Central　Nervous　System　and Cerebrospinal Fluid.

The distribution of drugs to the CNS from the blood stream is unique, mainly in that entry of drugs into the CNS extracellular space and cerebrospinal fluid is restricted. The restriction is similar to that across the gastrointestinal epithelium. Endothelial cells of the brain capillaries differ from their counterparts in most tissues by the absence of intercellular pores and pinocytotic vesicles. Tight junctions predominate, and aqueous bulk flow is thus severely restricted. This is not unique to the CNS capillaries (tight junctions appear in many muscle capillaries as well). It is likely that the unique arrangement of pericapillary glial cells also contributes to the slow diffusion of organic acids and bases into the CNS. The drug molecules probably must traverse not only endothelial but also perivascular cell membranes before reaching neurons or other drug target cells in the CNS. Cerebral blood flow is the only limitation to permeation of the CNS by highly lipid-soluble drugs. With increasing polarity the rate of diffusion of drugs into the CNS is proportional to the lipid solubility of the nonionized species (see Rall in the symposium edited by La Du et al., 1971).Strongly ionized agents such as quaternary amines or the penicillins are normally unable to enter the CNS from the circulation.