540 - Drug Delivery Systems - Exam Iv - Cns Drug Delivery

Front 1

What does the frontal lobe of the brain do?

Back 1

Possesses the centers for speech and motor cortex

Front 2

What does the parietal lob of the brain do?

Back 2

Houses the sensory cortex

Front 3

What does the occipital lobe do?

Back 3

Contains the center for vision processing

Front 4

What does the temporal lobe do?

Back 4

Contains the center for auditory processing

Front 5

What comprises the Forebrain?

Back 5

1) Thalamus
2) Hypothalamus
3) Cerebrum

Front 6

What comprises the Hindbrain?

Back 6

1) Cerebellum
2) Pons
3) Medulla

Front 7

Where is CNS fluid predominately produced?

Back 7

In the ventricular system of the brain

Front 8

Describe neurons and their metabolic requirements?

Back 8

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

Front 9

What is the Circle of Willis?

Back 9

It is a circle of arteries which supplies blood to the brain

Front 10

What is a prominent physical characteristic of veins which distinguishes them from arteries?

Back 10

They are not as straight as arteries

Front 11

What comprises the neurovascular unit?

Back 11

1) Endothelia cells
2) Pericytes
3) Astrocytes
4) Neurons

Front 12

What makes drug delivery from CNS/brain capillaries so difficult?

Back 12

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.

Front 13

What are the three major barriers which guard the CNS from bloodborne drugs?

Back 13

1) Blood-Brain Barrier (neurovascular unit)
2) Blood-CSF Barrier (arachnoid epithelium)
3) Blood-CSF Barrier (choroid plexus epithelium)

Front 14

What are the three minor barriers which guard the CNS from bloodborne drugs?

Back 14

1) Blood-Retina Barrier (inner and outer)
2) Blood-Nerve Barrier
3) Blood-Labyrinth Barrier

Front 15

What are the potential drug targets in the brain?

Back 15

1) Pericytes
2) Endothelial Cells
3) Astrocytes
4) Neurons
5) Microglia
6) Oligo-dendrocytes

Front 16

What are the characteristics of typical CNS pharmaceuticals?

Back 16

1) Small molecules
2) New chemical entities
3) Production involves chemical synthesis
4) Lipinski's "Rule of 5"

Front 17

What are the characteristics of typical CNS biopharmaceuticals?

Back 17

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

Front 18

What are the physiological actors affecting drug delivery to the CNS?

Back 18

1) Paracellular Aq pathway
2) Transcellular lipophilic pathway
3) Transport Proteins
4) Receptor-Mediated Transcytosis
5) Adsorptive Transcytosis

Front 19

What is unique about the adsorptive transcytosis of drugs into the CNS?

Back 19

It needs to be positively charged as it is crossing a dense area of negative charge. Typically these are albumin or other plasma proteins.

Front 20

How does lipid solubility and molecular weight effect delivery of small molecule pharmaceuticals to the CNS?

Back 20

Increasing the lipid solubility of a small molecule less than 400-600 Da can increase penetration

Front 21

How does ionization of the drug effect delivery of small molecule pharmaceuticals to the CNS?

Back 21

Unionized form may cross transcellular lipophilic pathway

**Ionized form will not cross**

Front 22

How does plasma protein binding effect delivery of small molecule pharmaceuticals to the CNS?

Back 22

Generally the free drug will cross the BBB more efficiently

Front 23

What can alter CNS transporter expression?

Back 23

1) Certain xenobiotics (rifampin)
2) Stress
3) Disease

Front 24

What disease(s) decrease Pgp in the brain?

Back 24

1) Alzheimer's
2) Parkinson's
3) HIV
4) Normal aging

Front 25

What disease(s) increase Pgp in the brain?

Back 25

1) Epileptic Seizures
2) Brain Cancer

Front 26

What is the diffusion barrier?

Back 26

Drugs must distribute through small (~50 nm wide) extracellular spaces for effect

Front 27

By what method does passive diffusion occur in brain capillaries?

Back 27

Via the transcellular lipophilic pathway due to tight junctions

Front 28

What is the main efflux transporters at the BBB?

Back 28

P-glycoprotein (Pgp)

Front 29

What are three important points regarding efflux transporters at the BBB?

Back 29

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

Front 30

What are three important points regarding BBB permeability?

Back 30

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

Front 31

What major CNS disease globally effects the brain?

Back 31

Alzheimer's

Front 32

Which major CNS disease effects the brain focally?

Back 32

Parkinson's

Front 33

Describe the cause and effect of BBB changes

Back 33

1) BBB gets leakier with disease/injury
2) Changes may be transient (stroke, epilepsy)
3) Changes may be longer lasting (MS)

Front 34

What is the main problem with biologics?

Back 34

An inability to cross the BBB

Front 35

What is the systemic approach to CNS drug delivery?

Back 35

To enhance delivery across the BBB

Front 36

What is the central approach to CNS drug delivery?

Back 36

To bypass the BBB

Front 37

What are the two pharmacologically-based strategies of the systemic approach to CNS drug delivery?

Back 37

1) Increase lipophilicity of drug
2) Pgp modification for drugs that are Pgp substrates

Front 38

What are the physiologically-based strategies of the systemic approach to CNS drug delivery?

Back 38

1) Exploit carrier-mediated transport systems
2) Exploit receptor-mediated transcytosis systems (Trojan Horse Method)

Front 39

What are the advantages to the systemic approach to CNS drug delivery?

Back 39

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

Front 40

What are the disadvantages to the systemic approach to CNS drug delivery?

Back 40

1) Lack of targeting
2) By using the vascular system, potentially all tissues are exposed --> peripheral side effects/toxicity

Front 41

Describe the central approaches to CNS drug delivery

Back 41

**All invasive**
1) Intraparenchymal - direct inj/inf into brain parenchyma
2) Intracerebroventricular - inj/inf into lateral ventricles
3) Intrathecal - inj into the thecal space

Front 42

What is the advantage to the central approach to CNS drug delivery?

Back 42

It is targeted

Front 43

What are the disadvantages to the central approach to CNS drug delivery?

Back 43

1) Invasive
2) Distribution is often limited by diffusion

Front 44

Describe the Trojan Horse Method

Back 44

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

Front 45

What is tissue distribution affeced by in Intraparenchymal Infusion?

Back 45

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

Front 46

What are three facts regarding Intracerebroventricular (i.c.v.) drug delivery?

Back 46

1) Targeted
2) Much experience
3) Often shows great promise based on preclinical studies

Front 47

What are three facts regarding Intrathecal (i.t.) drug delivery?

Back 47

1) Diffusion limited
3) Less invasive than Intraparenchymal
3) Much experience