility,sleep, and energy and experienced pain, socialisolation, and altered emotional reactions. Part 2showed that patients experienced problems inrelation to work, home management, social life,relationships, sex life, hobbies, and holidays.Interestingly, patients in this survey had almostidentical scores for part 1 of the health profile asdid patients with coronary artery disease; bothgroups experienced lack of energy, feelings ofsocial isolation, and emotional upset. 9Perhaps because skin diseases are so visible andthus potentially stigmatizing, dermatology patientscan be impacted significantly in terms of QOL;however, the effect of CIU appears to be particularlyacute. Using the validated Dermatology LifeQuality Index (DLQI), a survey of 170 consecutivepatients had results that showed that patients withCIU experienced greater QOL impairment thanoutpatients with either psoriasis, acne, or vitiligoand experienced a comparable level of impairmentto patients with severe atopic dermatitis. 10 Becauseof CIU’s devastating effect on health-related QOLand the discomfort of CIU, appropriate treatmentselection is crucial. The ideal treatment for CIUwould not only rid the patient of the wheals,edema, and pruritus that characterize the conditionbut also improve QOL. This review outlines thetreatment options available, focusing on oral H 1antihistamines, and offers a means of differentiatingthis class of agent.Antihistamines in the Treatment of CIUIt is well established that elevated tissue levels ofhistamine are found in the skin of patients withdifferent forms of chronic urticaria. 11-13 Althoughmore subclasses of histamine receptors have beenidentified, those initially isolated—H 1and H 2—are involved in the cutaneous responses seen inurticaria. Specifically, the binding of histamine tothe H 1receptor causes erythema (by vasodilation),edema (by increasing vascular permeability), anditching. The same responses, with the exception ofitching, are caused by histamine binding to the H 2receptor. In 30% to 50% of patients diagnosed withCIU, histamine release from mast cells leads towheal formation because of an autoimmune process.VOLUME 76, AUGUST 2005 119
Antihistamines for CIUIn contrast, patients with CIU without this autoimmuneresponse experience the same effects ofmast cell degranulation and subsequent release ofhistamine by a process yet to be elucidated.The sentinel involvement of histamine in CIUis, therefore, unequivocal; irrespective of etiology,the appropriate use of H 1antihistamines—whichstabilize an active conformation of the H 1receptorand thus prevent activation by histamine—remainsthe basis of treatment. 14 However, for patientsunresponsive to conventional H 1-antihistaminemonotherapy, adjunctive treatments often are prescribedincluding a combination of H 1antihistamines(either 2 different newer-generation agents concurrentlyor a newer-generation agent plus a firstgenerationagent at night), H 2antihistamines,tricyclic antidepressants (principally doxepin),antileukotriene therapy, and intermittent pulses ofcorticosteroids. 15 In the event of inadequate symptomcontrol after these therapies have beenexplored, immunomodulatory agents such ascyclosporine have been used to treat patientsrefractory to conventional therapy. 14The method of activity for the adjunctive treatmentsis based on the following approaches: blockingH 1and H 2receptors, blocking nonhistaminemediators of urticaria, and blocking the cellular andinflammatory components of the urticarial reaction.In summary, because H 1antihistamines are first-linetherapy for CIU, and for many patients remain theonly option available, the selection of the optimalantihistamine is of vital importance.Selection of AntihistaminesThe first antihistamine was developed in 1937;in the 1940s, phenbenzamine became the firstcommercially available antihistamine, followed bysimilar H 1-receptor antagonists such as chlorpheniramine,brompheniramine, and diphenhydramine.Despite its relative antiquity, diphenhydramineremains the most widely used antihistamine in theUnited States. 16 These first-generation H 1-receptorantagonists, though effective in the treatment ofurticaria and allergic rhinitis, were shown to causeundesired side effects for 2 distinct reasons: theirlack of selectivity for the H 1receptor and theirpropensity to cross the blood-brain barrier and affectthe central nervous system. 17As a result of their lack of selectivity, oldergenerationagents cause anticholinergic effects suchas dry mouth, headache, and urinary retention. 18-20Furthermore, at supraclinical doses, some antihistaminesare toxic 16 and have been shown to causesinus tachycardia. 21 Children have been known toexperience severe toxic reactions and even deathfollowing overdose of older-generation antihistaminesbecause of the drug’s lack of selectivity. 22-25Because older-generation antihistamines canbind to H 1receptors in the brain and histamine inthe brain plays a role in central nervous systemarousal and alertness, these agents also are associatedwith sedation and cognitive impairment (eg,impaired sensorimotor coordination and decreases inattention span, memory function, ability to processinformation, and psychomotor performance 16,26,27 ).The binding of first-generation antihistamines tocerebral H 1receptors has been demonstrated inmany studies employing objective psychometric testsand also by the relatively new technique of positronemission tomographic imaging. 28-30Newer-Generation AntihistaminesNewer-generation antihistamines were developed inthe early 1980s with the aim of being more specificfor the H 1receptor, as well as of overcoming theadverse events observed with older agents. As testamentto achieving this goal, allergists agree thatnewer-generation antihistamines are preferred tofirst-generation agents because of their more favorableefficacy:safety ratio. 16,18 Although there is nosuch formal consensus among dermatologists andthose specifically treating CIU, it is likely the samelogic would apply if equivalent efficacy between oldand new antihistamines can be established for CIU.This review explores the newer-generation antihistaminesavailable in the United States for thetreatment of CIU: fexofenadine, loratadine, desloratadine,and cetirizine. An evidence-based analysisof the efficacy of these agents and an analysis of thetherapeutic window of these antihistamines, withparticular focus on their sedation and cognitiveimpairment potential, are emphasized (Table).Efficacy of Newer-Generation AntihistaminesNumerous randomized double-blind clinical studieshave demonstrated the efficacy of fexofenadine, 31-34loratadine, 35,36 desloratadine, 37,38 and cetirizine 39,40 inrelieving the symptoms of CIU.Fexofenadine—The safety and efficacy of variousdoses of fexofenadine at relieving the symptomsof CIU has been established in several largerandomized controlled clinical trials. Two similarCIU studies investigated the efficacy of fexofenadineHCl using doses of 20, 60, 120, and 240 mgtwice daily (BID). In both studies, doses of 60 mgor more BID were shown to reduce severity ofpruritus, number of wheals, and interference withsleep and normal daily activities compared withplacebo. 33,34 Furthermore, studies in Japanese andThai patients have indicated that the effectiveness120 CUTIS ®
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Review of H1 Antihistamines in the Treatment of ... - Ob.Gyn. News

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