Flashcards in Blood-Brain Barrier/ Blood-CSF Barrier (6A, Part 4) Deck (21):
What is different about endothelial cells in capillaries in the brain vs. capillaries in the rest of the body?
They have tight junctions rather than fenestrations; therefore, substances must pass through the cells themselves and cannot pass via intercellular route. These tight junctions effectively create the blood brain barrier
Besides the tightly approximated endothelial cells, what also contributes to the blood brain barrier?
Astrocytes also have perivascular feet which line the capillaries. However, the blood brain barrier for all intensive purposes is made by the tight junctions between capillary endothelial cells
The choroid plexus is created by outpouchings of ______ and the ____ mater intot eh ventricular space.
2. Pia mater
Choroid plexus sandwiches capillary blood vessels between layers of the arachnoid membrane and Pia mater
What are cells lining the ventricular wall called?
Ventricular ependymal cells
What are cells lining the choroid outpouchings of ventricles called?
Choroid epithelial cells
What is a key feature that distinguishes choroid epithelial cells from ventricular ependymal cells?
Choroid epithelial cells have tight junctions between them, whereas ventricular ependymal cells have fenestrations
Why are tight junctions found between choroid epithelial cells, but not between ventricular ependymal cells?
Choroid epithelial cells line the choroid outpouchings, places where capillaries (along with Pia mater) dip down into the ventricles. The tight junctions keep potentially toxic substances from leaving the capillaries and getting into to CSF. (In these areas, I don't think the capillaries have tight junctions) Portions where ependymal cells line the ventricles are separated from the capillaries by CNS tissue; they need fenestrations to allow exchange between the ventricles and extracellular spaces in CNS tissue.
What prevents backflow of CSF from venous sinuses back into the arachnoid villi?
Tight junctions between arachnoid villi cells.
What are two main circumventricular organs? What does this mean?
1. Neurohypophysis (post. pit.)
2. Organum vasculosum (of the lamina terminalis) (OVLT)
These structures require direct access to the substances in the blood (specifically electrolytes and hormones) to monitor them; therefore, the BBB isn't found in these areas (no tight junctions in the capillaries)
What three factors determine the uptake of drugs across the BBB?
1. Lipid solubility
2. Molecular weight
3. Whether or not drug is a substrate for P-gp (if it is, it will be pumped out of endothelial cells and not enter the CNS)
What are three pathological conditions that can break down the integrity of the BBB?
2. Advancing age
3. Alzheimer's dz
What is probably the most important factor in permeability of a drug to BBB?
Lipid solubility. This allows it to be penetrable to the lipid bilayer of the capillary endothelial cells, important since nothing can pass between the cells.
Higher lipid solubility = more rapid onset of drug activity and higher levels of drug in the CNS
Why do highly lipid-soluble drugs have a short duration of action in the CNS?
Due to concentration gradients. The drugs rapidly distribute into the brain, due to its high fat content and high vascularity, but then easily come out following the now high-low concentration gradient between the brain and rest of body.(they readily exit the CNS, due to ease of passage across the BBB, same thing that got them in there in the first place) The drugs then undergo rapid distribution to other parts of the body. (The short duration of action is NOT due to rapid elimination)
Why do I.V. Anesthetic drugs (highly lipiphilic) go to brain, heart, kidney, lung first, then to skeletal muscle and skin?
It all has to do with the relative amount of blood flow these organs receive. Brain, heart, kidneys, etc all have high rates of blood flow, so get eh drug first and so on. The drugs end up in peripheral adipose tissue.
What accounts for the long elimination half life of a highly lipiphilic drug?
The drugs are redistributed quickly into adipose tissue. Since they are lipophilic, they are not eliminated quickly (need to be water soluble to be eliminated efficiently)
What is an ABCB1 pump?
Other name for P-gp.
What accounts for the in effectiveness of some antipsychotics and anti-depressants?
Some are substrates for P-gp; therefore they get pumped out of endothelial cells before they can get into CNS
Why are brain malignancies generally poor responders to pharmacological therapy?
Difficulty in getting past BBB
Individual polymorphisms in what two things cause varying response to antidepressant therapy?
2. CYP activity
How can differences in CYP activity be overcome to achieve therapeutic responses?
By altering dose; but only works up to a point