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

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Antihistamines for CIUIL-6, IL-8, IL-13, prostaglandin D 3, leukotriene C,tryptase, histamine, and the tumor necrosis factor–induced chemokine regulated upon activationnormal T cell expressed and secreted, in additionto eosinophil chemotaxis and adhesion molecules. 47For example, both loratadine and desloratadine(10 mol/L) significantly inhibited the expressionof intercellular adhesion molecule-1 and class IIHLA antigen (HLA-DE) in nasal epithelial cells invitro. 49 However, many of these anti-inflammatoryeffects have only been observed at high drugconcentrations. 47 For example, an in vitro studyof cetirizine assessing the inhibition of IL-5–dependent eosinophil survival revealed a concentrationof 100 mol/L was required to achievesignificant inhibition—much higher than thatused clinically. 47,50Clearly, if clinical anti-inflammatory effectsnecessitate doses higher than those recommendedfor allergic diseases, drugs that can be used at higherdoses without causing unwanted side effects such assedation and cognitive impairment may be of thegreatest utility in the treatment of CIU. This is aparticularly pertinent point because patients withCIU may be prescribed much higher doses than recommendedto manage symptoms effectively. 17The Therapeutic Window—Because of the lack ofrigorously designed clinical trials comparing the efficacyof second-generation antihistamines and theputative anti-inflammatory activities of these agentsthat may occur at higher-than-recommendeddosing levels, the relative safety of agents maydirect the selection of the optimum antihistaminefor the treatment of CIU. Ideally, an agent wouldbe effective at a wide range of doses withoutcausing unwanted side effects. This is because awide therapeutic window permits the physician tooptimize treatment to the individual. The safety ofthe newer-generation antihistamines has beenassessed in numerous clinical trials, usually assecondary analyses to efficacy parameters; indeed,all of the efficacy studies described here indicateda good safety and tolerability profile for each ofthe antihistamines.Clinical trials, however, do not always reflect thereality of clinical practice. Patients taking antihistaminesfrequently overcomply with their medication,51 particularly if they do not experienceimmediate relief. Furthermore, as previously mentioned,it is occasionally necessary for dermatologiststo prescribe high doses of antihistamines for patientswho do not respond to standard-dose first-line therapy.17 Thus, it is valid to examine the safety of thedifferent antihistamines at high doses to obtain atrue picture of how drugs may be affecting patients.Sedation and Impairment—A number of studiesusing objective psychometric tests have indicatedthat newer-generation antihistamines generallyhave better sedative profiles than first-generationagents; however, at higher doses, sedation andimpairment become evident.Two meta-analyses of published data on antihistaminesreport that newer drugs had lowerimpairment/nonimpairment ratios than olderagents. 28,29 That is, proportionally more studies indicatednonimpairment versus impairment with thenewer agents compared with their predecessors.However, the same meta-analyses revealed thatboth loratadine and cetirizine were associated withsedation/impairment in a number of tests, oftenwhen they were used at higher-than-recommendeddoses. In contrast, fexofenadine, even at doses of upto 360 mg, was not associated with any sedation orimpairment and had an impairment:nonimpairmentratio of zero. 28,29A study by Mann et al 52 corroborates the findingthat different newer-generation antihistamines havethe potential to cause sedation, with fexofenadinebeing the least likely of those studied to do so. Thisprescription-event monitoring study showed thatthe odds ratios for the incidence of sedation were0.63 for fexofenadine and 5.53 for cetirizine comparedwith loratadine. 52 Higher-than-recommendeddoses of loratadine 53 and desloratadine 54 also cancause sedation.A recent approach to the question of bloodbrainbarrier penetration involves the use ofpositron emission tomography. This technique hasbeen used to study the binding of antihistamines tocerebral H 1receptors. Tashiro et al 30 used positronemission tomographic imaging to compare fexofenadinewith cetirizine by examining relative H 1receptor occupancy in the brain. Quantitativeanalysis showed that fexofenadine did not occupyH 1receptors in the cerebral cortex, while cetirizineoccupied between 20% to 50% of the H 1receptors,depending on the brain region. 30 These findingssupport evidence from comparative trials thatindicate that although cetirizine is less sedatingthan older antihistamines, it causes more sedationand impairment of performance than other secondgenerationantihistamines. As a result, the US Foodand Drug Administration has classified cetirizine assedating rather than nonsedating, and the productcarries the full sedation precaution.CommentAntihistamines can be used effectively to controlthe symptoms of CIU; newer-generation antihistamineshave been shown to be as effective asVOLUME 76, AUGUST 2005 123
Antihistamines for CIUtheir predecessors at relieving patients of theirsymptoms 35,40 and improving their QOL. 43 However,there is a paucity of well-designed placebo-controlledcomparative clinical trials; the data available indicatethat agents are effective and safe, but they donot provide a means to assess which agent is thesafest and most effective. Instead, we must examinealternative sources of evidence to help us select theoptimum antihistamine for the treatment of CIU.Evidence from pharmacologic studies indicatesthat newer agents demonstrate some antiinflammatoryactivity, which could provideadditional therapeutic benefit. However, thesestudies have largely been limited to in vitro testsand animal modeling and do not yet provide themeans to differentiate agents.Newer-generation antihistamines vary in theirpropensity to cause sedation and cognitive impairment,with cetirizine representing the most impairingof the class, as recognized by its sedating descriptionby the US Food and Drug Administration. At recommendeddoses, fexofenadine, loratadine, anddesloratadine have not been found to cause significantimpairment and are labeled as nonsedating bythe US Food and Drug Administration. However,patients with urticaria are known to take aboverecommendeddoses 51 and physicians occasionallyprescribe off-label doses to achieve the desired levelof symptom control. The risk of sedation caused bythese 2 factors should be considered in practicewhen selecting an antihistamine.Sedation and impairment affect QOL and manifestas decreased classroom learning ability anddecreased work productivity. 28 Furthermore, it hasbeen suggested that cerebral H 1-receptor blockade isassociated with falls in the elderly and cognitive slowing,and is a contributing factor in traffic accidents. 27ConclusionIn controlled clinical studies of CIU, the secondgenerationH 1-antihistamines have been proven tobe clinically comparable to the most potent of thefirst-generation antihistamines, such as hydroxyzine.Clinical studies comparing these agents arefew and have shown no statistically significant differencesin efficacy.If sedation and cognitive impairment are to beconsidered relevant to the choice of therapy for CIUbecause of their impact on QOL and safety, thennewer-generation agents should be selected overolder-generation antihistamines. 37,40 Furthermore, ofthe new agents, those that are labeled nonsedatingat recommended doses (fexofenadine, loratadine,and desloratadine) should be selected over cetirizine.However, in cases where the physician judgesthat a higher-than-recommended dose should beprescribed or when the patient is likely to take ahigher dose, fexofenadine should be considered. Inaddition to its proven efficacy in treating the symptomsof CIU, 31,33,34 fexofenadine is the only antihistaminethat is nonsedating, even at doses 2 to4 times above the recommended levels.REFERENCES1. Greaves MW. Chronic idiopathic urticaria. Curr OpinAllergy Clin Immunol. 2003;3:363-368.2. Hide M, Francis DM, Grattan CE, et al. Autoantibodiesagainst the high-affinity IgE receptor as a cause of histaminerelease in chronic urticaria. N Engl J Med.1993;329:1599-1604.3. Kaplan AP, Finn AF Jr. Pathogenesis of chronic uticaria.Can J Allergy Clin Immunol. 1999;4:286-292.4. Greaves MW, O’Donnell BF, Winkelmann RK. Chronicurticaria—evidence for autoimmunity. Allergy Clin ImmunolNews. 1995;7:36-38.5. Barnetson R. Allergy and the Skin. Allergy Immunologicaland Clinical Aspects. Hoboken, NJ: John Wiley andSons; 1994.6. Mathews KP. The urticarias—current concepts in pathogenesisand treatment. Drugs. 1985;30:552-560.7. Sibbald R, Cheema A, Lozinski A, et al. Chronic urticaria.evaluation of the role of physical, immunologic and othercontributory factors. Int J Dermatol. 1991;30:381-386.8. Jacobson DL, Gange SJ, Rose NR. Epidemiology and estimatedpopulation burden of selected autoimmune diseasesin the United States. Clin Immunol Immunopathol.1997;84:223-243.9. O’Donnell BF, Lawlor F, Simpson J, et al. The impact ofchronic urticaria on the quality of life. Br J Dermatol.1997;136:197-201.10. Poon E, Seed PT, Greaves MW, et al. The extent andnature of disability in different urticarial conditions. Br JDermatol. 1999;140:667-671.11. Greaves MW, Sabroe RA. Histamine: the quintessentialmediator. J Dermatol. 1996;23:735-740.12. Stern RS, Thibodeau LA, Kleinerman RA, et al. Risk ofcutaneous carcinoma in patients treated with oralmethoxsalen photochemotherapy for psoriasis. N Engl JMed. 1979;300:809-813.13. Sulzberger MB, Witten VH, Yaffe SN. Prolonged therapywith cortisone for chronic skin diseases. J Am Med Assoc.1954;155:954-959.14. Greaves M. Chronic urticaria. Curr Rev Allergy ClinImmunol. 2000;105:664-672.15. Mateus C. Treatment of chronic idiopathic urticaria unresponsiveto type 1 antihistamines in monotherapy [inFrench]. Ann Dermatol Venereol. 2003;130:1S129-1S144.16. Casale TB, Blaiss MS, Gelfand E, et al, for theAntihistamine Impairment Roundtable. First do no124 CUTIS ®
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