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E: Neuropsychopharmacology > Delivering drugs to the CNS > Flashcards

Delivering drugs to the CNS Flashcards

1
Q

Name the two catagories of CNS diseases?

A
  1. Neurodegenerative
  2. Psychiatric
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2
Q

Biodistribution of Oral Drugs?

A

Absorbed into the gut.

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

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3
Q

Pharmacokinetics?

A

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

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4
Q

Brain: blood partitioning

A

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

Ratio between them is described as Kp

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5
Q

Kp>1?

A

Means higher concentration in the brain than the blood

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6
Q

KP<1?

A

Means lower concentration in the brain than the blood

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7
Q

Testing receptor occupancy assay?

A

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

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8
Q

Equlibration?

A

Two compartments

Passive diffusion until they are at equal concentrations.

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9
Q

Paracellular?

A

Passive

Selective variable and regulated

eg. tight junctions.

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10
Q

Transcellular?

A

More hydrophobic compouds can pass

Plus active transport

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11
Q

Permeability?

A

Rate at which compound crosses membrane.

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

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12
Q

What can slow permeability have an effect on?

A

It can limit exposure to tissues

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

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13
Q

Content of media?

A

Affects compound potency.

serum free media to 100% plasma

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14
Q

Free drug hypothesis?

A

Binding to plasma proteins limits biological activity.

Also binding to membrane, lipids etc limit this too

Pharmacological activity is dependent on ‘free drug’.

AS5

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15
Q

Calculation for the potency?

A

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

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16
Q

Equation for fraction of drug bound?

A

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

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17
Q

Fractional binding is affected?

A

By the concentration of proteins not the concentration of drug

18
Q

Equation for the affinity?

A

([protein]/Fb)-[protein]

19
Q

What concentration in serum albumin present in the plasma

A

600uM

Must higher than most drugs

20
Q

Fractionaion of drug bound is only used if?

A

Concentration of protein is higher than the concentration of drug

21
Q

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

A

TD2-(Dt+Tt+Kd)TD+Tt.Dt=0

22
Q

Paritioning is affected by?

A

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

23
Q

Pathway to the brain?

A

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.

24
Q

Brain ISF?

Differences to plasma?

A

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

25
Q

How to measure unbound fraction in brain tissue?

A
  1. Brain homogenates (equlibrium dialysis)
  2. Brain slices (microdialysis)
26
Q

Kpu,u?

A

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

Better measure of brain pentration

27
Q

Kpu,u <> 1?

A

Then something other than passive diffusion is taking place

28
Q

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

A

Specialised tight junctions.

Important to protect ionic concentrations in CNS

29
Q

Function of the blood brain barrier?

A

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

30
Q

Strucutre of the tight junctions?

A

aS6

Two layers of blockage.

Prevents molecules from passing

31
Q

P-glycoprotein (P-gp)

A

Endothelial cells contain transporters that actively pump molecules back out to prevent transcellular permeation.

Saptially localised only on the apical side of the cell.

32
Q

How does P-gp work?

A

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

33
Q

Measuring P-gp activity?

A

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

34
Q

Apical side?

A

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

35
Q

Measuring CNS penetration?

A

CSF sampling.

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

36
Q

Drawbacks to CSF sampling?

A

Equilibration is slow.

Innacurate when active transport is occuring.

37
Q

Positron Emission?

A

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

38
Q

PET imaging?

A

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

39
Q

Applications of PET?

A

CNS penetration

Gives an indication that some compound gets into the brain.

Demonstrating recptor engagement by displacement.

Localising regions of brain.

40
Q

Apply PET to drugs?

A

Make the drug radioactive

Can see how much gets into the brain

E: Neuropsychopharmacology (9 decks)

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