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Why are non-sedating antihistamines non-sedating?

Authors


Professor H. Timmerman Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083 NL-1081, HV Amsterdam, The Netherlands.

Abstract

In this paper several factors which may influence the potential of a certain antihistamine to cause CNS-related side-effects are discussed. It is shown by pharmacological studies that the H1 receptors occurring in CNS tissue or in peripheral organs do not differ with regard to their affinity for H1 blockers. There is also no other evidence for subtypes of the H1 receptor. The sedating properties are caused by H1 blockade. The level of brain penetration (passage of the blood–brain barrier) is not fully determined by the lipophilicity (log P) of an individual compound. Compounds with a low or a high lipophilicity (log P) do not penetrate. For compounds with a basic centre the log D should be applied, replacing the log P; the log D corrects for the level of ionization of such compounds, as neutral species only readily enter into the CNS. For compounds with an intermediate log P or log D a Δlog P is introduced; a Δlog P indicates a large hydrogen binding capacity. A strong hydrogen binding capacity means a strong (serum) protein binding and consequently a poor brain penetration. Also the role of the P-glycoprotein as a transporter out of the CNS is introduced. Finally the influence of histamine on the permeability of the blood–brain barrier is discussed; it is shown that histamine increases the extravasation of, for example, albumin.

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