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Drew 924 > 4_5Brain > Flashcards

4_5Brain Flashcards

(54 cards)

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1
Q

What are the components of the BBB?

A

1) astrocyte feet, 2) endothelial cells, 3) microglial cells, 4) pericytes

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2
Q

astrocyte function

A

supportive cell for basement membrane

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3
Q

endothlial function at BBB

A

surround capillaries

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4
Q

Microglical function at BBB

A

scavenger immune cells

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5
Q

pericyte function at BBB

A

support for endothelial cells

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6
Q

What are the targets for brain delivery?

A

1) systemic (infections/metastasis), 2) localized (neurologic, meningtis, tumors)

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7
Q

What percentage of small molecule drugs cross the BBB

A

2%

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8
Q

What percentage of all drugs are CNS-active?

A

12%

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9
Q

What percentage of systemic drugs are active in CNS?

A

1%

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10
Q

What are the transport pathways across the BBB?

A

1) paracellular, 2) transcellular, 3) transport proteins, 4) efflux pumps, 5) receptor-mediated transcytosis, 6) absorptive transcytosis, 7) cell-mediated transcytosis

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11
Q

What are the barriers from apical to basolateral in the BBB?

A

TJ, JAM, AJ

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12
Q

function of JAMs

A

1) strengthen/control TJ, 2) promote passage of small hydrophilics, 3) leukocyte trafficking

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13
Q

function of Adherens Junction

A

1) anchors endothelium to basement membrane, 2) regulates cell-cell adhesion

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14
Q

What are cadherins?

A

globular transmembrane proteins that make up adherens junctions

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15
Q

What is VE-cadherin?

A

vascular endothelial cadherin

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16
Q

Describe the composition of TJs.

A

interconnected transmembrane and cytoplasmic proteins

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17
Q

What are occludin and claudins?

A

transmembrane proteins that make up TJs

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18
Q

What things make up TJs

A

occludin, claudins

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19
Q

What things make up Ajs

A

cadherins

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20
Q

Why are TJs tightest in the brain?

A

astrocyte involvement

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21
Q

What are types of efflux transporters at the BBB?

A

1) MDRP, 2) P-gp, 3) OATP, 4) BCRP

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22
Q

MDRP

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A

multi-drug resistant protein

23
Q

P-gp

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A

p-glycoprotein

24
Q

OATP

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A

organic anion transport protein

25
BCRP
breast cancer resistant protein
26
Where are active efflux pumps distributed most?
most on apical (luminal) membrane
27
How do efflux pumps work?
via passive or active transport
28
What is the blood-tumor barrier?
a barrier with partial BBB and partial parent tumor vasculature characteristics that results in heterogeneous drug permeability
29
What are characteristics of conventional drugs as candidates for brain delivery?
1) BCS Class I and some II, 2) log P ~2, 3) less than 400 Da, 4) less than 8 total H bonds
30
Which molecules will not cross BBB?
those with > 1 carboxy or any quaternary ammonium
31
How can conventional drugs be modified to increase BBB transport?
1) structural modification to decrease H-bonding; 2) decrease active transport mechanism
32
Which drugs are an example of structural modification to increase passage across BBB?
morphine and heroine (heroine has methyl esters instead of OH)
33
What are the requirements for TJ opening?
reversible and (ideally) dose-dependent
34
What are the advantages of TJ-opening?
1) no API modification, 2) targeted for only brain delivery, 3) allows for hydrophilics, macromolecules, and nanoparticles
35
What are disadvantages of TJ-opening
increase passage of toxins/pathogens and specificity
36
What are the classes of TJ-opening enhancers?
1) biological, 2) chemical, 3) physical
37
What are biological TJ-opening enhancers?
1) vasoactive compounds (VEGF), 2) cereport (bradykinin analog), 3) viral vectors
38
What are chemical TJ-opening enhancers?
1) sodium dodecyl sulfate (anionic surfactant), 2) CD (ammounium CD for decreased toxicity)
39
What is the advantage to using physical TJ-opening enhancers?
highly localized
40
What are physical TJ-opening enhancers?
1) electromagnetism, 2) ultrasound, 3) microwave
41
What are methods to enhance drug delivery to the brain?
1) direct infusion, 2) TJ-opening, 3) efflux pump inhibitors, 4) receptor-mediated transcytosis, 5) cell-assisted transcytosis, 6) absorptive-mediated transcytosis
42
Describe the turnover of macrophages.
80% turnover in 3 months
43
What is cell-assisted transcytosis?
utilizing macrophages to engulf nanoparticles and cross the BBB
44
What is absorptive-mediated transcytosis?
usage of nanoparticles with little BBB specificity
45
Describe receptor-mediated transcytosis.
transporter receptor recognizes mAb with modified drug; receptor attaches ligand to nanoparticle with API payload
46
What are targets for receptor-mediated transcytosis?
1) insulin, 2) transferrin, 3) LDLRP 1/2, 4) diphtheria toxin receptor
47
What are the targets of efflux pump inhibitors?
MDRP and P-gp
48
What is an example of an efflux pump inhibitor?
Pluronic P85 block co-polymer micelles
49
Describe the structure of Pluronic P85 block co-polymer micelles
25x PEO on the outsides - hydrophilic; 40x PPO on the inside (lipophilic); forms micelles
50
What is the disadvantage to absorptive-mediated transcytosis?
extremely toxic to other tissues
51
What is the disadvantage to structural modification of conventional drugs?
inconsistent results
52
What is the most important aspect of enhancing delivery to the brain
specificity
53
What is convection-enhanced delivery?
adding contrast for MRI-guided direct infusion delivery and response
54
How is glial cell-derived neurotropic factor for parkinsons administered?
via pump that provides constant direction infusion with refill q 2 months

Drew 924 (16 decks)

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