Pharmaceutics - De Bank Flashcards
How does the brain get important molecules, like glucose and AAs, past the BBB?
Transporters
Explain Mesoporous Silica Nanoparticles
Inert and thermally stable nanoparticles that can house drugs
They have holes that can be plugged to prevent the drug from leaving until we want it to
These can be removed by: pH, magnetism, antigen, S-S reduction or saccharide
What are the 2 types of Diffusion-Controlled DDS?
Reservoir–> Dependent on the pores in the membrane and the concentration gradient
Monolithic (matrix) –> Dependent on the water ingress, with the release rate decreasing over time
Used mainly for implantable devices
What is the major benefit of implantable devices?
No oral drugs need to be taken, so compliance is 100% (no missed doses!)
How does Water Penetration Controlled DDS work?
Swelling –> HPMC is used that forms a hydrogel when water is intorudced, allowing the drug to leave (as can pass through this gel)
The drug is in the middle, whilst the outside swells and must be wetted before the drug can pass it slowly
Osmotically Controlled –> A hole is lasered into the top of the membrane, allowing the drug to be ‘pushed out’ with the introduction of water, creating an osmotic gradient
What’s the ideal LogP and MW for a drug to passivly diffuse through the BBB?
LogP = 1.5-2.5
MW = 400
What is Chemically-controlled DDS?
What are the 3 different versions?
The matrix is degraded via chemical means often done with the use of enteric coatings
Can also be done via hydrolysis, where the bonds keeping the drugs water insoluble and broken, causing them to become water soluble
Bulk Erosion –> The greater the MW the longer it takes to degrade fully
Surface Erosion –> Hydrophobic polymers with reactive surface groups are broken down. This is cataylsed by acidic molecules (eg, more lactic acid = more degradation). The geometry of the device can change the degreadation rate.
Pendant Systems –> A polymer backbone and cleavable linkers are used to control the drug release
Why is lipophillicity still important regarding passively diffused drugs in the BBB?
You need a little lipophillicity to ensure it can enter the membrane…as too much hydrophillicity will mean it wont want to go into the membrane, and too much lipophillicity will mean it never leaves the membrane!
What are the 6 things that can effect drug release in responsive DDS?
pH –> changes in ionization affect sol-gel behaviour (eg, insulin)
Chemicals (metabolites)
Enzymes –> The membrane which encapsulates the drug can be broken down by specific enzymes (eg, amylase in the colon)
Ultrasound
Magnetism
Light
What disease states can cause a disruption in the BBB?
Stroke
Alzheimers
HIV
Brain tumours
MS
Parkinsons
This allows drugs to pass into the brain with greater ease
How does a hyperosmotic solution disrupt the BBB?
It pushes water out of the cell, causing the drug/BBB to be pushed out with it!
What enzymes does the brain have increased levels of for protective purposes?
Glutathione S-transferases
Catechol O-methyl transferases
Sulphotransferases are present, but at much lower levels
What is the Ommaya Reservoir?
Delivers drugs into the ventircles via interstitial delivery, and allows CSF sampling
What is CED? And what are its benefits?
Convection Enhanced Delivery
Continous positive pressure of a drug that bypasses the BBB and is targeted to the disease region. It’s also is low doses (so lower chance of toxicity)
How do Drug Eluting Stents (DES) work?
They’re made up of a polylactic acid backbone, which is is degraded (bioabsorbed) via bulk erosion in 2 years
What is FUS?
Focused Ultrasound
Herceptin (a mAb) is injected
Sonication
An MRI contrast agent (microbubbles) are injected in
This process allows large drugs to access the brain (eg, monoclonal antibodies)
What are the 3 different forms of vaginal rings?
Reservoir
Matrix
Pod
What is a neurovascular unit (NVU)?
The constituent cells of the BBB that seperate the the blood and the brains ISF. They acts as a physical and biochemical barrier
Astrocyte
Pericyte
Endothelial cell
Basal lamina
What are the 5 ways of imporving brain delivery of drug via non-invasive measures?
Improving Peripheral PK –> Eg, PEGylation to keep it in the body for longer
Increased Lipophillicity –> –> Eg, esterification
Pro Drugs –> Like heroin
Mimicking Substrate Transporters –> Eg, gabapentin
Inhibiting efflux transporters –> To prevent the drug being removed (eg, veramapril can inhibit these)
What does the brains interstiutal fluid contain?
Low levels of proteins, sodium and potassium
High levels of magnesium
(when compared to blood plasma)
Why is the brain good for drug absorption?
And why is it bad?
Good: Huge vasclature with a large absorption
Bad: Need to pass the BBB to get into the brain
Explain a specific way that GI delivery time can be extended using a different formulation?
A capusle that has linkers in acidic conditions (the stomach) which prevents it from passing through the stomach. This therefore has long term resistance against acid
These linkers then fall off when it passes through the stomach, allowing the capusle to move through the GI easily
What are the 5 ways that drugs can pass the BBB?
Paracellular Aqueous Pathway –> Water soluble drugs
Transcellular Lipophilic Pathway –> Lipid soluble agents
Transport Proteins –> Glucose and AAs
Receptor-Mediated Transcytosis –> Insulin
Adsorbtive Transcytosis –> Albumin and other plasma proteins
How can we hijack cells in the brain for our benefit
Put magnetic drugs into a phagocytic cells that accumulate an places of inflammation
We then place a magnet at the place of need, which attracts the cells (with the drug)
Why do we use Controlled Drug Delivery Systems (CDDS)?
Reduce drug fluctuations
Reduce dosing frequency
Control delivery site
Timed release
What is AAV2?
Adeno-Associated Virus
A virus used for gene delivery to neonatal neurones and adult astrocytes
What type of drugs can passively diffuse into the brain, through the BBB?
Small hydrophillic drugs
What layer in a Electrospun Matrice reservoir system is the limiting factor?
The PCL layers
As the PEVA layers don’t degrade
Why is L-Dopa and Ketoprofen-lysine amide effective in crossing the BBB?
They are substrates of LAT1
