3.11: Physiological Barriers

Physiological barriers are semi-permeable cellular structures restricting drug diffusion into intracellular compartments and tissues. There are six types of physiological barriers: blood endothelial, cell membrane, blood-brain, blood-cerebrospinal fluid (CSF), blood-placenta, and blood-testis barriers.

The blood endothelial barrier is the most porous of these. It allows all small ionized, un-ionized, and lipophilic molecules to pass through the endothelial lining into the interstitial space easily. Still, it excludes large complexes such as drugs bound to plasma proteins.

The cell membrane is a lipid bilayer that facilitates cellular drug absorption. Depending on the size, drug molecules can pass through the cell membrane by passive diffusion, bulk flow, or active transport.

The blood-brain barrier comprising capillaries in the brain is highly specialized. Unlike other capillaries, these consist of endothelial cells joined by tight junctions that prevent the diffusion of most hydrophilic substances from passing between the endothelial cells. Only lipophilic molecules and molecules transported actively by carrier proteins gain access to the brain.

Similar to the blood-brain barrier, the blood-CSF barrier is also impervious to most substances. Although the capillary lining of the choroid plexus has gaps to allow the free passage of drugs, the choroidal cells are tightly held together by tight junctions, restricting the entry of molecules. In addition, the CSF‒a clear homogeneous fluid surrounding the central nervous system‒dilutes the drug and prevents achieving a high drug concentration.

The blood-placental barrier separates the mother's blood vessels from the fetal blood vessels using multiple layers of trophoblast cells. Compared to the blood-brain or the blood-CSF, it is not an effective barrier. It allows molecules such as barbiturates, gaseous anesthetics, antibiotics, steroids or narcotic analgesics to easily pass through by simple diffusion, exposing the fetus to teratogens. Drug consumption must be restricted during pregnancy.

Lastly, the blood-testis barrier is formed by neighboring Sertoli cells joined together by tight junctions that restrict drugs from diffusing into nearby capillaries and reaching the spermatids.

Drugs cross different physiological barriers to move into intracellular compartments. These barriers, such as vascular endothelium, cell membrane, blood-brain, and blood-placental barriers, are semi-permeable and restrict drug distribution in tissues.

Of these, the vascular endothelium is freely permeable to most drugs, including ionized, un-ionized or lipophilic drugs smaller than 600 Daltons.

After diffusing from capillary walls into the extracellular fluid, drugs must cross the cell membrane to enter cells. While lipophilic drugs and small molecules can easily permeate the cell membrane, others require active transport via carrier proteins.

Unlike other capillaries, the capillaries in the brain are made of endothelial cells held together by continuous tight junctions forming the blood-brain barrier.

It is impervious to all non-lipophilic drugs but allows some drugs to be actively transported into the brain.

Lastly, the blood-placental barrier allows lipophilic molecules smaller than 1000 Daltons to pass into fetal circulation by passive diffusion. This barrier is less effective than the blood-brain barrier. So to avoid teratogenicity, drug usage is restricted during pregnancy.