(PM3B) CNS Drug Delivery Flashcards
What are the compartments of the brain?
(1) Blood
(2) Cerebrospinal fluid
(3) Brain
Where is cerebrospinal fluid held?
(1) Ventricles
(2) Subarachnoid + intrathecal spaces
What is the volume of the cerebrospinal fluid?
140mL
What is the rate of production of cerebrospinal fluid?
35 mL/hr
At what rate does blood flow through the brain?
60 L/hr
What barrier is between the brain and the blood?
Blood brain barrier
What barrier is between the blood and the cerebrospinal fluid?
(1) Arachnoid villi
(2) Chloroid plexus
What barrier is between the cerebrospinal fluid and the brain?
Ependyma
What is the blood brain barrier?
Tight junctions between cells
Blocks diffusion of polar solutes
Limited paracellular pathways
How is the blood brain barrier selective?
Brain capillaries have restricted permeability compared to peripheral capillaries
Permeability restricted to <600Da (small molecules) + lipophilic substances
How do cells in the brain get solutes?
(1) Small lipophilic drugs diffuse freely
(2) Carrier-mediates transport of glucose/ amino acids/ proteins from high to low concentration
What are efflux pumps?
Transporters
Responsible for extruding drugs from brain
ATP-binding cassette transporter P-gp + multidrug resistant protein are key principles of efflux mechanism
What are some strategies for CNS drug delivery?
(1) Between tight junctions of BBB
(2) Through BBB –enhancement of transport across the endothelium
(3) Around the BBB – direct intracranial drug delivery
What is intracarotid drug delivery?
Injection directly into carotid artery
What is the role of osmotic agents in CNS drug delivery?
Strategy to cross BBB
Usually hypertonic mannitol
(1) 25% solution infused into carotid artery over 30 seconds
(2) Injection of drug through same cannula it can freely diffuse into the CNS
How does mannitol increase blood brain barrier permeability (mechanism of action)?
(1) Hypertonic solution thought to osmotically pull water out of endothelial cells – causes cell shrinkage
(2) Cause disengagement of extracellular domains of proteins forming the tight BBB junctions
What is the purpose of disruption of blood brain barrier via penetration enhancers?
Strategy to cross BBB
(1) Surfactant molecules disrupt BBB by acting with phosphatidylcholine head groups
e. g. ethanol surfactants: SDS/ glycerol/ polysorbate-80
What are some potential issues with disruption of blood brain barrier via penetration enhancers?
Toxicity issues
(1) Neuronal damage
(2) Infarction
(3) Learning impairment
(4) Gliosis – scars in CNS
What is the purpose of the use of prodrugs at the blood brain barrier?
Strategy to cross the BBB
(1) DP-VPA is designed to penetrate CNS intact
(2) Release VPA through hydrolytic activity of phospholipase A2
In testing – phase 2 trials have begun
What are some potential benefits of combining drugs and pumps for brain/ CNS delivery?
(1) Significantly lower dose – fewer side effects
(2) Target effectiveness – avoiding 1st pass metabolism
(3) Improved adherence – overcomes inability to take medication
(4) Additional drug options –targeted nature of delivery allows for more drug candidates
What is intracerebral (intraparenchymal) delivery?
Drug delivery directly into parenchymal space in brain
(1) Can be injected directly by intrathecal catheters
(2) via controlled-release matrices
(3) via microencapsulated chemicals
(4) via recombinant cells
Why is a high local dose required for intracerebral (intraparenchymal) delivery?
To drive convection enhanced diffusion (CED)
Drives drugs to larger tissue regions
What are intracerebral devices?
Implants made of either biodegradable/ non-biodegradable polymeric materials
Encapsulate drugs within them
e.g. Ommaya reservoir
Used to deliver chemotherapy
What are Ommaya reservoirs?
Intracerebal devices
Used to deliver chemotherapy
Contain etoposide (anti tumour agent)
Treatment of metastatic brain tumour
Give an example of an osmotic implant.
DUROS
What is DUROS?
Osmotic implant
Delivers drug for 3-12 months
Precise zero order delivery kinetics
What is a GLIADEL wafer?
Polymer depot
Approved for brain-tumour therapy
Contains carmustine
What is inrtaventricular delivery?
Transcranial drug delivery
Bypasses BBB
Injection directly into cerebral ventricle
Best suited for meningioma treatment + metastatic cells of cerebrospinal fluid
Distributes drugs mainly into ventricles + subarachnoidal area of the brain
Give an advantage of intraventricular delivery.
Lack of interconnection with interstitial fluid of brain – unlike intracerebal delivery
Achieves higher concentration in the brain
Give a disadvantage of intraventricular delivery.
Chance of causing subependymal astrogliatic reaction
- Due to high drug exposure at ependymal surface of brain
What is DepoCyt?
Liposomal sustained-release formulation
Contains cytarabine
Direct administration into cerebrospinal fluid
Give an advantage of using DepoCyt.
(1) Half-life of 5.9-82.4hrs compared to just 10 minutes
(2) Systemic exposure is low following intrathecal administration
What is intrathecal drug delivery?
Direct administration of drugs through intrathecal route into cisterna magna of brain
What is ITB?
Intrathecal baclofen
Treatment of spasticity
Give an advantage of intrathecal delivery.
Less invasive than intraventricular
Give a disadvantage of intrathecal delivery.
Chance of drug spreading along distal space of spinal canal
What are some types of non-opioid drugs used for treatment of chronic pain via the spinal route?
(1) Local anaesthetics
(2) Adrenergic agonists
(3) NMDA antagonists
(4) Others – e.g. aspirin/ baclofen/ gabapentin
