Delivering drugs to the CNS

Question 1

Name the two catagories of CNS diseases?

Answer 1

1. Neurodegenerative
2. Psychiatric

Question 2

Biodistribution of Oral Drugs?

Answer 2

Absorbed into the gut.

Taken to the liver to be metabolised and excreted from the gut.

Question 3

Pharmacokinetics?

Answer 3

the action of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues, biotransformation, and excretion

Question 4

Brain: blood partitioning

Answer 4

Measure the drug in the blood and then the drug in the brain.

Ratio between them is described as Kp

Question 5

K_p>1?

Answer 5

Means higher concentration in the brain than the blood

Question 6

K_P<1?

Answer 6

Means lower concentration in the brain than the blood

Question 7

Testing receptor occupancy assay?

Answer 7

This tests the activity of the brain for the time it is exposure to the brain

Question 8

Equlibration?

Answer 8

Two compartments

Passive diffusion until they are at equal concentrations.

Question 9

Paracellular?

Answer 9

Passive

Selective variable and regulated

eg. tight junctions.

Question 10

Transcellular?

Answer 10

More hydrophobic compouds can pass

Plus active transport

Question 11

Permeability?

Answer 11

Rate at which compound crosses membrane.

All will reach equilibrium but this determines how fast they reach that state.

Question 12

What can slow permeability have an effect on?

Answer 12

It can limit exposure to tissues

Cause a time delay between Cmax in blood and Cmax in tissue

Question 13

Content of media?

Answer 13

Affects compound potency.

serum free media to 100% plasma

Question 14

Free drug hypothesis?

Answer 14

Binding to plasma proteins limits biological activity.

Also binding to membrane, lipids etc limit this too

Pharmacological activity is dependent on ‘free drug’.

AS5

Question 15

Calculation for the potency?

Answer 15

Potency in presence of protein= potency in absence of protein/ fraction unbound

Question 16

Equation for fraction of drug bound?

Answer 16

Fraction of drug bound= [protein]/ ([protein]+affinity)

Question 17

Fractional binding is affected?

Answer 17

By the concentration of proteins not the concentration of drug

Question 18

Equation for the affinity?

Answer 18

([protein]/Fb)-[protein]

Question 19

What concentration in serum albumin present in the plasma

Answer 19

600uM

Must higher than most drugs

Question 20

Fractionaion of drug bound is only used if?

Answer 20

Concentration of protein is higher than the concentration of drug

Question 21

What happens if the concentration of proteins is equal to the drug?

Answer 21

TD²-(Dt+Tt+K_d)TD+Tt.Dt=0

Question 22

Paritioning is affected by?

Answer 22

Free drug.

Only the free drug can equlibrate across compartments.

With passive diffusion, the free drug will be the same in all compartments.

High binding drives higher concentrations- as equilbrium is only affect by free drugs

Question 23

Pathway to the brain?

Answer 23

The brain is highly vascularised

Large area- drug has plenty of opportunity to enter.

Uses the brain intersititial fluid to enter instead of CSF as the BIF is a lot bigger.

Question 24

Brain ISF?

Differences to plasma?

Answer 24

Plasma has double as many proteins while the brain ISF has 20x more lipids.

Question 25

How to measure unbound fraction in brain tissue?

Answer 25

1. Brain homogenates (equlibrium dialysis) 2. Brain slices (microdialysis)

Question 26

K_pu,u?

Answer 26

Defined as the ratio of unbound drug concentration in the brain and the blood. Better measure of brain pentration

Question 27

K_pu,u \<\> 1?

Answer 27

Then something other than passive diffusion is taking place

Question 28

What ensures no paracellular transport occurs between the blood brain barrier?

Answer 28

Specialised tight junctions. Important to protect ionic concentrations in CNS

Question 29

Function of the blood brain barrier?

Answer 29

Allows distribution of very small moelcules. Prevents ionic flux that might affect neuronal function. Provides selective uptake mechanisms for required molecules. Provides protected environment for CNS

Question 30

Strucutre of the tight junctions?

Answer 30

aS6 Two layers of blockage. Prevents molecules from passing

Question 31

P-glycoprotein (P-gp)

Answer 31

Endothelial cells contain transporters that actively pump molecules back out to prevent transcellular permeation. Saptially localised only on the apical side of the cell.

Question 32

How does P-gp work?

Answer 32

Drug sits up between the 2 protein chains. ATP hydrolysis to open the cell. Once the drug is excreted the ATP is lost: channel closes again

Question 33

Measuring P-gp activity?

Answer 33

Comapre rates of permeability when drug is added to the basal side or apical side. Generates the efflux ratio ER=1: The permeabiltiy is passive ER\>1: compounds puped out by P-gp

Question 34

Apical side?

Answer 34

the layer of plasma membrane on the apical side (the side toward the lumen) of the epithelial cells in a body tube or cavity.

Question 35

Measuring CNS penetration?

Answer 35

CSF sampling. Minimal barrier between CSF and ISF- therefore concentration in CSF= ISF

Question 36

Drawbacks to CSF sampling?

Answer 36

Equilibration is slow. Innacurate when active transport is occuring.

Question 37

Positron Emission?

Answer 37

a proton inside a radionuclide nucleus is converted into a neutron while releasing a positron and a neutrino Because positron emission decreases proton number relative to neutron number, positron decay happens typically in large "proton-rich" radionuclides

Question 38

PET imaging?

Answer 38

uses a radioactive drug (tracer) to show this activity detects pairs of gamma rays emitted indirectly by a tracer (introduced into the body) concentrations of tracer imaged will indicate tissue metabolic activity by virtue of the regional glucose uptake

Question 39

Applications of PET?

Answer 39

CNS penetration Gives an indication that some compound gets into the brain. Demonstrating recptor engagement by displacement. Localising regions of brain.

Question 40

Apply PET to drugs?

Answer 40

Make the drug radioactive Can see how much gets into the brain