3 Clinical psychopharmacology3.2 Pharmacokinetics
3.2.4.2 The blood brain barrier
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Written by Resident Doctor Committee · Published
Structure
The blood-brain barrier is formed by brain capillary endothelium, which has few fenestrations, little non-specific transcytosis and specialised transporters and enzymes.
Tight junctions between endothelial cells, formed mainly by claudin-5 with occludin and junctional adhesion molecules, close the paracellular route to polar molecules; gap junctions do not provide the seal.
Astrocyte end-feet ensheath the capillary and induce barrier properties, but they leave gaps between them and do not form the barrier.
Endothelium, pericytes, astrocytes, neurones and microglia together form the neurovascular unit.
Barrier | Formed by | Guards |
|---|---|---|
Blood-brain | Brain capillary endothelium | Brain extracellular fluid |
Blood-cerebrospinal fluid (CSF) | Choroid plexus epithelium | CSF |
CSF drug levels need not equal free brain tissue levels.
Passive entry
Lipid solubility, measured by the lipid-water partition coefficient, determines passive transcellular entry together with molecular size, ionisation and protein binding.
Lipophilic molecules enter readily and water-soluble ones poorly.
Small, lipid-soluble, un-ionised molecules (often below 400 to 500 Da) and gases diffuse across, as ethanol and caffeine do.
Carrier-mediated entry
Polar molecules need a carrier.
Substrate | Route |
|---|---|
Glucose | Glucose transporter 1 (GLUT1) |
Large neutral amino acids, levodopa | L-type amino acid transporter (LAT1) |
Transferrin, insulin | Receptor-mediated transcytosis |
Polar amine transmitters are kept out: levodopa enters on LAT1, whereas dopamine and circulating catecholamines penetrate poorly.
P-glycoprotein
P-glycoprotein (ABCB1) is an ATP-dependent efflux transporter on the luminal membrane of brain capillary endothelium.
It pumps lipophilic drugs and toxins back into the blood, so it limits brain entry of otherwise permeable drugs.
Loperamide has little central opioid effect at usual doses because P-glycoprotein removes it.
Antihistamines
Generation | Brain entry | Effect |
|---|---|---|
First | Small, lipophilic, not P-glycoprotein substrates, so they enter | Sedation |
Second | Poor | Little sedation or antimuscarinic effect, though cetirizine can still cause drowsiness |
Circumventricular organs
Circumventricular organs lack a normal barrier because their capillaries are fenestrated and open to the circulation; the thalamus, like most brain, has an intact barrier.
Organ | Function |
|---|---|
Area postrema | Detects circulating emetic signals and is reached by domperidone |
Posterior pituitary | Releases vasopressin and oxytocin |
Median eminence | Releases hypothalamic hormones into portal blood |
Subfornical organ, organum vasculosum of the lamina terminalis | Sense osmotic and hormonal signals |
Local barriers stop spread, so entry to a circumventricular organ does not mean cortical access.
Bypassing the barrier
Intranasal drugs can reach the brain without crossing the barrier, by nose-to-brain transport along olfactory and trigeminal nerve pathways.
Disease and drug effect
Inflammation, infection, injury, hypoxia, seizures and tumours change permeability regionally and selectively, not uniformly.
Brain entry is not efficacy: positron emission tomography occupancy shows engagement, not benefit.
A high brain-to-plasma ratio can reflect binding to brain lipid and protein while free drug stays low.