11 Getting meds to CNS Flashcards
what is the blood brain barrier (BBB)
a permeability barrier that separates the circulating blood from the brain extracellular fluid
what is the blood brain barrier made of
3 lines of defence
what is the first line of BBB defence
a barrier of endothelial cells of the brain capillaries with tight junctions
the basement membrane
surrounding astrocytes
what is the second line of BBB defence
an enzymatic barrier of degrading enzymes localised in endothelial cells
what is the third line of BBB defence
transport systems actively transporting substances from the brain back into the blood
what are the purposes of the BBB
- provide essential nutrient supply to the brain
- to ensure a constant internal milieu within the CNS
what is a drug delivery issue relating to the BBB
limits transport into brain, makes it hard for drugs to get into brain
what drugs can easily cross the BBB
drugs that are lipid soluble and and have a molecular weight of under 400Da
can drugs that are lipid insoluble and have a MW of over 400Da cross the BBB
yes but minimally
what are the transport mechanisms at the BBB
- paracellular aqueous pathway
- transcellular lipophillic pathway
- carrier mediated transport
- receptor mediated transport
- adsorptive transcytosis
how does paracellular aqueous pathway transport work
there is a severe restriction of penetration of water-soluble compounds by the junctions
are some transporters energy dependent
yes and act as efflux transporters
how does adsorptive transcytosis work
uptake by adsorptive-mediated endocytosis and transcytosis
increased by cationisation of poorly transported proteins
what are the pharmacological based strategies to delivery drugs to the brain
- chemical modification of a drug
- use of a trojan horse strategy
how does the chemical modification of a drug strategy work
objective is to increase lipohillicity
doesn’t work as MW is increased above 400Da
how does the trojan horse strategy work (simple)
encapsulation of the drug in a delivery system that is able to cross the BBB
works by carrier or receptor mediated endocytosis
how does the trojan horse strategy work (biology)
works by carrier or receptor mediated endocytosis
what limits paracellular transport of large drugs across the BBB
by the presence of tight junctions
strategy to stop the tight junctions limiting transport
opening of the BBB by administration of pharmacological agents or osmotic opening
examples of pharmacological agents administered to open BBB junctions
- vasoactive agents
- peptidase inhibitors
- angiotensin II
- bradykinins
how does osmotic opening of BBB junctions work
intracarotid injection of hypertonic solutions of mannitol or urea
causes shrinking of the size of endothelial cells and opening of junctions
limitations of opening junctions
- should be reversible and short lasting
- risk of neurological damage
- side effects
- aphasia and hemi paresis
can you bypass the BBB by nasal delivery
yes
issues with nasal delviery
lack of efficacy, not many drugs reach brain
