Drugs and BBB Flashcards
what is a tight junction?
anchor between 2 cells with proteins
separates luminal side and basement membrane
not waterproof
varying degrees of tightness
absorption at a tight junction
reduced
what is a cleft?
gap between epithelial cells
increased absorption
what are fenestra?
4-layer lipid membrane, there is no cytosol in the cell
increases absorption
what is pinocytosis?
transport across membrane of fluids
invagination of membrane and release into the cell
what factors influence the rate of diffusion?
molecular size concentration gradient ionisation lipid solubility protein binding
what factors are directly proportional to the rate of diffusion?
concentration gradient
lipid solubility
what factors are inversely proportional to the rate of diffusion?
molecular size
ionisation
protein binding
the higher/ larger the slower the rate of diffusion
local anaesthetic
unionised outside the cell
can enter cell by passive diffusion
lower intracellular pH means it becomes ionised inside the cell and so is no longer lipid soluble
ionised local anaesthetic blocks the sodium ion channel and prevents propagation of action potentials
local anaesthetic in infected tissue
doesn’t work
because pH is lower in extracellular fluid so the local anaesthetic will be ionised outside the cell and so less will enter the cell
how do substances cross the BBB?
paracellular pathway transcellular lipophilic pathway transport proteins efflux pumps receptor mediated transcytosis adsorptive transcytosis/ pinocytosis cell mediated transcytosis
paracellular pathway
water soluble molecules can travel between tight junctions down concentration gradient
transcellular lipophilic pathway
lipid soluble small molecules can travel through cell membranes across the cell down a concentration gradient
transport proteins
allow glucose, amino acids and nucleosides to enter the brain/ CSF by facilitated diffusion through the cell via these proteins
receptor mediated transcytosis
insulin and transferrin
bind to receptor and released on inside of cells - pinocytosis
adsorptive transcytosis
pinocytosis
excreted on opposite side
efflux pump
active transport to remove unwanted substances from endothelial cells and prevent them entering the brain and CSF
cell mediated transcytosis
phagocytosis of whole cells which are then released on opposite side
common CNS diseases
meningitis brain abscess brain tumour MS alzheimer's disease parkinson's disease can all disrupt BBB
common drugs used in CNS diseases
antibiotics
levodopa
anticholinergics
treatment for bacterial meningitis
benzylpenicillin
how does benzylpenicillin cross BBB?
it is large, charged but has a lipophilic ring
during meningitis there is cytokine storm and oxidative stress which disrupts the integrity of the BBB so large charged molecules can cross it
what are the causes of disrupted BBB?
ROS MMPs angiogenic factors inflammatory cytokines autoantibodies leukocyte adhesion immune cell extravasation pathogens
what are the consequences of a disrupted BBB?
imbalance of ions and neurotransmitters leakage of plasma proteins entry of toxins and pathogens microglial/ astroglial activation release of cytokines/ chemokines neuronal dysfunction neuroinflammation neurodegeneration
non-invasive common approaches to getting drugs across the BBB
lipophilic analogues
pro drugs
how does levodopa cross the BBB?
non-polar
pro drug as dopamine is too polar to cross the BBB
anticholinergics use
increase heart rate
example of anticholinergic
atropine
how does atropine cross the BBB?
non-polar
can be made charged so it cannot cross BBB and prevents CNS side effects so only works in periphery
atropine side effects
anti-muscarinic effect in periphery and CNS
causes confusion and other unwanted CNS side effects
receptor/ vector mediated transport
viruses are altered to make them safe, then attached to a drug
there are some risks = unwanted immune response, endogenous recombination and mutagenic behaviour leading to oncogenesis
colloidal drug carriers
very small molecules enveloped into colloidal carriers making the substance lipophilic so can cross the BBB
invasive drug delivery to CNS
breaks barrier
- intraventricular route via ommaya reservoir
- subarachnoid route - intrathecal via injections and pumps
ommaya reservoir
tube/ catheter
ends in lateral ventricles
attached to subcutaneous reservoir in head
can deliver high concentration low volume substances
long-term
uses of ommaya reservoir
reduced systemic side effects
reduced dosage needed as targeted
chemo
antibiotics
injection
spinal injection straight into CSF small volume high concentration targeted quick effect effect occurs below site of injection cannot be topped up
intrathecal drug delivery system
allows long-term administration
tube enters thoracic spine from access via lumbar spine
pump attached subcutaneously
allows infusion of drugs directly into CSF
nose-brain drug pathway
allows access to CNS richly irrigated area quick onset pH in nasal epithelium is low - affecting drug ionisation can cause irritation of mucosa
