Delivering drugs to the CNS Flashcards
Name the two catagories of CNS diseases?
- Neurodegenerative
- Psychiatric
Biodistribution of Oral Drugs?
Absorbed into the gut.
Taken to the liver to be metabolised and excreted from the gut.
Pharmacokinetics?
the action of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues, biotransformation, and excretion
Brain: blood partitioning
Measure the drug in the blood and then the drug in the brain.
Ratio between them is described as Kp
Kp>1?
Means higher concentration in the brain than the blood
KP<1?
Means lower concentration in the brain than the blood
Testing receptor occupancy assay?
This tests the activity of the brain for the time it is exposure to the brain
Equlibration?
Two compartments
Passive diffusion until they are at equal concentrations.
Paracellular?
Passive
Selective variable and regulated
eg. tight junctions.
Transcellular?
More hydrophobic compouds can pass
Plus active transport
Permeability?
Rate at which compound crosses membrane.
All will reach equilibrium but this determines how fast they reach that state.
What can slow permeability have an effect on?
It can limit exposure to tissues
Cause a time delay between Cmax in blood and Cmax in tissue
Content of media?
Affects compound potency.
serum free media to 100% plasma
Free drug hypothesis?
Binding to plasma proteins limits biological activity.
Also binding to membrane, lipids etc limit this too
Pharmacological activity is dependent on ‘free drug’.
AS5
Calculation for the potency?
Potency in presence of protein= potency in absence of protein/ fraction unbound
Equation for fraction of drug bound?
Fraction of drug bound= [protein]/ ([protein]+affinity)
Fractional binding is affected?
By the concentration of proteins not the concentration of drug
Equation for the affinity?
([protein]/Fb)-[protein]
What concentration in serum albumin present in the plasma
600uM
Must higher than most drugs
Fractionaion of drug bound is only used if?
Concentration of protein is higher than the concentration of drug
What happens if the concentration of proteins is equal to the drug?
TD2-(Dt+Tt+Kd)TD+Tt.Dt=0
Paritioning is affected by?
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
Pathway to the brain?
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.
Brain ISF?
Differences to plasma?
Plasma has double as many proteins while the brain ISF has 20x more lipids.
How to measure unbound fraction in brain tissue?
- Brain homogenates (equlibrium dialysis)
- Brain slices (microdialysis)
Kpu,u?
Defined as the ratio of unbound drug concentration in the brain and the blood.
Better measure of brain pentration
Kpu,u <> 1?
Then something other than passive diffusion is taking place
What ensures no paracellular transport occurs between the blood brain barrier?
Specialised tight junctions.
Important to protect ionic concentrations in CNS
Function of the blood brain barrier?
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
Strucutre of the tight junctions?
aS6
Two layers of blockage.
Prevents molecules from passing
P-glycoprotein (P-gp)
Endothelial cells contain transporters that actively pump molecules back out to prevent transcellular permeation.
Saptially localised only on the apical side of the cell.
How does P-gp work?
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
Measuring P-gp activity?
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
Apical side?
the layer of plasma membrane on the apical side (the side toward the lumen) of the epithelial cells in a body tube or cavity.
Measuring CNS penetration?
CSF sampling.
Minimal barrier between CSF and ISF- therefore concentration in CSF= ISF
Drawbacks to CSF sampling?
Equilibration is slow.
Innacurate when active transport is occuring.
Positron Emission?
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
PET imaging?
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
Applications of PET?
CNS penetration
Gives an indication that some compound gets into the brain.
Demonstrating recptor engagement by displacement.
Localising regions of brain.
Apply PET to drugs?
Make the drug radioactive
Can see how much gets into the brain
