Antihistamines in pediatric allergy

Histamine is a key mediator in allergic diseases, where it exerts most of its effects through the H1 receptor and to a less extent the H2 receptor. H1antihistamines provide rapid relief of many of the allergic symptoms and are considered the main stay of treatment of allergic rhinoconjunctivitis and urticaria. H1 antihistamines comprise first generation (old) and second generation (new) H 1 antihistamines with different pharmacological aspects, efficacy and safety profile. Few studies dealt with H1 antihistamines in pediatric population. This review will highlight the characteristics of H1 antihistamines and their indications in pediatric allergic disorders. Allergic diseases constitute the most common causes of chronic illness in developed countries and the incidence rising in developing countries. It has been proposed that there is a worldwide epidemic of allergic diseases which is likely to be a consequence of the changing environment and improved general health, superimposed on a range of genetic susceptibilities. Therefore, the treatment of allergy should have high priority in most countries. Histamine (one of the key mediators released from mast cells and basophils), plays a major role in the pathophysiology of allergic diseases, including rhinitis, urticaria, asthma and anaphylaxis. The effects of histamine are exerted through three well defined classical G protein coupled histamine receptor (HR) subtypes termed H1R, H2R, and H3R and the more recently described H4R. There is also a fifth category including ill-defined histamine receptors such as an intracellular receptor labelled Hic. Its existence has so far only been inferred by the presence of small amounts of histamine in cells not traditionally thought to contain histamine. All have constitutive activity, which is defined as the ability to trigger downstream events even in the absence of ligand binding. Histamine signalling through H1R is responsible for the majority of the immediate manifestations of allergic disease namely pruritus, pain, vasodilatation, vascular permeability, hypotension, flushing, headache, tachycardia, bronchoconstriction, and stimulation of airway vagal afferent nerves and cough receptors as well as decreased atrioventricular-node conduction. However, certain effects such as hypotension, tachycardia, flushing, headache, itching and nasal congestion are mediated through both H1 and H2 receptors. Considering all the above roles of histamine on H1 receptors, it is clear that antiH1antihistamines are the most common drugs used to treat allergic diseases. H1 antihistamines are not receptor antagonists as previously thought, but are inverse agonists. When neither histamine nor antihistamine is present, the active and inactive states of the H1 receptor are in equilibrium or a balanced state. Histamine combines preferentially with the active form of the receptor to stabilise it and shift the balance towards the activated state and stimulate the cell. Antihistamines stabilise the inactive form and shift the equilibrium in the opposite direction. H1 antihistamines reduce the expression of proinflammatory cell adhesion molecules and the accumulation of inflammatory cells, such as eosinophils and neutrophils. Major clinical effects of H1 antihistamines are seen in suppression of the early response to allergen challenge in the conjunctiva, nose, lower airway and skin. The anti-inflammatory effects of H1 antihistamines are exerted through receptordependent and -independent mechanisms. Receptor-dependent mechanisms involve the stabilization of the histamine receptor in its inactive conformation. A possible site where they could exert an anti-inflammatory activity is at the level of the transcription factors, NF-kB and GATA3. This would lead to inhibition of these factors dependent cytokines and adhesion molecules. Receptor-independent effects consist of inhibition of inflammatory cell activation including the de novo generation of proinflammatory products such as superoxide radicals, and the arachidonic acid products LTB4 and LTC4, and the release of granule associated products, such as neutrophil elastase and Review article