Histological Structure of the BBB
The barrier is a multi-layered structure where each component performs a specialized filtration function.
- Brain capillary endothelial cells. Unlike peripheral vessels, these cells lack intercellular clefts. They are joined by tight junctions (zonula occludens), specific proteins that block paracellular (intercellular) transport. Additionally, pinocytosis (fluid uptake) is virtually absent in brain endothelium.
- Basement membrane.
- Pericytes (pericytae).
- Astrocytes (astrocyti), glial cells whose foot processes wrap around the capillaries externally.
Mechanisms of Drug Permeability
A drug's ability to penetrate the brain depends directly on its chemical structure.
- Lipophilic (non-polar) substances can cross endothelial cell membranes via passive diffusion.
- Hydrophilic (polar) substances cannot cross tight junctions. They rely on specific pathways: receptor-mediated endocytosis (used by insulin) or transport proteins (e.g., for levodopa).
The BBB is not merely a physical wall but an active transport system. It features efflux transporters, most notably P-glycoprotein (along with ATP-binding cassette transporters and solute carrier [SLC] organic anion transporters). Their role is the active extrusion of xenobiotics and lipophilic drugs from brain tissue back into the bloodstream.
Clinical example: The prokinetic agent Metoclopramidum penetrates the CNS and causes extrapyramidal symptoms. Its analog Domperidonum is a P-glycoprotein substrate, is actively pumped out of the brain, and acts solely in the periphery without causing central side effects. Similarly, the second-generation antihistamine Fexofenadinum is removed by transporter proteins, rendering it non-sedating.
Factors Altering Permeability
BBB permeability can be altered by:
- Physical factors: increased arterial blood pressure or plasma osmotic pressure, radiation, and microwaves.
- Biochemical mediators: histamine (Histaminum) and bradykinin.
- Pathological states: traumatic brain injury, ischemia, neurodegenerative diseases (Alzheimer's disease, multiple sclerosis), and inflammation.
Clinically, these changes are often harnessed therapeutically. For instance, in bacterial meningitis, the barrier becomes permeable even to hydrophilic molecules, allowing effective treatment with intravenous Benzylpenicillinum. In neuro-oncology, osmotic opening of the BBB is utilized: administration of Mannitolum raises plasma osmotic pressure, disrupts endothelial tight junctions, and enhances paracellular transport, facilitating the entry of chemotherapeutic agents.
Strategies to Overcome the BBB
A major challenge in treating CNS disorders is that active efflux reduces drug concentrations in the brain below therapeutic levels. Pharmacology employs several bypass strategies:
- Prodrugs. An inactive substance is administered that becomes active only within the brain. The molecule is modified to increase lipophilicity (e.g., gabapentin) or to bind specific transporters (levodopa).
- Efflux transporter inhibition. Combining a drug with a P-glycoprotein inhibitor. For example, the blocker Verapamil increases the brain concentration of antifungal agents (itraconazole) or HIV protease inhibitors.
- Nanotechnology. Drugs are encapsulated within biodegradable polymer nanoparticles (10–1000 nm in size) or surface-conjugated. This enables the transport of peptides (dalargin), bypasses P-glycoprotein (loperamide), or delivers oncological drugs (doxorubicin).