CNS Delivery Flashcards
What are the CNS barriers?
BBB and blood CSF barrier
What is the function of the BBB?
Create ionic homeostasis
What is the blood CSF barrier?
Interface between choroid plexus and CSF
CSF secreted across choroid plexus epithelial cells into brain
From where is cerebral spinal fluid secreted from?
Choroid plexus
What are the characteristics of the blood brain barrier?
Tight junctions between endothelial cells lining capillaries in the brain. tight junctions restrict paracellular aqueous pathway
Capillaries are covered by astrocytes
What are the functions of the blood brain barrier?
-Ion regulation/homeostasis- potassium is higher and plasma than the CSF
-Segregation of neurotransmitters- control and peripheral transmitters are kept separate
-supplement the brain with nutrients- not albumin or thrombin
-protection from neurotoxins- endogenous metabolites or proteins, bacteria or viruses
How do drugs cross the blood brain barrier?
-Paracellular aqueous pathway is limited because hydrophilic drugs are kept out
-trans cellular lipophilic diffusion
-Carrier mediated transport
-receptor mediated endocytosis- for large molecules
-Active efflux transport- P – glycoprotein- main barrier
How is blood CSF a barrier?
Choroid plexus has outer epithelial cells with microvilli
how do substances pass the blood brain barrier?
Brain cells very close to capillaries and diffusion distance to neurons are short
How substances enter the brain via the blood CSF barrier?
Across the choroid plexus via CSF
What are examples of direct CNS delivery?
-intra cerebral, intraventricular, intrathecal
What are the advantages of intracerebral and intraventricular delivery?
-Can deliver higher concentration by direct injection with reduced peripheral concentrations
-bypass the blood brain barrier
-Can insert cerebral implant for controlled release
What are the disadvantages of cerebral and interventricular delivery?
-highly invasive- need burr holes (drill), craniotomy
- limited brain distribution needs to be potent with narrow focal area
What is intrathecal delivery?
Injection into intrathecal space that holds spinal fluid
What is the advantage of intrathecal delivery?
Less invasive
What are the disadvantages of intrathecal delivery?
Drug spreads distally along spinal cord leading to ataxia (loss of movement of muscles)
No controlled release as doesn’t accumulate in brain parenchyma
What are examples of nondirect CNS delivery?
-intravenous, intra arterial/entry carotid, transnasal
When would intra arterial delivery be used?
For enhanced intra tumoural concentrations in combination with blood brain barrier disrupting agents (hypertonic mannitol)
What are the advantages of transnasal delivery?
Bypass the blood brain barrier (olfactory region has cells extending into cranial cavity)
Non-invasive
What are the disadvantages of transnasal delivery to the brain?
Not all drug absorbed- some drops down throat and swallowed
What are examples of blood brain barrier disruption?
Opening tight junctions via-
-Hypertonic mannitol- high osmotic pressure shrink cells
-Ultrasound/electromagnetic radiation- temperature or ultrasonic waves create lesions
What other methods can be used to increase CNS drug absorption?
-chimeric peptides
-cationic proteins
-Liposomes
-Nano particles
-Pro drugs
How do chimeric peptides increase CNS absorption ?
Drug is covalently bond to vector to form transportable fused molecule
How do catatonic proteins increase CNS absorption?
Increases positive charge on drug molecule by modifying free carboxyl groups
Which interact with anionic functional groups on brain surface
