Drugs and BBB

Question 1

what is a tight junction?

Answer 1

anchor between 2 cells with proteins
separates luminal side and basement membrane
not waterproof
varying degrees of tightness

Question 2

absorption at a tight junction

Answer 2

reduced

Question 3

what is a cleft?

Answer 3

gap between epithelial cells

increased absorption

Question 4

what are fenestra?

Answer 4

4-layer lipid membrane, there is no cytosol in the cell

increases absorption

Question 5

what is pinocytosis?

Answer 5

transport across membrane of fluids

invagination of membrane and release into the cell

Question 6

what factors influence the rate of diffusion?

Answer 6

molecular size
concentration gradient 
ionisation 
lipid solubility 
protein binding

Question 7

what factors are directly proportional to the rate of diffusion?

Answer 7

concentration gradient

lipid solubility

Question 8

what factors are inversely proportional to the rate of diffusion?

Answer 8

molecular size
ionisation
protein binding
the higher/ larger the slower the rate of diffusion

Question 9

local anaesthetic

Answer 9

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

Question 10

local anaesthetic in infected tissue

Answer 10

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

Question 11

how do substances cross the BBB?

Answer 11

paracellular pathway
transcellular lipophilic pathway
transport proteins
efflux pumps
receptor mediated transcytosis
adsorptive transcytosis/ pinocytosis
cell mediated transcytosis

Question 12

paracellular pathway

Answer 12

water soluble molecules can travel between tight junctions down concentration gradient

Question 13

transcellular lipophilic pathway

Answer 13

lipid soluble small molecules can travel through cell membranes across the cell down a concentration gradient

Question 14

transport proteins

Answer 14

allow glucose, amino acids and nucleosides to enter the brain/ CSF by facilitated diffusion through the cell via these proteins

Question 15

receptor mediated transcytosis

Answer 15

insulin and transferrin

bind to receptor and released on inside of cells - pinocytosis

Question 16

adsorptive transcytosis

Answer 16

pinocytosis

excreted on opposite side

Question 17

efflux pump

Answer 17

active transport to remove unwanted substances from endothelial cells and prevent them entering the brain and CSF

Question 18

cell mediated transcytosis

Answer 18

phagocytosis of whole cells which are then released on opposite side

Question 19

common CNS diseases

Answer 19

meningitis
brain abscess
brain tumour
MS
alzheimer's disease
parkinson's disease 
can all disrupt BBB

Question 20

common drugs used in CNS diseases

Answer 20

antibiotics
levodopa
anticholinergics

Question 21

treatment for bacterial meningitis

Answer 21

benzylpenicillin

Question 22

how does benzylpenicillin cross BBB?

Answer 22

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

Question 23

what are the causes of disrupted BBB?

Answer 23

ROS
MMPs
angiogenic factors
inflammatory cytokines 
autoantibodies 
leukocyte adhesion 
immune cell extravasation 
pathogens

Question 24

what are the consequences of a disrupted BBB?

Answer 24

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

Question 25

non-invasive common approaches to getting drugs across the BBB

Answer 25

lipophilic analogues

pro drugs

Question 26

how does levodopa cross the BBB?

Answer 26

non-polar

pro drug as dopamine is too polar to cross the BBB

Question 27

anticholinergics use

Answer 27

increase heart rate

Question 28

example of anticholinergic

Answer 28

atropine

Question 29

how does atropine cross the BBB?

Answer 29

non-polar

can be made charged so it cannot cross BBB and prevents CNS side effects so only works in periphery

Question 30

atropine side effects

Answer 30

anti-muscarinic effect in periphery and CNS

causes confusion and other unwanted CNS side effects

Question 31

receptor/ vector mediated transport

Answer 31

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

Question 32

colloidal drug carriers

Answer 32

very small molecules enveloped into colloidal carriers making the substance lipophilic so can cross the BBB

Question 33

invasive drug delivery to CNS

Answer 33

breaks barrier

• intraventricular route via ommaya reservoir
• subarachnoid route - intrathecal via injections and pumps

Question 34

ommaya reservoir

Answer 34

tube/ catheter
ends in lateral ventricles
attached to subcutaneous reservoir in head
can deliver high concentration low volume substances
long-term

Question 35

uses of ommaya reservoir

Answer 35

reduced systemic side effects
reduced dosage needed as targeted
chemo
antibiotics

Question 36

injection

Answer 36

spinal injection 
straight into CSF
small volume
high concentration 
targeted
quick effect
effect occurs below site of injection 
cannot be topped up

Question 37

intrathecal drug delivery system

Answer 37

allows long-term administration
tube enters thoracic spine from access via lumbar spine
pump attached subcutaneously
allows infusion of drugs directly into CSF

Question 38

nose-brain drug pathway

Answer 38

allows access to CNS
richly irrigated area 
quick onset
pH in nasal epithelium is low - affecting drug ionisation 
can cause irritation of mucosa