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Drew 924 > 4_5Brain > Flashcards

4_5Brain Flashcards

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

A

multi-drug resistant protein

23
Q

P-gp

A

p-glycoprotein

24
Q

OATP

A

organic anion transport protein

25
Q

BCRP

A

breast cancer resistant protein

26
Q

Where are active efflux pumps distributed most?

A

most on apical (luminal) membrane

27
Q

How do efflux pumps work?

A

via passive or active transport

28
Q

What is the blood-tumor barrier?

A

a barrier with partial BBB and partial parent tumor vasculature characteristics that results in heterogeneous drug permeability

29
Q

What are characteristics of conventional drugs as candidates for brain delivery?

A

1) BCS Class I and some II, 2) log P ~2, 3) less than 400 Da, 4) less than 8 total H bonds

30
Q

Which molecules will not cross BBB?

A

those with > 1 carboxy or any quaternary ammonium

31
Q

How can conventional drugs be modified to increase BBB transport?

A

1) structural modification to decrease H-bonding; 2) decrease active transport mechanism

32
Q

Which drugs are an example of structural modification to increase passage across BBB?

A

morphine and heroine (heroine has methyl esters instead of OH)

33
Q

What are the requirements for TJ opening?

A

reversible and (ideally) dose-dependent

34
Q

What are the advantages of TJ-opening?

A

1) no API modification, 2) targeted for only brain delivery, 3) allows for hydrophilics, macromolecules, and nanoparticles

35
Q

What are disadvantages of TJ-opening

A

increase passage of toxins/pathogens and specificity

36
Q

What are the classes of TJ-opening enhancers?

A

1) biological, 2) chemical, 3) physical

37
Q

What are biological TJ-opening enhancers?

A

1) vasoactive compounds (VEGF), 2) cereport (bradykinin analog), 3) viral vectors

38
Q

What are chemical TJ-opening enhancers?

A

1) sodium dodecyl sulfate (anionic surfactant), 2) CD (ammounium CD for decreased toxicity)

39
Q

What is the advantage to using physical TJ-opening enhancers?

A

highly localized

40
Q

What are physical TJ-opening enhancers?

A

1) electromagnetism, 2) ultrasound, 3) microwave

41
Q

What are methods to enhance drug delivery to the brain?

A

1) direct infusion, 2) TJ-opening, 3) efflux pump inhibitors, 4) receptor-mediated transcytosis, 5) cell-assisted transcytosis, 6) absorptive-mediated transcytosis

42
Q

Describe the turnover of macrophages.

A

80% turnover in 3 months

43
Q

What is cell-assisted transcytosis?

A

utilizing macrophages to engulf nanoparticles and cross the BBB

44
Q

What is absorptive-mediated transcytosis?

A

usage of nanoparticles with little BBB specificity

45
Q

Describe receptor-mediated transcytosis.

A

transporter receptor recognizes mAb with modified drug; receptor attaches ligand to nanoparticle with API payload

46
Q

What are targets for receptor-mediated transcytosis?

A

1) insulin, 2) transferrin, 3) LDLRP 1/2, 4) diphtheria toxin receptor

47
Q

What are the targets of efflux pump inhibitors?

A

MDRP and P-gp

48
Q

What is an example of an efflux pump inhibitor?

A

Pluronic P85 block co-polymer micelles

49
Q

Describe the structure of Pluronic P85 block co-polymer micelles

A

25x PEO on the outsides - hydrophilic; 40x PPO on the inside (lipophilic); forms micelles

50
Q

What is the disadvantage to absorptive-mediated transcytosis?

A

extremely toxic to other tissues

51
Q

What is the disadvantage to structural modification of conventional drugs?

A

inconsistent results

52
Q

What is the most important aspect of enhancing delivery to the brain

A

specificity

53
Q

What is convection-enhanced delivery?

A

adding contrast for MRI-guided direct infusion delivery and response

54
Q

How is glial cell-derived neurotropic factor for parkinsons administered?

A

via pump that provides constant direction infusion with refill q 2 months

Drew 924 (16 decks)

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