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MPharm Y3S2 > Drug Delivery CNS > Flashcards

Drug Delivery CNS Flashcards

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1
Q

What type of drugs could it be possible for them to pass the BBB?

A

MW less than 400
Less than 8 H bonds
Excludes all larger/ more hydrophilic drugs

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2
Q

What are the 2 endogenous transport systems in the BBB?

A

Carrier-Mediated Transport (CMT)
Receptor- Mediated Transport (RMT)

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3
Q

What is the disadvantage of simple diffusion from CSF into brain?

A

Logarithmic decrease in drug conc with distance into the brain (10-20 fold decrease per mm of penetration)
Will only penetrate 5mm, parts of the human brain are more than 50mm away from CSF interface so not good
Efficient drug delivery via CSF route to brain needs to be atleast 5 orders of magnitude more dosage than therapeutic level needed
Increase SEs, toxicity very likely

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4
Q

Why can’t paracellular, lipid absorption and particulate absorption not occur at the BBB?

A

Paracellular involves route through tight junctions- but can’t as tight junctions too tight
Lipid and particulate are specific to intestine

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5
Q

How many drugs can pass through the BBB on their own?

A

98% of small drugs and all large ones do not cross BBB unless couple to transporter systems- transcellular

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6
Q

Name the 3 mechanisms of intravascular trans BBB delivery:

A

A) Transcellular lipophillic pathway (passive transcellular)
B) Carrier-mediated transport (typically smaller molecules)
C) Receptor mediated transcytosis (larger molecules)

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7
Q

Describe the requirements for transcellular lipophilic pathway across the BBB:

A

Need to be < 400mw and highly lipid soluble (high log P, low H bonding)
Only 6-12% meet this criteria
CNS active drugs need fewer than 7 H bonds (more hydrophobic decreasing H bonds)- hydrophilic drugs less likely to permeate through BBB
BBB permeation decreases 100 fold from going MW 350 to 450
This reflects a polar SA change to 100Å

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8
Q

Name an example of a modification of drugs for the transcellular lipophillic pathway across the BBB:

A

Heroin (2 acetylated groups)- less h bonding so increase BBB transport by 100x
Morphine ( 2OH groups)
But removing H bonds has generally not proved a useful route to drug modification as H bond blocking groups are either easily hydrolysable or affect drug activity

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9
Q

What is the Polar Surface Area (PSA)?

A

The surface sum over all polar atoms (usually oxygen and nitrogen) including also attached hydrogens
Can be predicted, don’t need to make and test the molecule

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10
Q

What is the correlation value for PSA and BBB permeation?

A

Molecules with a low SA are much more likely to be in the brain and less in the blood

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11
Q

What is the PSA of CNS drugs that penetrate the brain by passive transport?

A

Most have a PSA below 70A2

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12
Q

What is the PSA of most orally administered non-CNS drugs?

A

Larger values up to PSA 120A2

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13
Q

Describe the process of CMT:

A

Instead of trying to modify H bonding functional groups while retaining activity, can instead adapt drug molecules to increase their affinity to endogenous transporters
Part of the drug molecule, or modification of the drug, acts as a carrier for the drug itself, being taken up by one of many transporters

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14
Q

Describe the glucose requirement for the brain:

A

Transported by Glucose Transporter Type 1 (GLUT1)
Glucose is the brains energy source, glycolysis rates of 500-1000 nmol/min/g brain
Material required more than 100x greater uptake of glucose across the BBB than that of the a.a

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15
Q

Why is the GLUT1 transporter needed for glucose uptake?

A

The amount of glucose required is much greater than what is possible by passive transcellular diffusion (and glucose is hydrophilic) therefore need rapid transport across BBB by another route

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16
Q

Describe the function of the GLUT1 transporter:

A

GLUT1 capable of being this rapid carrier
Mediated transport (50,000x) faster than transmembrane diffusion of glucose and other hexoses e.g mannose
GLUT1 is a uniport transmembrane protein transporter- one way only
Follow Michaelis-Menten kinetics
Present in almost all tissues, not just the brain

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17
Q

Name other carrier mediated transporters:

A

LAT1- Large neutral A.a Transporter 1
CAT1- Cationic A.a Transporter 1
MCT1- MonoCarboxylic acid Transporter 1
CNT2- Concentrative Nucleoside Transpoter 2

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18
Q

What are the substrates for LAT1?

A

Phenylalanine and other large neutral a.as, some small neutral a.a

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19
Q

What are the substrates for CAT1?

A

Arginine, lysine, ornithine

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20
Q

What are the substrates for MCT1?

A

Lactate, pyruvate, other mono carboxylic acids

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21
Q

What are the substrates for CNT2?

A

Adenosine , guanosine, inosine, uridine

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22
Q

Why is L-dopa an effective treatment for Parkinson’s?

A

As a large neutral a.a, it has a strong affinity for LAT1
Has a similar structure to phenylalanine which is an alpha a.a

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23
Q

How can gabapentin be an effective treatment for Parkinson’s even though it doesn’t meet the criteria?

A

It is a water soluble drug that is effectively transported by LAT1
LAT1 is specific for alpha a.a (the amino group is in the first carbon after the carboxylic acid)
However this is unexpected as gabapentin is a gamma a.a
Affinity comes fro the cyclic nature of gabapentin, so amine and carboxylic acid positions mimic those of an alpha a.a

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24
Q

Can you use couple a drug to glucose as a way of affinity engineering the drug via CMT?

A

No- it fails
As glucose-drug conjugate no longer transported, affinity is destroyed by conjugation

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25
What is a molecule used to affinity engineer drugs using CMT and how?
Couple the drug to L-cysteine (a small neutral a.a with low affinity for LAT1) When drug is coupled to L-cycsteine, get better affinity than cys alone as conjugate is now larger (so higher affinity for LARGE a.a transporter)
26
Could you inhibit Active Efflux Transporters as a way of moving drugs into the BBB via CMT?
Yes but AETs have other physiological roles so inhibiting them can lead to neurotoxicity and other SEs
27
Name and describe the factors mitigating against absorption across the BBB:
Pgp and Cyp3A4 both found in brain capillary endothelia Cyp3A4 acts to decrease the amount of drug absorbed through the BBB Pgp acts to remove drug back into the blood, may also remove drug metabolites from the cell Overall Pgp and Cyp3A4 act in concert to decrease systemic exposure
28
Describe the process of Receptor-Mediated Transport (RMT):
This differs from CMT as the transported molecule binds to a receptor on the apical (blood) facing side of the cell and is then trafficked through the cell into a vesicle before being released on the basolateral (brain) face This vesiculation allows much larger molecules, such as insulin, nanoparticles and antibodies to cross the BBB
29
Name an example of RMT:
Transferrin transport of iron into brain by Transferrin receptor (TfR)
30
Describe the process of transferrin transport using RMT:
TfR is expressed at high levels in the BBB * Transferrin (Tf) bindings Fe3+ to become a complex “Holo-Tf” * At neutral pH TfR (sits in clathrin coated pit) is able to bind Holo-Tf * Endocytosis of TfR and bound Holo-Tf due to pit is able to form vesicle * Endosomal acidification (pH 5.5) & reduction of transferrin bound iron (Fe3+ to Fe2+) (membrane oxidoreductase) releases iron (Fe2+) while allowing apotransferrin “Apo-Tf” to still remain bound to receptor. * Classically Apo-Tf recycled to original membrane where at physiologic pH it is released. * Free Fe2+ in the endosome is transported into cytoplasm by divalent metal transporter (DMT1). * Iron (Fe2+) transported across basolateral membrane (to brain) via ferroportin-1
31
Describe the importance between the difference of anti-TfR antibodies with high and low affinity:
Anti-TfR antibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower-affinity anti-TfR antibodies variants are released from the BBB into the brain
32
Describe examples of endogenous transported molecules in RMT:
Transferrrin, insulin, leptins Therapeutics can be conjugated to ligands that are taken up by the RMT with more freedom than in the case of CMT therefore need to engineer drug to couple to ligand Properties of drug much less important than in CMT Antibody-drug conjugation
33
What conditions in the front of the eye are treated using ocular drug delivery?
Hayfever (allergies) Dry eye syndrome Cataracts Infection
34
What conditions in the back of the eye are treated using ocular drug delivery?
Glaucoma Retinopathy Age-related macular degeneration
35
Name the outer layers of the eye:
Sclera Cornea
36
Name the middle layers of the eye:
Iris Ciliary body Choroid
37
Name the inner layer of the eye:
Retina
38
Describe the tear film:
Turnover 1µl/min Restores 2-3 mins
39
What space is at the front and back of the eye?
Front= anterior chamber Back= posterior chamber
40
What space is in the middle of the eye?
Vitreous cavity
41
Describe the anterior/posterior chamber:
Aqueous humour Colourless, watery fluid containing electrolytes, solutes, growth factors and proteins
42
Describe the vitreous cavity:
Hydrogel made of 98% water 2% of collagen fibres and HA, proteins, salts and glucose pH 7.5 2-4 times more viscous than water
43
Name the routes of drug admin to the eye:
Topical Subconjunctival Lens Intrascleral Intravitreal Anterior/ posterior sub-Tenon's Suprachoroidal Subretinal
44
What are the barriers to topical ocular drug delivery?
Cornea Conjunctiva Sclera Iris Ciliary body
45
What are the barriers to systemic ocular drug delivery?
Blood-aq barrier Blood-retinal barrier
46
Describe the barriers for topical ocular drug delivery:
Pre-corneal factors: solution drainage, blinking, tear film, tear turnover Induced lacrimation leads to low contact time of drug with the absorptive membrane Mucin present in the tear film plays a protective role by forming a hydrophilic layer that moves over the glycoalyx of the ocular surface and clears debris and pathogens Anatomical barriers- layers of the eye
47
Describe the barriers for systemic ocular drug delivery:
Retinal capillary endothelial cells and retinal pigment epithelium (RPE) known as the inner and outer blood-retinal barrier Specific oral or IV targeting systems are needed to transport molecules through the chorioid into deeper layers of the retina Limited accessibility through ocular tissues limits utility of oral as high oral doses needed
48
What is visudyne?
Injection (systemic) Treat certain retinal conditions such as wet age related macular degeneration (ARMD)
49
What are the considerations for ophthalmic formulations?
Osmolality pH Surface tension Viscosity Sterility
50
What is osmolality?
Conc of a solution expressed as the total number of solute particles per kg of solvent (mOsmol/kg) Determined by the conc of salts in lacrimal fluids (Na+, K+, Ca2+, Cl-,HCO3-)
51
What is the normal osmolality/ tear osmotic pressure for healthy eyes?
302 mmol/kg Normal tear osmotic pressure 0.9-1.0% sodium chloride Tear can tolerate 0.6-1.3% NaCl
52
What if the eye was presented with a hypotonic solution?
Increase corneal epithelial permeability causing oedema
53
What is the pH of tears?
6.9-7.5 Can tolerate pH 3.5-9.0, but formulate as close to physiological pH as possible
54
What if the eye was presented with a hypertonic solution?
Dehydrate corneal epithelium
55
What is the eye pH controlled by?
CO2, HCO3-, lysozyme(-), prealbumin(+) No buffering capacity
56
Why is the eye pH important?
Controlling ionisation and corneal permeability Weak buffers-borate, phosphate, citrate, sodium acetate
57
What is the surface tension of a healthy tear fluid?
43.6-46.6mN/m
58
What occurs if drops are added to the eye that lowers the surface tension?
Means that lipids are in the product: -destabilise the tear film -disperse lipid into droplets -solubilised by drug/ surfactants in formulation
59
Why would an ocular topical formulation need viscosity?
To prolong drug retention in tear film: -enhances drug absorption -decrease drainage rate -increases thickness of pre corneal tear film -osmolality
60
Name some viscosity enhancing polymers:
PVP PVA MC HPMC
61
Name the normal blinking force and why can this limit viscosity?
Normal 0.2-0.8N Above 0.9N may be painful
62
How would you maintain sterility during manufacture?
Terminal sterilisation adopted where possible (or filtered) Raw materials should be sterile Manufacture should be sterile Labelled with duration once opened
63
How would you maintain sterility during use?
Preservatives, broad spectrum- benzalkonium chloride (may cause intolerance over time) Single dose unit preparations (more expensive) Antibacterial packaging
64
Where is topical ocular delivery targeted at?
Anterior segment
65
What are the disadvantages of ocular topical admin?
Difficult to instil Variable dosing Dilution and washout Require high drug conc Ocular and systemic SEs Major compliance and execution issues
66
How much of the drug is bioavailable from eye drops?
1-5%
67
What are the advantages of solution eye drops?
Easy to manufacture Lowest cost of production Relatively easy to admin Rapid onset of action (no dissolution) Good dose uniformity
68
What are the disadvantages of solution eye drops?
Rapidly drained from eye Rate of drainage proportional to size of drop Volume administered can be 25-56µl -shape of dropper -physiochemical properties -manual usage of bottle
69
What is the purpose of suspension eye drops?
Admin of sparingly soluble aq drugs (e.g steroids)- poorly soluble Relatively small particle size to not cause discomfort
70
What are the advantages of suspension eye drops?
To prolong drug release -particles are retained in eye between eye lid and eye ball Readily dispersible on shaking
71
What are the disadvantages of suspension eye drops?
Size limitations due to irritation Homogeneity should be maintained Polymorphic changes with storage- change solubility Ostwald ripening, caking can be a problem, so increase viscosity to avoid
72
Why are eye gels/ ointments used?
Semi-solid system comprising of a water soluble base Use polymers (PVA, HPMC, carbopol, carbomer) dispersed in a liquid Gels can be activated to undergo phase transition in the eye
73
Name and describe an example of an eye gel:
Pilocarpine Pilogel + single gel installation vs QDS solution + solution dose 8mg/day + gel dose 2mg/day
74
Name types of systemic drug delivery routes:
Intravitreal injections Intraocular implants
75
Name different types of intraocular injections:
Intracorneal injection (anterior chambers) -intravitreal injection (non uniform distribution)
76
Describe intraocular injections:
Low molecular weight drugs can rapidly distribute through the vitreous, whereas the diffusion of larger molecules is restricted and can be slowed
77
Describe intravitreal admin:
Most efficient way of getting drugs to the back of the eye Poor patient compliance Drug retention in the vitreous space determines the frequency of admin
78
Name examples of intravitreal admin:
Pegaptanib sodium (macugen) Ranibizumab (Lucentis) Dexamethasone Triamcinolone acetate
79
Name different types of periocular injections (front of eye):
Subconjunctival Subtenon Retrobulbar Peribulbar
80
Describe the use of drugs for glaucoma management:
Decrease aq production (BB, aa, and CAIs) Improve aq outflow (cholinergic and PGas) Topical BB and CAIs are associated with fewer systemic SEs than their oral forms and are better tolerated PGas have the advantage of effectiveness in lowering IOP with OD dosing, but some patients have irreversible iris colour changes
81
Name different ocular drug delivery devices:
Punctal plugs Injectable implants Ocular iontophoresis Drug eluting contact lenses TODDD- topical ophthalmic drug delivery device
82
Describe the use of punctal plugs:
Plugs are inserted into tear ducts where they stay (slowly release drug) for 2-3 months Plugs are made of different polymers: -silicone -hydrogel -polycaprolactone
83
Name 2 different ocular injectable implants:
Iluvien (fluocinolone acetonide intravitreal implant) Durasert (latanoprost implant)
84
Describe the Iluvien implant:
0.19mg: designed to release the corticosteroid over 3 years after being implanted in the back of the eye For treating diabetic macular oedema (DME) It is a non-bioerodible implant made of polyimide
85
Describe the durasert latanoprost implant:
Biodegradable drug delivery system for latanoprost that is injected into sunconjunctival space with 25G needle The implant is bioerodable and is expected to deliver an appropriate dosage of latanoprost for about 3 months
86
Describe ocular iontophoresis for charged drugs:
The basic electrical principle that oppositely charged ions attract and some charged ions repel is the central principle of iontophoresis The ionised substances are driven into the tissue by electrorepulsion at either anode (+ drug) or the cathode (- drug)
87
Describe ocular iontophoresis for neutral drugs:
Electroosmotic flow is the bulk fluid flow which occurs when a voltage difference is imposed across a charged membrane Since the human membranes are -ve changed above pH 4, the electroosmotic flow occurs from anode to cathode This is good as it increases bioavailability and more therapeutic effects to decrease freq of dosing
88
Describe drug eluting contact lenses:
Drug can be coated on the inner side of lenses or imprinted in the lens Nanoparticles also have even used to prolong the lease of drug from the lenses Provides steady drug release which may be beneficial for chronic conditions None yet
89
Describe TODDD:
A soft, flexible divice that floats on the sclera completely concealed under the eyelid Insert once for 3-90 days of continuous drug delivery Non invasive In human clinical trial
90
What is Sensimed Triggerfish?
Closed loop IOP date collection A contact lens device that capable of continuous IOP measurements Provides an automated recording of continuous ocular dimensional changes over 24 hours Contact lens sensor contains strain gauges that measure corneal curvature changes caused by IOP Microprocessor and antenna integrated Recommend by NICE

MPharm Y3S2 (22 decks)

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