drug delivery to CNS Flashcards
what can drug delivery to the brain treat
neurological disorders (alzheimers, epilepsy), mental health disorders (depression, anxiety), pain, brain tumours, brain infections
name 4 barriers drugs have to pass to reach the brain
meningeal, blood brain, blood CSF, glymphatic circulatory system
what is CSF
cerebrospinal fluid
function of blood brain barrier
shields brain from toxic substances in blood, supplies brain tissue with nutrients and filters harmful compounds back into blood stream
describe the blood brain barrier
part of neurovascular unit, epithelium different from peripheral capillaries (it has tight junctions, basement membranes, low endocytosis activity), lots of ABC transporters, drug metabolising enzymes, altered functions in brain diseases (?)
describe the mechanisms across the blood brain barrier
-paracellular diffusion is not significant
-can transcellular diffusion if high lipophilicity, MW<400kDa, not recognised by efflux pumps, high bioavailability
-transporter mediated transport
-transcytosis for proteins and peptides
what models are used to predict drug absorption into the brain
-imaging techniques as sampling in brain is not possible
-animal models to compare plasma and total brain concentration after injections
-measurements of unbound concentrations in brain by microdialysis
name 3 in vitro models of the blood brain barrier
isolated brain microvessels- contains endothelial cells, basement membrane, pericytes, astrocyte feet, studies only in brain to blood direction
porcine/bovine primary cultures- different configurations non validated
cell lines
name 3 strategies to increase drug transport across blood brain barrier
- modify drug properties -increase lipophilicity, targeting endogenous transport mechanisms (transporters and receptor mediated transcytosis)
- alterations of blood brain barrier- osmotic opening, focused ultra sounds
- avoiding blood brain barrier- invasive methods, nose to brain delivery
limitations of increasing lipophilicity to increase drug penetration to brain
not largely applicable approach, lacks specificity, often leads to decreased bioavailability
describe targeting transporters to increase drug penetration to brain
BBB has high expression of transporters, majority of drugs crossing BBB are transporter substrates, design of prodrugs recognised by transporters
describe targeting receptor mediated transcytosis to increase drug penetration to brain and its limitations
coupling of endogenous ligand to drug, can be applied to small or large molecules/liposomes/nanoparticles
limitations- competition with endogenous molecules, conjugation to antibody or short peptide sequence recognising the receptor, not specific approach
what is osmotic opening
infusion of drug with hyperosmotic solution of mannitol, shrinkage of endothelial cells (due to water leaving? difference in water potential), affects entire BBB
what is focused ultra sounds
vibration of injected microbubbles, opens tight junctions, non invasive, affects one specific area of BBB
name 6 ways to avoid blood brain barrier
-intrathecal injection
-intraventricular delivery
-delivery to CSF
-intracerebral injection/infusion
-intracerebral implants
-nose to brain delivery
what is intrathecal injection and what is it used for
injects into spinal canal between two lumbar vertebrae
for anaesthesia, pain, chemotherapy
what are limitations of intraventricular delivery (needle into brain)
slow infusion needed to avoid damage, highly invasive
limitations of delivery to cerebrospinal fluid
poor diffusion into parenchyma
limitations of intracerebral injection/infusions
(directly into parenchyma, localised therapy, formulation pumped into catheter)
poor drug diffusion into tissue due to cell packing, highly invasive
how does intracerebral implants work and what is it made of
inserted into tumour site after surgical removal, made of polyanhydride polymer, fast degradation, drug released over 2-3 weeks, protects drug from water, erosion faster than water penetration into bulk
describe the mechanisms of nose to brain delivery
paracellular (loose tight junctions between neurons and epithelial cells), transcellular through epithelial cells (passive diffusion, transporter mediated), transcytosis in olfactory neurons
what is olfactory regions function
enables sense of smell
advantages and limitations of nose to brain delivery
advantages- non invasive, easy administration, no need for drug modification, easy formulation
limitations- small surface area not easily accessible, drug absorption into systemic or lymphatic circulation, variable drug absorption, poor prediction of clinical data from animal studies
advantages and delivery issues of nose to brain delivery
convectional nose spray- reproducible dose administered, only 2% reaches olfactory region
nasal drops- spreads well in nasal cavity, dose delivered not accurate, rapid clearance from nasal cavity, complex administration
