CNS drug delivery Flashcards
What is the CNS comprised of
- Extracellular fluid compartments make up BRAIN and SPINAL CORD PARENCHYMAL INTERSTITIAL FLUID (ISF) and the CEREBROSPINAL FLUID (CSF)
- ISF and CSF are contained within ventricles of brain and cerebral + spinal subarachnoid spaces
What are the three compartments of the brain and describe each one in relation to the other
Blood CSF Brain
Blood to brain: BBB
CSF to brain: diffusion
Brain to CSF: Ependyma bulk flow
CSF to blood: Choroid plexus
Describe the blood brain barrier, what its made up of and how it works
- Endothelial cells at their adjacent margins form TIGHT JUNCTIONS- made by several transmembrane proteins that project and seal the PARACELLULAR PATHWAY
- Interaction of these junctional proteins: OCCLUDIN and CLAUDIN diffusion for polar solutes from blood
- Denies these solutes free assess to brain interstitial (extracellular fluid)
- Any molecule entry into brain parenchyma via parenteral administration is controlled by BBB and the blood cerebrospinal fluid barrier
What does a high turnover rate of CSF lead to
Continuous flushing of injected drug back to blood
What does the blood brain vessel have compared to a normal cell
Glial brain cells support barrier
Tight junction (no pores) create barrier
Operates by carrier mediated transport
Give an example of a small drug molecule
GABAPENTIN
What do the peripheral capillary and brain capillary allow
- Protein and glucose
2. Small molecules and lipophilic substances
What are the various transmembrane transporters
GLUT1 glucose carrier
LAT1 Amino acid carrier
Transferring receptors and insulin receptors
Lipoprotein receptors
ATP family of efflux transporters like P-gp
What is carrier mediated transport
- Binding of a solute such as glucose or amino acids to a protein transporter on one side of the membrane
- Triggers conformational change in protein resulting in transport of substance to the other side of membrane (HIGH TO LOW
What are efflux pumps responsible for
Forcing drugs out of brain
Mechanism: accumulation of a wide range of biological active molecules
Principle mechanism:
ATP binding cassette ABC transporter
Give examples of drugs that goes through carrier mediated transport and explain it
- LEVODOPA (L-DOPA): Small, water soluble, does cross BBB via LAT1
Dopamine: Small, water soluble, does NOT cross BBB
- GABApentin: small, water soluble, does cross BBB via LAT1
Conformation puts carboxyl and amine in positions to mimic alpha amino acid
Similar to baclofen
What are the strategies for CNS drug delivery
- Between: permeabilise TIGHT Junctions
- Through: enhance transport across endothelium
- Around: direct intracranial drug delivery
Describe intracerebral (intraparenchymal) delivery
- Direct delivery of drug into parenchymal space of brain- cerebrum
- Drugs injected directly (bolus or infusion) via intrathecal catheters, controlled release matrices, micro encapsulated chemicals or recombinant cells
- High dose: required for appropriate drug concentration in parenchymal due to closely packed arrangement of cells in both gray and white matter- restricts diffusion
- Convection enhanced diffusion (CED) drive drugs in larger tissue region
What is an intracerebral implant
- Devices that control release of drug at target site of brain
- Made up of biodegradable/non biodegradable polymeric materials encapsulating drugs in it
- CSF: fluid that surrounds brain and spinal cord made in ventricle
Give examples of intracerebral implants (3)
- Ommaya reservar pump: dome shaped device with a catheter attached to the underside (delivers chemo such as etoposide for brain tumour)
- DUROS: osmotic phenomena, delivers drugs from 3 months to 1 year with precise zero order delivery
- Polymer depots: delivers drug into cerebral environment in tumour cavity of brain
Present in polymer matrix as core material, offers sustained release of drug by biodegradation of polymer
Give an example of a polymer depot
Gliadel Water
Treats brain tumour therapy by containing carmustine
Releases over a period of 5 days when placed in tumour resection cavity
What is intraventricular delivery (transcranial drug delivery)
- Approach to bypass BBB: therapeutic agents instilled directly into cerebral ventricles
- Route best suited for meningioma treatment and metastatic cells of CSF
- Distributes drugs mainly into ventricles and subarachnoidal area of brain (bone area)
What are the advatanges of intraventricular delivery
- Lack of interconnection with interstitial fluid of brain unlike intracerebral delivery
- Drug achieves higher concentration in brain compared to extravascular distribution
What are the disadvantages of intraventricular delivery
- Chance of causing subependymal astrogliatic reaction
2. High drug exposure of ependymal brain surface
What is a depocyt
Sustained release formulation of API cytarabine that is designed for direct administration into cerebrospinal fluid (CSF) intrathecally
What are the benefits of delivering drugs directly to brain fluid
- Significant lower dose: less side effect risk and organ toxicity, improved tolerability
- Target effectiveness: consistent drug levels, lessen difficulty finding therapeutic ratio for each patient
- Last pass metabolism: drugs do not go firs through GI tract then liver
- Adherence: overcoming patients inability to take medicine
- Allows assess to additional drug candidates
Give an example of a drug given by intracerebroventricular drug delivery and describe it
Drug: ICVrx001
Indication: refractory epilepsy
Duration: life long
Effect: reduce seizure frequency and severity, reduce adverse effects
What is intrathecal delivery and its disadvantages
Delivery of neurotherapeutic agents to brain by cisterna magna of brain (back of brain)
Low drug accumulation in parenchymal structures of the deep brain: essential for sustained release of drug
Disadvantage: chance of drugs spreading across the distal space of spinal canal: lead to loss of co-ordination and ataxia
Give examples of intrathecal devices that have been made
Infumorph: intrathecal morphine device
Gablofen: intrathecal baclofen device- treatment of dystonia
Give examples of local anaesthetics used in the spinal route
Bupivicaine
Ropivicaine
Tetracaine
Give examples of adrenergic agonists used in the spinal route
Clonidine
Tizanidine
Give examples of NMDA antagonists used in the spinal route
KETAMINE
What is intracarotid drug delivery, how can it disrupt the BBB, the agent used and the mechanism of it
- Infusion via internal/external/common carotid artery
- Hyperosmotic agent: administered via intracarotid arterial infusion along with drug via cannula
- Osmotic agent = mannitol
- Mechanism: hypertonic solution osmotically pulls water out of endothelial cells (cell shrinkage), disengagement of extracellular domains of proteins forming + regulating tight junctions
What are penetration enhancers and give examples of these agents
- Surfactant molecules able to disrupt BB via interaction with phosphatidylcholine head groups
- Examples: Ethanol, glycerol, surfactants, polysorbate 80, polyethylene glycol, hydroxy stearate
