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SIU5 Neurology > Pharmaceutics > Flashcards

Pharmaceutics Flashcards

1
Q

What type of drugs cannot enter the brain from systemic circulation

A
  1. > 98% of small-molecule drugs 2. virtually all large-molecule drugs
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2
Q

Why it is hard to let drug enter the brain?

A
  1. the brain req sig amount of small, hydrophilic mo e.g. glucose and AA
  2. CNS and peripheral pools of NT need to be kept separate
  3. brain intersitial fluid has LOW protein, LOW na nad k and HIGH mg than blood plasma, otherwise similar
  4. ion conc need to be tightly controlled (to allow neuron firing)
  5. passage of these species is very tightly controlled by barriers (for neurotoxic compo)
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3
Q

describe what is a neurovascular unit

A

the constituent cells of the BBB

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4
Q

what does the NVU do?

A
  1. acts as physical and biochemical barrier

2. separates blood and brain ISF

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5
Q

what is the key junction for passage of mol into bbb?

A

tight junction- physical restriction

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6
Q

BBB is a molecular barrier due to…?

A

transporters

metabolic enzymes

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7
Q

what are the extracellular enzymes present in brain (nvn)

A

peptidases

nucleosidases

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8
Q

what are the intracellular enzymes in brain (nvu)

A 
monoamine oxidases MAO
CYP450 isoforms (3A4/5not present)
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9
Q

what are the two enzymes that have a higher concentration in whole brain than liver?

A

glutathione s- transferase (detoxification)

catechol-o-methyltransferase (COMT degrades catecholamines eg NA,A,DA)

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10
Q

is sulphotransferase - degrade drugs, present in brain?

A

yes but low level

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11
Q

what are the active efflux pumps in the BBB?

where do the drugs go?

A 
luminal:PGP
BCRP (Breast Cancer Resistance Protein)
MRP1,2,4 (Multidrug resistant protein)
luminal and albuminal: OATP2 (organic anion transporter)
albuminal: OATP3
pump out into ISF
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12
Q

what are the transport pathways across the BBB?

A
  1. paracellular aq pathway (water sol via diffusion)
  2. transcellular lipophilic pathway
  3. transporters (glu, aa, nucleoside)
  4. rec-mediated transytosis (insulin, trasferrin, bind to surface of mol, form vesicles)
  5. adsorptive transcytosis (albumin, other pp, charged mol interact with rec with opposite charge)
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13
Q

what are the key parameters of drug for passive diffusion?

is the diffusion saturable?

A

logp 1.5-2.5 (poor ab for mannitol- hydrophilic=logp -3, high ab for nicotine= 1.2) mw~400, h-bond~low, low PSAcomapre to oral
non-saturable diffusion down conc grad

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14
Q

what are the special cases in ab vs logp correlation?

A

L-dopa, logp -2, hydrophilic but much higher ab than expected due to transporter
phenytoin/barbital, low ab due to highly pp bound

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15
Q

what are the three strategies for drug delivery to brain?

A

1 non invasive (chem/bio methods/nanomed)
2 invasive (bbb disruption, implants, intraventricular intrathecal intersititial)
3 alternative

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16
Q

describe the non invasive delivery- chemical method

A
  • improve peripheral pk (PEGylation, more stable, longer circulating in brain, better uptake)
  • improve logp (esterification, conjugation of lipid, reduce h bond)
  • pro-drugs
  • mimick transporter sub (eg gabapentin)
  • inhibit efflux transporters
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17
Q

the development of bbb penetrating drug is an… science because…

A

experimental science bc theory and practice may be v different

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18
Q

describe the prodrug approach

A

pro-moiety can aid passive/transporter uptake, bc increased logp e.g. heroin is a prodrug of morphine. improved diffusion across bbb
cleave pro-moiety after entered bbb

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19
Q

are ketoprofen or lysine a sub for LAT1? is the combined mol?

A

not a sub on their own but combined mol is… adding lysine to ketoprofen increase logp cause rapid uptake into brain via aa transporter

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20
Q

what is the prob w increased logp of drug

A

reduced specificity

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21
Q

pros and cons of inhibiting efflux system

what drug can inhibit pgp

A

pro- increase drug ab
cons- many endo, exoligands are sub of pgp, inhibiting pgp can potentially cause neurotoxicity by allowing toxic mol to enter (not selective)
CCB verapamil can inhibit pgp

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22
Q

describe the non invasive delivery - biological method (ims)

A

-hijack the endo mol
e.g. inflam in brain (in AD, parkinsons)
recruitment of monocytes and neutrophils
both are phagocytic
micro/nano particles loaded w drugs and target to these cells
across bbb
can use magnet to improve uptake if nanop are magnetic

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23
Q

describe the non invasive delivery - biological method (viral)

A

viral vectors for gene delivery

  • infect virals with therapeutic gene i
  • administer systemically, direct injection
  • virus crosses bbb
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24
Q

which virus has been proven to across bbb?

A

adeno-associated virus AAV - subtype RAAV9

virus that cause common cold!

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25
Q

what is the component in nvu that controls the size of the tight junction?

A

pericytes

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26
Q

how is AAV administered?

A

single intravascular injection

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27
Q

what is the name of the gene that can be delivered by AAV?
and where in adult’snvu does the gene mostly expressed?
what disease can be treated with that gene?

A

green fluorescent protein (GFP) gene
astrocytes in spinal cord and brain
neuronal disease in young pt or provide GF for degenerating neurons in adult (cant trt disease deep within the cns bc increase barrier function in adults)

28
Q

invasive delivery to CSF can be used to treat…

A

bacterial meningitis. leukaemia, brain tumours

29
Q

what does intrathecal and epidural mean

A

direct inj to the cerebrolapinal fluid of spinal cord

direct inj to epudural space of the spinal cord

30
Q

what is the name of the part of the brain that delivers drugs into the ventricles and allows sampling of the CSF

A

ommaya reservoir

31
Q

name and describe another method of invasive delivery

A

convection-enhanced delivery CED

use continuous +ve pressure infusion of drug via a pump or catheter

32
Q

what is the ad of CED

A

bypassess bbb
targeted to disease region
can be monitored in real time w contrast agent
better penetration than diffusion based delivery - lower dose and therefore toxicity

33
Q

list three invasive delivery methods that involve distruption of the BBB

A
  1. hyperosmotic infusion
  2. biochem disruption
  3. physical
34
Q

describe how hyperosmotic infusion method work

A
  • hypertonic sol of ARABINOSE or MANNITOL via intra-carotid (artery) infusion
  • osmolarity of EXC fluid > INC fluid in endothelial cells
  • water is drawn out of endo into blood vessel lumen
  • shrinkage of endo
  • net flow of water out of the brain cause vasodilation
  • stretch of endothelial cell mem
  • interactions bw actin and cadherin- cause endo cytoskeleton to contract
  • widening of tight junction allow paracellular transport
35
Q

how long does the hyperosmotic infusion effect last? comparing to biochem method?

A

10mins

15mins

36
Q

describe the biochem method of disruption of the bbb

A

vasoactive mol eg LT, histamine, BK
selectively increase permeability of abnormal brain cap
bc the enzymatic barrier present in normal bbb endothelium is missing there

37
Q

describe what we use in physical disruption of the bbb
what drug is it used for
what are the steps of this process

A 
FUS focused ultrasound 
used for protein drugs mAbs by disrupting bbb TEMPORARILY
1. inj of Herceptin
2. sonication
3. inj of MRI contract agent
38
Q

what are microbubbles for

A

microbubbles are used as contract agent in ultrasound imaging
we can encapsulate durg into bubbles- only release d when/where the sound hits

39
Q

what are the 2 compo of mircrobubbles

A

1protein or lipid shell

2perfluorocarbon gas

40
Q

name and describe one alternative method for CNS delivery

A

via olfactory epithelium

d can enter brain directly via PARAcellular diffusion or AXONAL TRANSPORT through olfactory nerves (DA)

41
Q

what are the challenges of olfactory delivery route

A
  • specificity, only deliver to olfactory epi avoid rest of nasal cavity
  • cillia push d abck hard to get localised d
42
Q

why do we have CDDS controlled drug delivery system?

A
  1. reduced drug conc fluctuation (s/e, narrow therapeutic window drug)
  2. reduce dosing frequency
  3. controlled delivery site
  4. timed release
43
Q

what are the 4 mechanism for contorlled drug release?

A
  1. water penetration controlled DDS
  2. diffusion controlled DDS
  3. chemical controlled DDS
  4. responsive DDS
44
Q

What is the name of the excipient used in swelling controlled devices

A

HPMC= hypromellose

45
Q

what are the 3 zones in swelling DDS

A

zone 1: swelling front- boundary bw the glassy and rubbery polymer
zone 2: diffusion front- boundary bw the solid and gel= dissolving drug
zone 3: erosion front-boundary bw the dissolution medium and matrix

46
Q

what are the phases involved in swelling DDS

A

1 swelling
2 swelling and erosion
3 dissolution
d increase in size as swelling, then eronde + swelling then go small as dissoluted

47
Q

what is the diff bw erodible and gellable barriers in water penetration controlled DDS

A

erodible layers on top and bottom of the HPMC+D start to erode as D swells, this increase the D release over time by increasing the SA exposed
gellable layers stop D being released from the top and bottom, only side to side= constant SA for release

48
Q

what sub are used in TIMERx® Controlled Release Delivery System
how is drug released?

A

LBG- locust bean gum- mannose backbone and galactose side chain =hairy
X- xanthan- heteropolysac =smooth
X helps cross link of LBG, drug trapped inside. swelling and erosion of matrix release durg
This delivery system can control the lag time of release. by controlling rate of water ingress into coating and subsequent disintegration of core.

49
Q

what are the bonds that can control release of drug (water penetration)

A

H bond and 1-4 link amylose, gap bw amyloses allow drug diffusion

50
Q

describe the Osmotically-controlled devices

A

Elementary Osmotic Pump (EOP): D mixed in water soluble core/inert salt NACI, KCl.
core surrounded by water INSOLUBLE mem with laser drilled small orifice
only water allowed to diffuse through orifice into core and increase osmotic salt conc, build up pressure
osmotic grad establish, pushing D out

51
Q

what are the types of osmotic controlled DDS

A
  • CPOP controlled porosity osmotic pump
  • PPOP push-pull osmotic pump (polymer can swell once contacting w water, can push D out too)
  • sandwiched push-pull osmotic pump (midpart swells and push D out via pores on top and bottom )
52
Q

what are the ad of Osmotically driven systems (e.g. PSOP- push-stick osmotic pump, OROS- osmotic release oral system)

A
  1. precise and controlled delivery over 24h
  2. can use a range of D (water sol/insol)
  3. allow large dose delivery
  4. can target specific area of the GIT, increase BA
  5. can be tailored for patterned delivery profile
  6. protect the D until release
53
Q

name two diffusion controlled DDS

A
  1. reservoir DDS- insoluble polymer mem and conc/ solid drug inside
  2. monolithic (matrix) DDS- D dissolved in INSOLUBLE polymer prior to device formation, matrix control the rate of D release
54
Q

what are the two diffusion pathways for reservior DDS

A

solution diffusion

pore diffusion

55
Q

how does the D release rate differ from reservior to matrix diffusion? (diffusion controlled DDS)

A

reservoir diffusion has a constant release rate whereas matrix diffusion DECREASES over time due to increased h (distance gap) between drug to the edge of matrix

56
Q

how is chemical controlled DDS different from diffusion controlled matrix device?

A

chemical controlled DDS - same process for D dissolve in polymer solution prior to device formulation but the polymer is DEGRADABLE and can dissolve! it is used for long term implantation.

57
Q

how does the polymeric device degrade in chemical controlled DDS?

A
  1. slow dissolution of polymer

2. degradation via chem or biological processes

58
Q

what is fused deposition modelling? what does it allow us to achieve

A

FDM is most accessible type of 3D printing involving melting polymer and add layer by layer to form enteric coating of different thickness. D and polymer can be melted together = a matrix, and printed with diff thickness of enteric coating. it allows personalised dosage form (release profile

59
Q

name some natural polymers used in chemically controlled DDS

A

CFC GSH
collagen, fibrin, chitin/chitosan.
gelatin, silk, hyaluronan

60
Q

name some synthetic polymers

A

EAOP

poly ester, poly anhydrides, ortho esters, phosphoesters

61
Q

why transdermal DD?

A
  • avoid pre-systemic metabolism (skin doesnt metab drugs) so lower daily dose achievable
  • avoid 1st pass metab, greater BA, less altered metabolites, less s/e
  • allow sustained release of D (over 7d), so less dosing frequency, increase patient compliance
  • maintain Cp bw MTC/MEC, avoid peak and trough so less toxic s/e
  • Cp can be manipulated by changing the patch area (rate in = A X J, big patch has small flux)
  • D termination simply by patch removal
  • Delivers difficult-to-formulate drugs. Whereas easy to mix with polymers
62
Q

limitations of TDD

A

Limited to potent drug molecules {potency}3
Physical chemistry:
* size… ‘small’ molecules <400 Da
* lipophilic (across SC), but good solubility in oil and water (OUT SC)
PK PD (short half life, high 1st pass metab – most suitable for TDD
Area of patch, max size= credit card 50cm2
Drug must not be locally irritating or sensitizing
patch may fall off over time
Barrier = SC, Acidic, lipid barrier, High resistance to transport

63
Q

EQ used to calculate patch area

A

Area (cm2) x J (μg cm-2 hr-1) = Cl (cm3 hr-1) x Css (μg cm-3)
daily dose of drug = D
“rate in” = D/24 mg hr-1 = (1000·D)/24 μg hr-1
so rate in = Area (cm2) x J (μg cm-2 hr-1) = {(1000 x D)/24} (μg hr-1)
FLUX UNIT: μg cm-2 hr-1

64
Q

what are the three TDDS?

A
  • adhesive system (backing layer-adhesive layer- liner)
  • layered system (with matrix if D cant dissolve in sticky adhesive)
  • reservoir system (reservoir-membrane-adhesive. cant be cutted)
65
Q

examples of D that are availble as transdermal patch

A
  • scopolamine (motion sickness)
  • nitroglycerin:30mg a day
  • clonidine (antihypertensive)
  • estradiol
  • fentanyl
  • nicotine:30mg a day
  • testosterone
  • estradiol/progestin
  • norelgestromin/ethinyl estradiol
  • buprenorphine (opioid dependence/pain)
  • oxybutynin (urinary incontinence)
  • methylphenidate (ADHD in children)
  • selegiline (TCA, antidepressant)
  • rivastigmine (AD)
  • granisetron (NV)
66
Q

what is the name of the D that was developed as transdermal patch in the first place instead of oral tablet

A

rotigotine for parkinson’s

67
Q

what controls the rate of release in TDDS?

A

Skin is in control of the rate of release of drug (e.g. GTN patch)

  • Patch design does not predetermine degree of rate control
  • less sensitive to drug loading, especially when skin controls input
  • Drug loading in patch and release mechanism are inappropriate measures for bioequivalence. Bioequivalence based on Cp levels
  • Ideally (for safety) drug loading is close to amount to be determined

SIU5 Neurology (13 decks)

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