Why are non-sedating antihistamines non-sedating?

In this paper several factors which may influence the potential of a certai n antihistamine to cause CNS-related side-effects are discussed. It is shown by pharmacological studies that the H-1 receptors occurring in CNS tissue or in peripheral organs do not differ with regard to their affin ity for H-1 blockers. There is also no other evidence for subtypes of the H -1 receptor. The sedating properties are caused by H-1 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. Co mpounds with a low or a high lipophilicity (log P) do not penetrate. For co mpounds 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 neu tral species only readily enter into the CNS. For compounds with an interme diate log P or log D a Delta log P is introduced; a Delta log 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 intr oduced. Finally the influence of histamine on the permeability of the blood -brain barrier is discussed; it is shown that histamine increases the extra vasation of, for example, albumin.