Effect of H1 antihistamines upon the central nervous system.

The antihistamines have been divided into fi rst and second generation drugs, according to their pharmacokinetic properties, structural characteristics and adverse effects. The effects exerted by these substances upon the central nervous system (CNS) are fundamentally determined by their capacity to cross the blood-brain barrier (BBB) and bind to the central H 1 receptors (RH1). The capacity to cross the BBB is dependent upon the lipophilicity of the drug molecule and on its affi nity for P glycoprotein (GpP) – the active transporter of the BBB – which “actively extracts xenobiotic substances from the CNS”. GpP is located on the luminal surface of the endothelial cells of the brain blood vessels [1]. The cerebral capillaries present tightly sealing intercellular junctions with a relative lack of transendothelial conduits for the passive diffusion of soluble molecules. The fi rst generation antihistamines are liposoluble, with scant affi nity for GpP – unlike the second generation molecules which are lipophobic and are regarded as GpP substrates. The distinction based on differences in molecular weight (the smaller the molecule, the easier it is to cross the BBB, at least in theory) is becoming increasingly less important. As an example, desloratadine has a molecular weight (mw = 338.9) similar to that of hydrazine (347.9), but permanence of the two drugs in brain tissue differs after administration. The criterion used to classify an antihistamine as possessing sedative action is based on three requirements that must be met to a minimally acceptable degree: a) Subjective impact upon sleepiness (presence of drowsiness). b) Objective evaluations of possible alterations in cognitive and psychomotor function. c) Central H 1 receptor occupation studies based on positron emission tomography (PET). Although the last two of these criteria are particularly important, all three must be present to classify the drug as possessing sedative action [2]. Chen et al [3] have studied the different concentrations reached by fi rst and second generation antihistamines in plasma and in brain tissue of normal mice and mice with mdr 1a /1b (multidrug resistance gene encoding for GpP) defi ciency. Expressed graphically, the results showed the area under the curve (AUC), refl ecting drug penetration of brain tissue, to be much greater (about 5.5-fold) in the case of the fi rst generation histamines versus the second generation molecules.