Antihistaminicos

H1

ANTIHISTAMINES IN ALLERGIC DISEASE
The second-generation H1 antihistamines cause much reduced CNS sedation and are essentially free of this effect at doses recommended for the treatment of allergic disorders. In addition, these drugs have few or no anticholinergic or other effects. Some second-generation drugs have also been claimed to have anti-allergic and anti-inflammatory effects whichmay contribute to their therapeutic benefit.1

Cas Motala, MB ChB, FCPaeds(SA), FACAAI, FAAAAI
Allergy Clinic, Division of Paediatric Medicine, School of Child & Adolescent Health, University of Cape Town & Red Cross War Memorial Children's Hospital, Rondebosch, Cape Town, South Africa

ABSTRACT
Histamine (one of the key mediators released from mast cells and basophils), plays a major rolein the pathophysiology of allergic diseases, including rhinitis, urticaria, asthma and anaphylaxis. Histamine exerts its effects through its interaction with one of four distinct receptors (H1, H2, H3, H4). In allergic disease, it is the H1 antihistamines which are of primary benefit, although H2 antihistamines may also play a therapeutic role. H1 antihistamines remain first-line medications forthe treatment of allergic rhinoconjunctivitis and urticaria. Second-generation antihistamines are preferred to their predecessors because of better benefit-to-risk ratios. The newer antihistamines are not only more potent, but also have anti-allergic and antiinflammatory properties. Although they are more expensive than the traditional antihistamines, the cost is substantially offset by theirsuperior efficacy and safety profile when used in recommended dosages.

MECHANISM OF ACTION
H1 antihistamines are not receptor antagonists as previously thought, but are inverse agonists.2 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 receptorto stabilise it and shift the balance towards the activated state and stimulate the cell (Fig. 1).3 Antihistamines stabilise the inactive form and shift the equilibrium in the opposite direction. Thus, the amount of histamine-induced stimulation of a cell or tissue depends on the balance between histamine and H1 antihistamines. Histamine effects stimulated through the H1 receptor includepruritus, 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. Although most of the effects of histamine in allergic diseases are mediated by H1 receptor stimulation, certain effects such as hypotension, tachycardia, flushing,headache, itching and nasal congestion are mediated through both H1 and H2 receptors.4 In the CNS, the effects histamine exerts through H1 receptors include cycle of sleep and waking, food intake, thermal regulation, emotion and aggressive behaviour, locomotion, memory and learning. Firstgeneration H1 antihistamines, such as chlorphenamine, diphenhydramine, hydroxyzine and promethazine, penetratereadily into the brain, in which they occupy 5090% of the H1 receptors.5 The result is CNS sedation. In contrast, second-generation H1 antihistamines penetrate the CNS poorly, as they are actively pumped out by P-glycoprotein, an organic anion transporting protein that is expressed on the luminal surfaces of vascular endothelial cells in the blood vessels that constitute the blood-brain barrier.6Their propensity to occupy H1 receptors in the CNS varies from 0% for fexofenadine to 30% for cetirizine. Thus, second-generation H1 antihistamines are relatively free of sedating effects. Through H1 receptors histamine has various effects on the immune system, including the maturation of dendritic cells and modulation of the balance of helper T-cell type 1 (Th1) and Th2 towards Th1. Histamine...