02.02.4 Blood Brain Barrier

In the systemic circulation, there are gaps between endothelial cells lining blood vessels (Figure 2.3) and, as the basement membrane is freely permeable, this allows most free water and lipid soluble drugs to move out of the systemic circulation (Figure 2.3).

Figure 2.3 Distribution across blood vessels (Copyright QUT University, Sheila Doggrell)

In the cerebral circulation, there are no gaps between the endothelial cells, and this forms a barrier (referred to as the blood brain barrier) mainly to water soluble drugs. Because of this barrier, water soluble drugs cannot get into the brain from the cerebral circulation. Only lipophilic drugs, and drugs that are actively transported, can cross the blood brain barrier. Most drugs used for central nervous system effects are lipophilic. The sedative diazepam is a lipophilic drug that moves across lipid membranes into the brain. L-dopa is an example of a drug that it is actively transported into brain. The barrier is deficient in chemoreceptor trigger zone, and some drugs act in this zone to exert emetic (vomiting) effects.

For central nervous system effects, we need drugs that cross the blood brain barrier. Alternatively, drugs can be administered into the cerebral spinal fluid to bypass the blood brain barrier. For instance, penicillin does not cross the blood brain barrier, which is fine when we have a peripheral infection, but not if the infection is within the central nervous system. For central infections, penicillin has to be administered into the cerebral spinal fluid (CSF) by the intrathecal route of drug administration.

For peripheral effects, drugs that do not cross the blood brain barrier are preferred. This is because, any central effects of a drug administered for a peripheral effect, may be adverse effects. For instance, the anti-histamine diphenhydramine was developed to treat allergy, a peripheral condition, but diphenhydramine crossed the blood brain to have central effects, notably a central sedative effect. Thus, subjects given diphenhydramine for allergy were at risk of falling asleep. The second generation anti-histamines (e.g. fexofenadine) were developed to have a reduced ability to cross the blood brain barrier and, consequently, do not exert a sedative effect. Presently, only the second generation anti-histamines are used to treat allergy, and diphenhydramine has been developed as a mild sedative.