Management of the New H1 Antihistamines in Allergic Rhinitis – General Practitioner Perspective


young and elderly, newer topical nasal steroids generally have an improved safety profile.


Since their introduction over half a century ago, H1 antihistamines have become the mainstay of treatment for AR. Until recently, first-generation antihistamines such as diphenhydramine, doxylamine, chlorphenamine and promethazine were widely used in the treatment of AR. However, they are associated with a number of side effects, of which sedation is the most problematic. These were followed by the development of non-sedating antihistamines and newer intranasal treatments offering increased local drug concentrations with faster onset of action.43,58


Despite the progress made with these


antihistamines, adherence to treatments still remains suboptimal, mainly due to either patients finding them unhelpful in alleviating symptoms or the persistence of undesirable side effects.


Limitations of First-generation Antihistamines First-generation H1 antihistamines, all of which are sedating, are generally regarded as safe. However, these drugs are commonly associated with central nervous system (CNS) depressant effects including reduced rapid-eye-movement sleep, impaired learning, reduced work efficiency, somnolence, sedation, drowsiness, fatigue and impaired concentration and memory.32,59


For example,


Impairment of function occurs even with the lowest doses of first-generation antihistamines recommended by manufacturers. Furthermore, first-generation H1 antihistamines have been implicated in civil-aviation, motor vehicle and boating accidents, with approximately 6 % of fatalities linked with their use.32,60,61


diphenhydramine has been shown to have greater sedative effects than alcohol, affecting mental alertness, eye–hand co-ordination and manual dexterity.59


Figure 3: Shared Mechanism of Action for Allergic Rhinitis and Asthma Patients


CCR3 CCR4 CCR5


Allergic rhinitis Mc Allergen


Histamine Tryrtase Cys L T PGs Il-4, IL-5 IL-6, IL-13 GM-CSF TNF-α


Asthma


Upregulated adhesion


molecules and Chemoattractants


Eosinophil Blood vessel Eosinophil Th2


IL-4, IL-5 IL-6, IL-13 RANTES Eotaxin


IL-3 IL-5


GM-CSF


CysL T1 R CysL T2 R IL-5 R, IL-3 R GM-CSF R


Eo/Ba progenitor VCAM-1 VLA-4 CCR3


CysL T1 R CysL T2 R


Bone marrow


Link between rhinitis and asthma Source: Pawankar, 2006.49


CCR = C-C chemokine receptor; Cys LTs = cysteinyl leukotrienes; Eo = eosinophil; GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; Mc = mast cell; PGs = prostaglandins; Th2 = T helper cell 2; TNF = tumour necrosis factor; VCAM = vascular cell adhesion molecule; VLA = very late antigen.


cetirizine are now available without prescription in the US, many European countries and elsewhere.69


Based on this evidence, members of the Global Allergy and Asthma European Network have called for the removal of older first-generation H1 antihistamines as over-the-counter, prescription-free drugs for self-medication of AR.32


There are also concerns about first-generation antihistamines with regard to fatalities occurring as a result of accidental or intentional overdosing in infants and young children and suicide in teenagers and adults.62,63


The Level of Patient Expectations and Reasons for Compliance and Non-compliance There are distinct differences in the perceptions of the patient and the physician with respect to the treatment of SAR and PAR. Physicians believe SAR is easy to treat and, as such, often give it low priority.71


PAR is


It is important to sufficiently understand the ARIA guidelines for the treatment of SAR and convey adequate information to patients so they can form realistic expectations of the treatment regimens (and thus improve compliance).7,56


Further limitations of first-generation antihistamines include an increased risk of inattention, disorganised speech, altered consciousness and impaired function or alertness, particularly among the elderly.64,65


The Emergence of Second-generation Antihistamines


In the 1980s a significant advance occurred in the development of second-generation antihistamines.66,67


These newer medications


include fexofenadine, ebastine, loratadine, desloratadine, levocetirizine and cetirizine, which are larger, more lipophobic molecules than first-generation compounds, making it more difficult for them to cross the blood–brain barrier and bind to central H1 receptors. In general, these newer medications also have a much higher specificity for the H1 receptor.68,69


This more


specific action results in fewer side effects on the neuronal and hormonal systems and thus they have fewer sedative side effects than the first-generation agents, with good safety profiles and improved cardiotoxicity profiles, although loratadine and desloratadine have caused some cardiac symptoms including ventricular arrhythmias.70


The second-generation antihistamines are now well established in the management of AR; loratadine and EUROPEAN RESPIRATORY DISEASE


considered to be less common but more serious than SAR and more difficult to treat. Physicians consider that the treatment gives only limited symptomatic relief but patients with chronic symptoms have high expectations71


which are infrequently met.


Despite the availability of treatment guidelines, there is evidence that the severity of disease is often not recognised and treatments prescribed by general practitioners (GPs) are therefore inadequate or inappropriate.72


Adherence to the ARIA guidelines on the management of AR could result in a more structured management plan for patients, with better outcomes.75


Second-generation antihistamines and intranasal steroids are effective in reducing the major symptoms of AR, including sneezing, itching and nasal blockage, and, since they are administered as a single daily dose, these drugs demonstrate high patient compliance (see Table 1).76,77 In contrast, topical antihistamines, administered as a twice-daily dosage, and first-generation antihistamines, with the frequent occurrence of induced adverse events, demonstrate comparatively lower compliance. Although nasal decongestants and systemic steroids also have good acute compliance rates, their use is limited by side effects associated with their prolonged administration.71,78


Interestingly, there also appears 113


GPs do not frequently use a guided treatment strategy and this can lead to low patient satisfaction and poor compliance.73,74


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