CNS drug delivery (spring) Flashcards
how many compartments does the brain have?
Three compartments
Blood ↔ CSF ↔ Brain
where is the CSF?
CSF is held within a defined set of compartments
> yellow – ventricles
> light blue – subarachnoid & intrathecal
Volume of CSF?
Rate of CSF production?
CSF turnover?
Blood flows through the brain at a rate of?
Volume of CSF: 140ml
Rate of CSF production: 35ml/hr
CSF turnover: 4-6x/day
Blood flows through the brain at a rate of 60 l/hr
fill in the diagram
describe the characteristics of the Blood brain barrier
Tight junctions between cells
Blocks diffusion for polar solutes from blood along these potential
Limited paracellular pathways and thus denies solutes access to brain interstitial fluid
CSF continuously flushing the injected drug (i.e. those injected into the ventricle) back to the blood
compare the permeability of the Peripheral Capillary and Brain Capillary
permeability of the Brain Capillary is restricted to small molecules (<600D) and lipophilic substances.
proteins can pass through the Peripheral Capillary but not the Brain Capillary
How do cells in the brain get solutes?
Carrier-mediated transport, glucose or amino acids to a protein from high to low concentration.
Free diffusion is limited to small lipophilic drugs
do the following drugs cross the BBB?
Levodopa (L-dopa)
Dopamine
Gabapentin
Levodopa (L-dopa) - Small, water soluble. Does cross BBB
Dopamine - Small, water soluble. Does not cross BBB
Gabapentin - Small, water soluble. Does cross BBB
what are efflux pumps and what do they do?
Efflux pumps or transporters are responsible for extruding drugs from the brain
ATP binding cassette (ABC) transporter P-gp and multidrug resistant protein (MRP) being the principle efflux mechanism of these agents
Different strategies been developed to reduce impact
give an example of an Anti-epileptic CNS drug
Phenytoin
give an example of an Anxiolytic CNS drug
Diazepam
give an example of an Anti-depressant CNS drug
Paroxetine
Strategies for CNS drug delivery?
- between - permeabilize tight junction
- through - enhance transport across the endothelium
- around - direct intracranial drug delivery
list Strategies to cross the BBB
- Use of osmotic agents
- Disruption of BBB via penetration enhancers
- Use of prodrugs
The use of osmotic agents is a strategy used to cross the BBB
how does this work?
any issues?
The osmotic agent usually employed is hypertonic mannitol
A 25% solution is infused into a carotid artery (in the human at a rate of 4–8 mL/sec) over a period of 30 sec.
This treatment opens the barrier rapidly and it remains open for up to 30 min.
If a drug is then administered through the same cannula while the barrier is open, it can freely diffuse into the CNS.
issue:
- The hypertonic solution is thought to osmotically pull water out of the endothelial cells, causing cell shrinkage.
- This may cause disengagement of the extracellular domains of the proteins forming and regulating the tight junctions.
Disruption of the BBB via penetration enhancers is a strategy used to cross the BBB
how does this work?
any issues?
Surfactant molecules are able to disrupt the BBB via interacting with the phosphatidylcholine head groups
The various examples of these agents are ethanol, surfactants like sodium dodecyl sulfate (SDS), glycerol and polysorbate-80 (Tween-80), polyethylene glycol hydroxy stearate
Toxicity issues (neuronal damage, infarction, learning impairment, gliosis)
The use of prodrugs is a strategy used to cross the BBB
how does this work?
any issues?
DP-VPA phospholipid prodrug of valproic acid
Designed to penetrate the CNS intact and release VPA through hydrolytic activity of phopholipase A2
Phase 2 trials underway
what are the benefits of combining drugs & pumps
for brain delivery?
Significantly Lower dose
- Less risk of side effects and organ toxicity
- Improved Tolerability
Target effectiveness
- Consistent drug levels
- Avoiding first pass metabolism
Adherence - Overcome patients inability to take medication
Additional drug options for refractory disease - targeted nature of the delivery platform allows additional drug candidates
what is Intracerebral (intraparenchymal) delivery?
Intracerebral delivery involves delivery of drug directly into parenchymal space of the brain
Drugs can be injected directly via intrathecal catheters, by controlled release matrices, microencapsulated chemicals or recombinant cells.
High local dose is needed to drive convection enhanced diffusion (CED) to drive the drugs to larger tissue regions
Intracerebral devices
Implants are made up of biodegradable/non-biodegradable polymeric materials encapsulating drugs inside it.
Devices like Ommaya® reservoir pump (a dome-shaped device, with a catheter attached to the underside used to deliver chemotherapy)
Containing etoposide, an antitumor agent used for treating metastatic brain tumor showed 100-fold more effective concentration
what are Osmotic implant DUROS™?
benefits?
DUROS™ have been developed as osmotic implant that delivers drug for 3 months to 1 year with precise zero-order delivery kinetics.
Formulation maximizes drug payload, stabilizes drugs chemically and physically at body temperature, and involves the use of aqueous and non-aqueous vehicles
what is a Gliadel® wafer?
A polymer depot that has been approved by FDA for brain tumor therapy (high-grade malignant gliomas) containing carmustine showed its release over a period of 5 days when placed in the tumor resection cavity
It consists of a copolymer matrix of 1,3-bis(p-carboxyphenoxy)propane and sebacic acid in a 20 to 80 molar ratio
what is Intraventricular delivery (transcranial drug delivery)?
what treatment is this route best suited for?
Like other approaches intraventricular route also act as an approach to bypass BBB where therapeutic agents are instilled directly into cerebral ventricle
This route is best suited for meningioma treatment and metastatic cells of CSF as it distributes drugs mainly into ventricles and subarachnoidal area of the brain
advantage and disadvantage of Intraventricular delivery (transcranial drug delivery)
Major advantage is its lack of interconnection with interstitial fluid of brain unlike intracerebral delivery. Hence the drug achieves higher concentration in brain
The major disadvantage is the chance of causing subependymal astrogliatic reaction due to high drug exposure at the ependymal surface of brain
what is DepoCyt?
half-life?
DepoCyt is a sustained-release formulation of the active ingredient cytarabine designed for direct administration into the cerebrospinal fluid (CSF)
The half-life for the free CSF cytarabine ranged from of 5.9 to 82.4 hours (Compared to10min!).
Systemic exposure to cytarabine was negligible following IT
which drugs are used for DepoCyt formulations?
Dioleoylphosphatidylcholine (DOPC)
Cholesterol
Dipalmitoylphosphatidylglycerol (DPPG)
what is Intrathecal delivery (intra-csf drug delivery)?
advantage and disadvantage?
Direct administration of drugs through intrathecal route into cisterna magna of brain-e.g. Intrathecal baclofen (ITB) has been used to treat spasticity since 1988
Substantially less invasive than intraventricular
The major disadvantage of this route is the chance of drug spreading along the distal space of spinal canal
Non-Opioid Drugs used for Treatment of Chronic Pain by the Spinal Route
Local Anesthetics:
Adrenergic Agonists
NMDA Antagonists
Local Anesthetics:
- Bupivicaine
- Ropivicaine
- Tetracaine
Adrenergic Agonists
- Clonidine
- Tizanidine
NMDA Antagonists
- Ketamine
