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47 Cards in this Set

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What does the frontal lobe of the brain do?
Possesses the centers for speech and motor cortex
What does the parietal lob of the brain do?
Houses the sensory cortex
What does the occipital lobe do?
Contains the center for vision processing
What does the temporal lobe do?
Contains the center for auditory processing
What comprises the Forebrain?
1) Thalamus
2) Hypothalamus
3) Cerebrum
What comprises the Hindbrain?
1) Cerebellum
2) Pons
3) Medulla
Where is CNS fluid predominately produced?
In the ventricular system of the brain
Describe neurons and their metabolic requirements?
They need huge resources to function and maintain membrane potential. There is almost no ATP in reserve which means they require a continuous supply of glucose and oxygen. Ischemia for every 4-5 minutes can result in permanent damage
What is the Circle of Willis?
It is a circle of arteries which supplies blood to the brain
What is a prominent physical characteristic of veins which distinguishes them from arteries?
They are not as straight as arteries
What comprises the neurovascular unit?
1) Endothelia cells
2) Pericytes
3) Astrocytes
4) Neurons
What makes drug delivery from CNS/brain capillaries so difficult?
They possess tight junction which block paracellular passive diffusion for most molecules. Additionally, the rates of pinocytosis / transcytosis are much lower than in non-brain capillaries.
What are the three major barriers which guard the CNS from bloodborne drugs?
1) Blood-Brain Barrier (neurovascular unit)
2) Blood-CSF Barrier (arachnoid epithelium)
3) Blood-CSF Barrier (choroid plexus epithelium)
What are the three minor barriers which guard the CNS from bloodborne drugs?
1) Blood-Retina Barrier (inner and outer)
2) Blood-Nerve Barrier
3) Blood-Labyrinth Barrier
What are the potential drug targets in the brain?
1) Pericytes
2) Endothelial Cells
3) Astrocytes
4) Neurons
5) Microglia
6) Oligo-dendrocytes
What are the characteristics of typical CNS pharmaceuticals?
1) Small molecules
2) New chemical entities
3) Production involves chemical synthesis
4) Lipinski's "Rule of 5"
What are the characteristics of typical CNS biopharmaceuticals?
1) Large molecules/macromolecular complexes (peptides, proteins, vaccines, gene therapy)
2) Production involves use of biological systems
3) Highly potent and specific
4) Very poor absorption/permeation
5) Does not cross BBB
What are the physiological actors affecting drug delivery to the CNS?
1) Paracellular Aq pathway
2) Transcellular lipophilic pathway
3) Transport Proteins
4) Receptor-Mediated Transcytosis
5) Adsorptive Transcytosis
What is unique about the adsorptive transcytosis of drugs into the CNS?
It needs to be positively charged as it is crossing a dense area of negative charge. Typically these are albumin or other plasma proteins.
How does lipid solubility and molecular weight effect delivery of small molecule pharmaceuticals to the CNS?
Increasing the lipid solubility of a small molecule less than 400-600 Da can increase penetration
How does ionization of the drug effect delivery of small molecule pharmaceuticals to the CNS?
Unionized form may cross transcellular lipophilic pathway

**Ionized form will not cross**
How does plasma protein binding effect delivery of small molecule pharmaceuticals to the CNS?
Generally the free drug will cross the BBB more efficiently
What can alter CNS transporter expression?
1) Certain xenobiotics (rifampin)
2) Stress
3) Disease
What disease(s) decrease Pgp in the brain?
1) Alzheimer's
2) Parkinson's
3) HIV
4) Normal aging
What disease(s) increase Pgp in the brain?
1) Epileptic Seizures
2) Brain Cancer
What is the diffusion barrier?
Drugs must distribute through small (~50 nm wide) extracellular spaces for effect
By what method does passive diffusion occur in brain capillaries?
Via the transcellular lipophilic pathway due to tight junctions
What is the main efflux transporters at the BBB?
P-glycoprotein (Pgp)
What are three important points regarding efflux transporters at the BBB?
1) Pgp is amazingly polyspecific (can transport different substrates)
2) Many multidrug transporters exist
3) Transporter expression can be altered in CNS disorders resulting in significant changes in brain:plasma drug levels
What are three important points regarding BBB permeability?
1) Drugs that use endogenous solute carriers get in better than expected based on lipophilicity alone
2) Drugs larger than 400-600 Da do not penetrate as well
3) Substrates of efflux transporters don't penetrate as well
What major CNS disease globally effects the brain?
Alzheimer's
Which major CNS disease effects the brain focally?
Parkinson's
Describe the cause and effect of BBB changes
1) BBB gets leakier with disease/injury
2) Changes may be transient (stroke, epilepsy)
3) Changes may be longer lasting (MS)
What is the main problem with biologics?
An inability to cross the BBB
What is the systemic approach to CNS drug delivery?
To enhance delivery across the BBB
What is the central approach to CNS drug delivery?
To bypass the BBB
What are the two pharmacologically-based strategies of the systemic approach to CNS drug delivery?
1) Increase lipophilicity of drug
2) Pgp modification for drugs that are Pgp substrates
What are the physiologically-based strategies of the systemic approach to CNS drug delivery?
1) Exploit carrier-mediated transport systems
2) Exploit receptor-mediated transcytosis systems (Trojan Horse Method)
What are the advantages to the systemic approach to CNS drug delivery?
1) It is the least invasive
2) Neurons are not further than 10-20 mm from capillaries so there is no diffusion limitation based on size
What are the disadvantages to the systemic approach to CNS drug delivery?
1) Lack of targeting
2) By using the vascular system, potentially all tissues are exposed --> peripheral side effects/toxicity
Describe the central approaches to CNS drug delivery
**All invasive**
1) Intraparenchymal - direct inj/inf into brain parenchyma
2) Intracerebroventricular - inj/inf into lateral ventricles
3) Intrathecal - inj into the thecal space
What is the advantage to the central approach to CNS drug delivery?
It is targeted
What are the disadvantages to the central approach to CNS drug delivery?
1) Invasive
2) Distribution is often limited by diffusion
Describe the Trojan Horse Method
Trojan Horse (TH) Moiety:
1) Antibody (higher affinity)
2) Ligand (lower affinity)

Drug binds to TH, TH binds to receptor on BBB and transports, drug then binds to second receptor in brain
What is tissue distribution affeced by in Intraparenchymal Infusion?
1) Infusion parameters - Flow rate, catheter size/design, proximity to low resistant pathways, backflow
2) Substance properties - shape, charge, binding
3) Tissue properties - Architecture, volume fraction of extracellular space, hydraulic conductivity
What are three facts regarding Intracerebroventricular (i.c.v.) drug delivery?
1) Targeted
2) Much experience
3) Often shows great promise based on preclinical studies
What are three facts regarding Intrathecal (i.t.) drug delivery?
1) Diffusion limited
3) Less invasive than Intraparenchymal
3) Much experience