CNS drug delivery Flashcards
Why is it so difficult to deliver drugs to the CNS?
Brain has its own separate circulation and brain compartments are in equilibrium with blood brain and CSF. There. is a fast blood flow and CSF turnover meaning a dynamic circulation - drugs do not stay in brain for long.
Additionally there is the blood brain barrier (with tight junctions) that blocks diffusion of polar solutes from blood and limits paracellular pathways which denies access to the brains interstitial fluids, glial cells are involved in supporting the barrier and tight junctions
also have. efflux pumps e.g. ATP binding cassette transporter
What is permeability into the brain restricted to?
Small molecules <600Da
Lipophilic molecules
What are the 3 main delivery strategies for delivering drugs to the brain
Between - permeabilising tight junctions and opening the gate so drug goes between
Through - enhance transport across epithelium ie making drug more. lipophilic as a. prodrug
(between and through also have intra-carotid into carotid artery)
Around e.g. not using BBB, direct intracranial delivery - including intracerebral (intraparenchymal), intraventricular (transcranial), intrathecal (intra-CSF)
What strategies can be used to CROSS THE BBB (between and through) ?
- osmotic agents e.g. hypertonic mannitol
- Penetration enhancers e.g. ethanol, SDS, glycerol
- pro drugs
How can osmotic agens work to cross the bbb (between)?
Hypertonic mannitol will change the osmotic pressure and open the gates to push water out (due to H bonding) - 25% solution infused into carotid artery over 30secs which opens the barrier for up to 30mins. - drug is. administered via the same cannula whilst the barrier is open so the drug can freely diffuse through - but drug must be small and polar as tight junctions are small
How can penetration enhancers work to cross the bbb (through)?
Surfactant molecules disrupt the BBB via interacting with the phosphatidylcholine head groups e.g. ethanol, surfactants, glycerol, polysorbate 80, polyethylene glycol hydroxy stearate
What are the issues surrounding the use of penetration enhancers?
They are essentially disrupting/dissolving the membrane so
- neuronal damage
- infarction
- gliosis
- learning disability/impairment
How can pro drugs work to cross the bbb (through)?
More lipophilic so enhance transport across the endothelium - DP-VPA phospholipid. pro drug of vaproic acid can penetrate the CNS intact and release the drug through hydrolytic. activity of phospholipase A2
What are the advantages of direct intracranial delivery (around the BBB)?
Lower dose used so reduced S/E and organ toxicity - better toleration (no need to worry abou metabolism)
- target effeciveness
- consistent drug level
- no first pass metabolism
- Adherence as don’t need to ‘take’ medicines
- can add in additional drug candidates as targeted nature - additional options for refractory disease
- can be combined with device for controlled release
What are the 3 ways of administering via intracranial delivery?
.1 intracerebral (intraparenchymal)
- intraventricular (transcranial)
- intrathecal (intra-CSF)
How does intracerebral (intraparenchymal) delivery work?
directly into the parenchymal space via inrathecal catherers
- high local dose needed. to drive convection enhanced diffusion driving. drugs into larger tissue regions
What are. some. examples of devices used for intracerebral (intraparenchymal)?
Implants- polymeric materials with drug inside
Devices - ommaya reservoir pump delivers etoposide
Osmotic implant - Duros relies on osmotic pressure
Gliadel wafer - Carmustine for brain tumour polymer depot
How does intraventricular (transcranial) delivery work?
Outline an advantage &. disadvantage
Deliver. directly into the ventricules - so CSF does not flush it out (deeper).
Used for metastatic cells of CSF as distributes drugs mainly, and meningioma
Advantage: lack of interconnection between interstitial fluid so. drug achieves. a higher conc (no diffusion into parenchymal space/CSF)
Disadvantage: chance of causing subependymal astrogliatic reaction due to high drug concentration exposure at the ependymal surface of brain
What is an example of intraventricular delivery? (transcranial)
Depocyt - sustained release formulation of Cytarabine directly - not flushed out by CSF. Liposomal formulation drug encapsulated in zwitterionic surfactant molecules - phospholipid spheres increases half life
What is intrathecal delivery?
Intra-CSF - direct administration of drugs through the intrathecal space into the cisterna magna of the brain
- less invasive than intraventricular
