Getting medications into the CNS Flashcards
what is the blood brain barrier?
a permeability barrier that separates circulating blood from the brain extracellular fluid
What are the 3 lines of defence of the BBB
1) An anatomical barrier of endothelial cell of the brain capillaries with tight junctions, the basement membrane and surrounding astrocytes
2) An enzymatic barrier of degrading enzymes (ie. carbopeptidases, aminopeptidases) localized in endothelial cell
3) transport systems actively transporting substances from the brain back to the blood
what is the dual purpose of the BBB
- to provide essential nutrient supply to the brain
- to ensure a constant internal milieu within the CNS
What is the problem with the BBB?
limits the delivery of drugs to the brain
What are different drug types and do they cross the BBB?
Peptides, proteins, antibodies, DNA/RNA do not cross
Small lipid soluble molecules with MW <400da do pass through
lipid insoluble or MW>400 da has minimal
What is paracellular aqueous pathway?
Severe restriction of penetration of water-soluble compounds (including polar drugs) by the tight junctions
What are transcellular lipophillic pathways?
lipid soluble agents are able to pass through tight junctions
What is carrier mediated transport?
Transport proteins (carriers) for glucose, amino acids, nucleosides and other substances
Some transported are energy dependent (eg. P-glycoprotein) and act as efflux transporters
What is receptor - mediated transcytosis?
specific receptor-mediated endocytosis and transcytosis for some proteins (ie. insulin and transferrin)
what is absorptive transcytosis?
uptake by absorptive medicated endocytosis and transcytosis increase by cationizing of poorly transported proteins ie. albumin
Would chemical modification by increasing lipophilicity of the drug cause the ability to cross the BBB via trancellular lipophilic pathways?
No
- increase of MW above 400da by adding side chains to drug
- increase of the drug uptake by all tissues by increasing lipid solubility
- increase in drug clearance from the blood
What is the Trogan horse strategy?
conjugation of the drug to a molecule able to cross the BBB
encapsulation of the drug in a delivery system to able to cross the BBB encapsulation
What is an example of conjugation of the drug to a molecule able to cross the BBB
By carrier or receptor mediated endocytosis
-ie. conjugation to a receptor - specific antibody which binds to a BBB receptor
Drugs in the laboratory setting
- vasoactive intestinal peptide
- brain derived neuropathic factor
What are ways drugs can be encapsulated in a delivery system?
Liposome
Micelle
Nano particle
What are strategies to the limitation of paracellulsr transport of large drugs to do tight junctions?
Pharmacological agents: Vasoactive agents peptidase inhibitors, angiotensin II and bradykins
Osmotic opening: intracarotid injection of hypertonic solutions mannitol or urea
- shrinkage of the size of endothelial cells
- opening of tight junction network
What are limitations of the strategies to get drugs across the BBB?
- should be reversible and short lasting
- risk of neurological damage (seizures)
- serious side effects of vasoactive agents
what is the limitation of nasal delivery of drugs to pass the BBB
<0.1% of the drugs in the nasal cavity could reach the brain
