Now that you have some familiarity with

drugs as chemicals and as molecules, we're

going to discuss the important topic of
how drugs do enter the nervous system.
We'll begin with our four drugs from
the previous session, and we'll talk about
nicotine.
nicotine, as you know can enter the body
by being smoked in tobacco cigarettes,
pipes, cigars.
It can also enter
through the mucous membranes of the mouth
by being chewed as
tobacco leaves or by being chewed as gum
for smoking cessation.
It can also be placed into skin patches,
and with a suitable solvent, it
can then pass through the skin and
enter the bloodstream for smoking
cessation purposes.
So, there are various routes for nicotine
to enter the body.
Lidocaine, the local anesthetic, is mostly
used as
an injected form, although it can also be
placed in creams, where it enters the body
for local relief, for instance in sunburn
creams.
Morphine can enter the body by being
smoked.
Opium leaves, by being injected for
analgesic or for anesthesia, or
for sedation.
And morphine can also be placed in
suppositories where it's quite effective.
And finally, Botulinum toxin, our protein
drug, for
drug purposes cosmetic purposes, is
usually injected locally.
when it is a poison having been, having
grown
in food it is usually eaten.
So these are a few routes into the body
for our drugs.
But let's look in detail about the events
that occur once a drug gets into the body.
We'll talk about it, typical alkaloid, for
instance, and in this case, the alkaloid
has a general other group, and it in
addition, it has an amine in this example.
It has a primary amine.
Now, perhaps the most important concept in
drug ent, entry into the brain is the fact
that neutral molecules often pass through
membranes, lipids, fats, by diffusion.
They are quite soluble in these fatty and
oily compartments.
And so they go right through.
However, the neutral molecule is usually
not the pharmacologically active form.

The active form, the form that acts on

the receptor, is usually the protonated
charged form.
And there's an equilibrium between the
neutral and the charged form.
This equilibrium occurs in the brain, and
it also occurs in other compartments of
the body.
So the concept that a drug acts in a
charged form, but permeates
in a neutral form, is quite important for
most of, drugs and the brain.
now, in some cases, we can move the
equilibrium toward the charged form,
toward the permeate form with higher PH.
And I'll show you an example of that,
in our next slide.
Moving to the specific
case of nicotine's path from the lungs to
the blood and the brain.
When a person takes a puff on the
cigarette, which happens about 150 billion
times a day in the world, vaporized
nicotine enters the lungs.
we then watch nicotine passing through six
cell membranes made up of three cells.
One of
those cells is the endothelium of the
alveolar epithelium.
And two other cells, as we'll see in a few
slides, are in the capillary in the brain.
So nicotine passes through those six cell
membranes and then enters the brain.
This doesn't take long, as any smoker
knows it take just a few seconds for
nicotine to get to the brain.
In the brain again, nicotine can be
protonated,
can gain a proton, can gain a positive
charge.
And it is this positively charged form
of nicotine that interacts with the
receptors.
The pKa, the pH at which roughly
half the nicotine is protonated and half
deprotonated,
is around eight.
The pH of extracellular fluid is around
7.4 so
that means that most of the nicotine in
the brain is in the charged form.
But again, this inter-conversion takes
just a millisecond or so.
Now, this inter-conversion can also occur
in the lungs.
Most cigarette, and cigarette
manufacturers know this.
And so, most cigarettes also contain
ammonium hydroxide,
to maintain neutral pH, or a bit basic.

As a result, in the lungs, or in the the

mouth, the nicotine is forced into
more of the uncharged permeate form, and
can permeate a, a bit more easily.
So this is the example of Nicotine,
obviously
a crucial one for drugs and the brain.
as a result, the concentration of Nicotine
reaches a spike within just a few seconds.
It's probably faster than indicated in
these data from 10 or 15 years years ago.
And then, Nicotine is metabolized by
enzymes, mostly in the
liver over the next 20 minutes to a couple
of hours.
And the result is that the Nicotine
concentration in the blood falls
to a steady state level between
cigarettes.
So here we have an example of the
pharmacokinetics of Nicotine.
Another example of drug permeation comes
to us from therapy for Parkinson's
Disease.
In Parkinson's Disease, al, as we'll learn
later on, most
of the neurons that make Dopamine in the
brain die.
And so the challenge is to replace
the Dopamine in the brain.
However, Dopamine itself does not cross
the blood brain barrier, does not go from
the blood into the brain, it's charged,
and therefore we need another tactic.
The tactic is to use L-dopa, or Levodopa,
which is
a derivative of Dopamine that does
permeate through the blood brain barrier.
The way it permeates is not by being non
polar.
It is indeed neutral, but it's still
fairly polar.
It is zwitterionic because it has both the
charged amine group and the charged
carboxyl group.
Instead the way Dopamine enters the brain,
is by being
transported by a specific protein that
lives in cell membranes.
Once it gets into the brain, an
enzyme which is a catalytic protein,
decarboxylates L-dopa.
Turns it into Dopamine which can then be
taken
up into dopaminergic neurons, and released
by dopaminergic neurons.
So, this is an example, if you like, of a
pro-drug.
a drug that turns into another drug
because

it is modified in the body.

What about this blood brain barrier?
We've talked about it.
Let's look at it in a bit more detail.
Outside the brain, a capillary is, has
connective tissue around it, but
it also has a layer of cells called
endothelial cells, outside the brain.
There are gaps between the endothelial
cells,
allowing various types of molecules to
diffuse
across the connective tissue into the
fluid outside the capillary.
Proteins can diffuse.
Non-polar moleucles can diffuse.
Polar molecules such as glucose can also
diffuse out of the capillary.
In the brain however there are no
spaces between the endothelial cells In
the capillaries.
There are capillaries of course, there are
endothelial cells,
but they have this structure called the
tight junction connecting them.
As a result proteins can't diffuse out of
the
capillary, polar molecules cannot diffuse
out of the capillary.
Non polar molecules can diffuse the way
nicotine does through the endothelial cell
membrane and, and into the brain.
So the brain has a specialized barrier
that prevents drugs from entering.
Another view of the blood brain barrier
emphasizes a
group of cells called the glial, or glue
cells.
Glial cells are not neurons.
There are, a large number of them in the
brain.
They send processes out that surround the
capillaries.
These are the glial feet.
It used to be thought
that the feet come closely together and
provide the blood brain barrier.
But now we know that, in fact, it's the
tight
junctions, between the endothelial cells
that cause the blood brain barrier.
Protects many drugs from diffusing out of
the capillary into the brain.
Again we have the tight junctions between
the endothelial cells.
Well what is this tight junction?
It is the structural basis of the blood
brain barrier.
And you could think of the tight junction
as a waterproof zipper.

These are individual protein molecules

that interact with each
other and hold the cell membranes of 2
adjacent cells
together in the capillaries of the brain.
So if we have the extra cellular space for
instance, in the blood here at the top,
the extracellular space in the brain here
at the bottom.
The tight junctions provide a continuity,
a seal, between cells, so that most small
molecules cannot diffuse through them.
So that's the structural basis of the
blood brain barrier.
Well, we've discussed drugs in the body
and in neurons at the organ system level.
We've talked about acid base equilibrium
and
permeability, uptake from the stomach,
uptake from smoke.
We've spent a little time on
a more reductionist level talking about
pro-drugs.
in later lectures, we'll talk about the
storage of drugs, more about
the enzymatic breakdown of drugs, and
about other
ways of breaking down drugs and finally,
elimination.
So, this topic would be called
pharmacokinetics.
We've talked about the blood in more
reductionist detail.
We've talked about the blood-brain
barrier.
Its molecular basis.
obviously the blood brain barrier is an
opportunity
for making specific drugs that don't enter
the brain.
But it's also a real problem if one wants
to make drugs that do enter the brain.
more reductionist still, we have mentioned
crossing the cell membrane.
And there are drugs that actually help
other
drugs, or prevent other drugs from calling
cell membranes.
We'll talk about neurotransmitter
transport inhibitors
in a later lecture.
And finally, a topic that's not usually
discussed in a neuropharmacology course, I
call subcellular pharmacokinetics.
we'll discuss drugs that short-circuit
synaptic
vesicles, allowing transmitters to leave
those vesicles.
And we'll also talk about pharmacological
chaperoning,

that takes place in the endoplasmic

reticulum.
That topic that I call inside-out
pharmacology.
So these are topics that we're going to
emphasize in later sessions.
But for now, let's get to the topic
of proteins and drug receptors in our next
session.