chapter  40
22 Pages

^#.^t40: TLC of Antihistamines

Histamine exhibits a wide variety of both physiological and pathological functions in different tissues and cells. Actions of histamine that are of interest both from a pharmacological and therapeutic point of view include (a) its important, but limited, role as chemical mediator of hypersensitivity and allergic inammatory reactions, (b) its major role in the regulation of gastric acid secretion, and (c) its emerging role as a neurotransmitter in the central nervous system (CNS). The term “antihistamine” historically has referred to drugs that block the actions of histamine at the H1-receptors rather than the other histamine receptor subtypes. H1-Antihistamines act as inverse agonists that combine with and stabilize an inactive form of the H1-receptor, shifting the equilibrium toward an inactive state. Based on pharmacological proles, the H1-antihistamines are now commonly subdivided into the two broad groups: the rst-generation (or classical) antihistamines and the second-generation (or “nonsedating”) antihistamines. The rst-generation H1-antihistamines are useful and effective in the treatment of allergic responses (e.g., hay fever, rhinitis, urticaria, and food allergy). These agents also exert effects at cholinergic, adrenergic, dopaminergic, and serotonergic receptors. Many of the rst-generation antihistamines readily penetrate the blood-brain barrier because of their lipophilicity and maintain signicant CNS concentrations, because they are not the substrates for the P-glycoprotein efux pump that is expressed on endothelial cells of the CNS vasculature. Blockade of central H1-receptors results in sedation, drowsiness, and decreased cognitive ability. The primary objective of antihistamine drug development over the past several decades has centered on developing new drugs with higher selectivity for the H1-receptors than those already existing and the lack of undesirable CNS and cardiovascular actions. These efforts led to the introduction of the secondgeneration antihistamines, which exert little antagonist activity on other neurotransmitter receptors, including muscarinic receptors, and the cardiac ion channels at therapeutic concentrations (Beale and Block 2011).