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
