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Professor Mark Saltzman: So, this week we're going
to talk about drug delivery, this is Chapter 14.
This is an example of what I call in the textbook
Biomolecular Engineering. This is one of my favorite
weeks of the course because this is my research specialty,
is drug delivery. What I want to do today,
Thursday, and then we'll continue in section is today I'm
going to sort of set up the problem,
talk about some definitions to think about, if one is building
drug delivery systems, think about some basic concepts
in drug delivery. We're going to do that by
thinking about sort of common modes of drug administration and
why some of them work with some drugs and not with others,
sort of lay the foundations today.
Then, on Thursday we'll talk about what's new in drug
delivery and what things you can expect in the future,
things that are still being built and then you'll get to
make some drug delivery systems in section on Thursday
afternoon. This is really a logical
extension of what we started talking about last week when we
moved from talking about the immune system and how it
operates to administration intentionally of vaccines to
alter the immune system or to change your body's response.
In some senses, you could think about delivery
of a vaccine like delivery of a drug or introducing something
not naturally in the body--into the body in order to have some
kind of biological effect. It's the same thing as delivery
of a drug. And we also thought about
delivery in a variety of ways: we thought about injection of
vaccines like the smallpox vaccine,
we thought about oral administration of vaccine,
in the case of the oral polio vaccine.
So, I just wanted to show you this picture to remind you that
you already know something about drug delivery.
What we're going to talk about is an extension of what we
started talking about last week. Now, in the case of a
vaccine, you'll remember, that the intent was to
administer either proteins, usually proteins or whole
viruses, or we talked at the end of the class on Thursday about
administering DNA with the intention that you're going to
bring some new molecules into a special class of cells called
antigen presenting cells. That those antigen presenting
cells are going to be changed as a result of their experience
with this vaccine such that they present new molecules on their
surface, that's the change that comes
about. Then, that change in this cell
is going to stimulate changes in other cells.
If humoral immune response or antibody mediated immune
response is generated, then the change in antigen
presenting cells is going to influence B-cells to
differentiate and proliferate, etc.
This is an example of a very particular example of what
happens when you administer a drug as well.
Chemicals are introduced into the body, the intent is usually
to make some kind of a biochemical change in cells or
maybe many cells in your body such that they're function is
altered in some way that's helpful to you.
We didn't really talk about it last week, but in some cases
immunization really is like drug delivery.
Particularly, in the case of what's called
passive immunization, where instead of introducing a
pathogen or a piece of a pathogen to an individual you
actually make antibodies outside of the individual.
So, manufacture them in some ways, and we talked about ways
of manufacturing antibodies a few weeks ago.
Then introduce those antibodies themselves into the person to
provide protection against whatever pathogen those
antibodies are directed against. If any of you have traveled
to areas of the world where Hepatitis A is common,
in parts of Asia for example, you might have gotten a shot of
gamma globulin which is really just antibodies that are
enriched for anti-Hepatitis A activity.
Now, the difference between that and a vaccine is that that
dose of antibodies only lasts for a certain length of time,
about 30 to 60 days. So, you have to get the shot 30
to 60 days before you're going to be in the area where you're
exposed. The same way we're going to
think a lot about the timing of drugs, how long do their effects
last, what determines how long they
last, and what does it mean if you still need the drug when its
effect is gone, how does taking subsequent
quantities of the drug effect its concentration in your body,
for example. I'm going to start with
some definitions and I realize that you can read this on your
own. Hopefully you already have read
some of this in the chapter, but just to make sure that we
have the vocabulary right, and some of these are words
that you're familiar with like drug.
A drug is any molecule which can be introduced into the body,
which alters body function on a molecular level.
You're used to thinking about drugs you might take for a
headache like aspirin or Ibuprofen.
Or if you asthma, for example,
you might take drugs that affect your bronchioles or the
pathways--the airways in your lung by dilating them so it's
easier to get air in and out. These are molecules which are
introduced into the body; they make some kind of change
in the body on a molecular level.
Pharmacology is the science of dealing with these
interactions of molecules that are introduced into the body.
They're usually molecules that are generated from outside the
body, maybe synthesized in some way.
They might be molecules that are not ordinarily found in our
bodies, but are known to have some effects.
They might be derivatives of molecules that are naturally
found in our bodies. For example,
Parkinson's disease is treated by a derivative of the
neurotransmitter Dopamine. You're introducing something
that looks very much like a natural molecule back into the
body to have an effect. Toxicology is that branch
of pharmacology that thinks exclusively about toxic effects
of the drug. One of the main challenges with
developing drugs and drug delivery systems is that drugs
have unwanted effects. They have the effect that you
desire at the tissue or within the cells that they were
designed to affect, but they can also effects in
other parts of the body and those effects are side-effects.
Those effects are toxicities or unwanted changes in the body as
a result of the drug. We're going to talk about
two important different but related concepts called
pharmacodynamics and pharmacokinetics.
Pharmacodynamics is the effect of a drug on a body and it's
usually on the body or on cells from the body.
It's usually defined by a dose-response curve.
Dose response means I give a certain amount of the drug and I
see what effect it has. I give more,
I see what effect that has, I give more I see what effect
that has. You can imagine that's a very
important thing to define for any drug because you want to
deliver the minimum dose that's needed to produce the desired
effect. You don't want to introduce any
more than necessary. So, understanding the
relationship between dose delivered and biological
response is very important. Often that's done first on
cells in culture, for example.
You want to understand how a chemotherapy agent,
a potential agent for treating tumors will affect tumors in a
person. The first thing you do is you
might have cultured tumor cells and you expose those cells to
different concentrations of the drug and you see at what dose do
I begin to see cell death or killing of the tumor cells.
That's one kind of dose response relationship.
Now, you could understand, probably, that that might be
very different if you administer that same dose into a person.
We're going to talk about why dose responses in people are
different than dose responses in cell cultures,
or in more artificial systems. The pharmacodynamic effect
of a drug, or the study of pharmacodynamics,
is 'what does the drug do to the body?
' Usually that's defined at specific doses,
what does it do. Pharmacokinetics has to do with
how your body handles the drug. The body has exquisite
mechanisms for getting rid of molecules.
Molecules that are produced naturally in your body only have
a certain lifetime. Likewise, antibodies that
we--molecules that we introduced from outside the body also have
a lifetime, and that depends on the
mechanism that your body uses to get rid of the compound.
Well, that manner in which the body handles a drug,
how the body changes the drug, how it excretes the drug is
called pharmacokinetics and that has to do with what the body
does to the drug, not what the drug does to the
body. That's the easiest way to think
about it. One pharmacokinetic concept
that's very important is the concept of bioavailability.
If I have a dose of the drug, let's say 100 milligrams of a
drug, and I administer it to an individual,
then how much of that drug actually gets into the body
where it can be useful? Bioavailability is going to
depend on how we administer the drug.
If we administer it orally versus inject it intravenously,
versus some of the other routes of administration we'll talk
about in a few minutes. The main effect of changing the
route of administration is to change the bioavailability or
how much of the drug actually reaches the active sites.
A related concept is biotransformation.
Biotransformation refers to all the mechanisms that your body
could use to convert a drug into something else.
Often, that conversion of a drug into something else is an
important part of how your body gets rid of a drug.
Many biotransformation reactions happen in the liver.
The liver is a very active site of metabolism and chemical
reaction. Many drugs that we take are
converted into other compounds in the liver,
by cells in the liver. Often, this conversion into
another compound is the first step in your body getting rid of
it; sometimes it's the only step.
Sometimes your liver is able to convert a molecule into
something that's completely inactive.
For example, if you take alcohol,
which is a drug, it's converted in the liver
into other molecules which don't have the biological effect of
alcohol. It's done by enzymes in liver
cells, including the enzyme alcohol dehydrogenase.
Sometimes--we won't talk so much about this but I want you
to at least realize it, is that sometimes we deliver
molecules that are inactive but don't have any response.
Your body doesn't have any response to them,
but we deliver them knowing that your liver is going to
convert them into something active,
that they're going to be biotransformed by some chemical
reaction into an active compound.
So, it's another aspect of biotransformation.
I want to spend the next 15 or 20 minutes or so talking
about how drugs are administered.
In particular, that question should be why are
they administered in different ways?
Why is Ibuprofen taken orally, for example,
but some antibiotics or chemotherapy drugs have to be
injected directly into the bloodstream.
Why is that do you think? Why are some drugs administered
in different ways?
It could be that you're targeting different parts of the
body and so you want to deliver them at their site of action,
that might be one reason to do it.
There what are you changing? You're changing the potential
for side-effects really, or the potential for toxicity
of the drug. If you can deliver more at the
site of action then less of it goes to the rest of the body
where it might cause unwanted effects,
so that's a very good reason to target it.
Student: [inaudible]Professor Mark
Saltzman: Sometimes there are biological barriers to drugs
entering different parts of the body.
We're going to start by talking about the body as sort of a
single unit or compartment. When I introduce drugs into
them those drugs are available everywhere, but that's not true.
There are some parts of the body that are protected from
entry of drugs, and the brain is the most
famous of those parts of the body that are protected.
It makes sense that the brain is protected,
because the function of the brain depends on the balance of
chemical concentrations within it,
the concentrations of ions and neurotransmitters,
and any molecules that could potentially interfere with ions
or neurotransmitters. Our brain chemistry has to be
very tightly regulated in order for us to stay awake and pay
attention and do the things that we normally do.
In contrast, the chemistry in our blood is
changing throughout the day. After you eat chemistry changes
because molecules are absorbed from the intestine,
and as those molecules get processed by the body
concentration in the blood changes.
If your brain chemistry was changing in that same way,
then you'd be slipping in and out of consciousness and you
notice that you do a little bit right after lunch.
It's a little bit harder to pay attention than before lunch
because the chemistry is changing,
but that change in chemistry is muted by the blood brain barrier
or the fact that molecules can't get very easily into the brain.
Why else might drugs be administered in different ways?
Think about insulin, what do you know about insulin
as a drug?
Student: [inaudible]Professor Mark
Saltzman: Speed of action is an important thing and we're
going to talk in a few minutes about some drugs where onset of
action is very important. It needs to act very quickly
and the way that you administer it has as big effect on how
rapidly concentrations in the body rise.
So, some things you need to act very rapidly,
you'll pick the mode of administration to do that.
There's another issue with insulin which we'll come too,
keep that one in mind. This is a table that's in
the book and I want to go through it relatively quickly
because I think you can read it and it's pretty understandable
on its own. I want to use these specific
examples of different routes of administration to think about
the answer to this question,' why are drugs administered in
different ways? ' More importantly,
to think about the biology or the physiology of your body that
leads to these alternate forms of administration.
One mode is intravenous injection and we're going to
talk --there are different kinds of injection.
You can put a needle into different parts of the body.
You can put it into a muscle, you can put it under the skin,
you can put it actually into the spinal fluid that surrounds
your spinal cord. Intravenous injection refers
specifically to a needle that's placed within the
bloodstream--within a vein, and so drugs are introduced
directly into the bloodstream. The advantages of that should
be obvious. That's what was related to
Caitlin's comment, that drug is immediately
introduced into the blood, and so it's immediately
distributed throughout your body and available for action
wherever it's needed. So, onset of action is very
rapid. In addition,
its bioavailability is 100%. We've introduced the drug into
the blood directly, into your circulatory flow,
so all of the molecules that are administered to the patient
are available for action. Now, usually we think about
bioavailability as the fraction of the drug that ends up in the
blood and you might say, 'well but that might not be
where the drug acts'. The drug might act in the brain
or it might act in the kidney, or it might act in your muscles
and being in the blood is not the same as being in those
tissues, and you're right.
It's hard to measure those concentrations in individual
tissues and so we define bioavailability as the fraction
of a drug dose that gets into the blood.
Now, why wouldn't we do intravenous administration for
everything? Because if it is fast,
usually you don't want to wait for--you want the drug to act as
rapidly as possible and you'd like all the drug molecules to
be bioavailable, you would like all of them to
be useful. So, why don't we use
intravenous administration all the time?
Well, it probably is obvious that not--that it's not so easy
to do. That in general,
safe intravenous administration requires trained medical
personnel. So, usually you're in a
doctor's office or a hospital, you don't do it yourself at
home. There is a risk because you're
introducing drugs at high concentration into the blood.
There's much more risk of overdose or toxicity because the
concentration's going to change very rapidly.
Even though you might know what the average response to a drug
is, average among a population of people,
we're all different in ways that are important to how drugs
act. You know this,
if you take Ibuprofen, you read the dosage on the
label, it will say something like 'if you're over 12 years
old you take one dose and if you're under 12 you take another
dose.' So, size of the person or age
of the person is an important determinant of how much dose you
take. Gender is often an important
determinant, your overall state of health is an important
determinant, and you can't know those things for everybody.
You could go on and on in this list and so you--one individual
might be more sensitive to doses of the drug than another.
If you're introducing all the drug at one time intravenously
the potential for an unwanted response is higher.
It's a risk of infection because you're introducing
something directly into the bloodstream if it's not done
properly, and it's not comfortable.
Most people don't want to have an intravenous injection.
So, you might not do it in cases where even if it would
benefit you, and so those are disadvantages.
It's a very safe and effective, and useful mode of
administration for some kinds of compounds.
For example, for antibiotics,
if you happen to have what's called sepsis or an infection
that's spread into your bloodstream,
one of the only ways to combat those infections effectively is
to introduce antibiotics directly into the bloodstream.
Intravenous infusion is a similar mode,
but now instead of a onetime injection,
with an intravenous injection you have a syringe full of drug,
a needle in the circulatory system,
and you introduce the drug all at once, in infusion you slowly
pump the drug in and you might be pumping it in continuously
over a long period time, maybe over hours or over days.
Sometimes this is done--you've seen on TV shows a bag of a
solution hanging up on a pole and a tube going into a
patient's arm. So, this is an infusion where
the infusion is driven by the gravity flow of fluid through
the tube into the patient's blood vessel,
that's one example of an infusion.
Other examples are there might be pump involved at some
point. You have a pump in between the
bag of fluid and the needle that goes into the arm.
In this way, you can control the flow much
more carefully.
One example of where that's done in the hospital is the
molecule Heparin, which is an anticoagulant.
It's needed for certain patients who are at risk of
having blood clots, for example.
This might be--they might be at risk for blood clots for a
variety of reasons, but you introduce the molecule
Heparin which reduces the likelihood that clots will form,
only you need to have a continuous level of Heparin.
You need to have that Heparin concentration continuously at
some level, and so you continuously infuse it directly
into the circulatory system. Now, this is a very effective
method for administering drugs because you're slowly adding the
drug and you're watching to see what concentration is maintained
in the person, and you're adjusting the rate
by tuning the pump until you get exactly the concentration that
you want. You can leave it there and as
long as the patient stays roughly the same,
then their concentration will remain roughly the same.
So, you can expose them to a drug over a long period of time
and have a biological effect that's constant over a long
period of time. That's very useful in certain
situations like this one I've mentioned.
Again, it's 100% bioavailable and you have
continuous control over plasma levels.
For example, what if you knew that the
patient was more at risk of developing blood clots at night?
Well, then you'd put a programmable pump on it,
and you'd program the pump so that the rate of infusion
increased during the night and then went down again in the
morning. In that way you could increase
the concentration of drug at night and then decrease it
during the day. So, you'd only be using the
amount of drug that was needed for a biological effect and
you'd be adjusting that biological effect for the needs
of the patient in a very sort of interactive way.
You can imagine, now, extending that very simple
approach with a needle in the bloodstream and a pump,
and a reservoir of fluid to deliver any pattern of drug that
was needed for that individual. Why isn't that done all the
time? Well, for the same reasons the
intravenous infusion aren't done all the time,
plus some, because this is even more complex,
right? So it requires continuous
monitoring and so there have to be people there in case there is
some unexpected event in order to turn off the pump or to
adjust the flow. So, that really requires
hospitalization in most cases. Now, we're going to get to the
point next time where we talk about some examples of infusion
using pumps that can be worn by individuals that can leave the
hospital with these pumps either implanted within them or
strapped to their belt, for example.
In general, that's done only in unusual situations.
Subcutaneous injection and intramuscular injection are
similar to intravenous injection in that it's an injection from a
needle. It's a onetime introduce the
drug all at once, but you're putting the needle
in a different place. Instead of intentionally
putting the needle into a vein so that you introduce drug into
the blood, you put it either in a muscle,
like a muscle mass of your arm, or your back side.
Have you ever had an injection there?
They don't do this so commonly anymore, I'm not sure why.
I can imagine why but--into a muscle mass and then the
molecules are absorbed from that muscle into the blood or
subcutaneously--is subcutaneous, cutaneous is skin,
sub is under, this is an injection under the
skin. So, you could pull up on your
skin a little flap, you can sort of pull it away
from the muscle and you'd insert the needle under there and
introduce a little reservoir of drug solution underneath the
skin. Now, this is how diabetics
administer insulin to themselves, usually.
They put a needle into the muscle and they inject a volume
of an insulin-containing solution into the muscle space.
I say on this sheet here that bioavailability in that case is
usually high, why is it--who do you think
bioavailability is high for these particular modes?
Why is it high for intramuscular injection?
It might be 80% or 90%, so it's not 100% but it's
pretty high, why is that?
How does the drug get into the blood from there if I inject it
into muscle?
Justin?Student: [inaudible]Professor Mark
Saltzman: Yeah, so your muscle is being
perfused by blood all the time. It gets blood flow,
there's arteries going in, capillary networks,
and veins that are collecting blood so there's a very rich
blood supply in muscle. So, you inject it into the
muscle tissue and the drug just sort of percolates in or
diffuses into the blood vessels that are already there.
Now, the effects tend to last longer than an intravenous
administration because it takes some time for the drugs to move
from this reservoir where you've injected them,
this little depot in the muscle, it takes some time for
the drugs to move into your bloodstream.
So, you get a prolonged effect because of that;
not all the drug is available at once.
You also don't get all the drug in because some of it is
metabolized locally or it doesn't go into the blood
vessels at all and so it doesn't get distributed.
So, bioavailabilities not 100% but it's often pretty high.
It's not as hazardous because you're not actually introducing
a needle into a vein. It can be done by individuals
at home and so diabetics can do this;
they can do it several times a day.
It's still uncomfortable, most people don't want to do it
and you wouldn't do it if there was an alternative.
Why is there no alternative for insulin?
Why do diabetics do it this way? Why do they inject insulin in
this way? I think most of you can
understand that they would prefer not to,
what would they prefer to do? If you were a diabetic patient
and you needed insulin what would you prefer to do?
Kate?Student: Orally.Professor Mark
Saltzman: You'd prefer to take a pill, right?
You prefer to take a pill and that's the next one on the list,
is oral administration. You prefer to take a pill but
you can't with insulin because insulin is a protein.
Insulin is a protein that is digested in the intestinal
tract. That's one of the functions of
our gut, is to digest foods that we eat, foods that contain
proteins for example. So, your intestinal system is
very efficient at breaking down proteins into their constituent
amino acids, and it does that so that you
can extract amino acids from food and use them for other
things. If a protein is a drug,
you need it to enter the bloodstream without being broken
down. When it's broken down it
doesn't have the effect any longer.
So, insulin can't be delivered orally, primarily because it's
digested within the stomach and small intestine before it's
absorbed. Another problem with developing
a pill or oral forms of insulin is that large molecules like
insulin, which is a protein,
has a molecule weight of about 5,000 are not absorbed very
easily through the intestinal wall.
We talked about this several weeks ago, your intestinal wall
is a--it's a tube that the surface of the tube is made up
of a continuous sheet or monolayer of cells and these
cells are connected by tight junctions.
Remember that picture I showed you several weeks ago?
Because of that for a molecule to enter it has to be able to go
through that monolayer of cells. Even if insulin wasn't broken
down to its constituent molecules it couldn't be
absorbed very easily because it's a large molecule.
Only molecules that are small and relatively lipid soluble can
go through monolayers of cells like the epithelium of the
intestine. There's two reasons why insulin
is not very bioavailable when it's given orally.
That's one way of saying insulin doesn't end up in the
blood, insulin is not bioavailable when delivered
orally. Some drugs are aspirin,
acetaminophen, Ibuprofen, things that you
might take routinely for muscle aches or headaches are available
orally. They're small molecules,
they aren't digested appreciably or only a fraction
of them are digested so that if you take ten milligrams,
maybe five milligrams of them are not broken down in the gut
and can be absorbed. One of the problems with oral
administration is that drugs are degraded before they're absorbed
into the body. Now, we could tolerate that
with aspirin, and why do you think that's
acceptable with aspirin to have some fraction of it broken down
in the body--broken down in the gut before it's absorbed?
Why is that acceptable?
How much does aspirin cost? Student:
[inaudible]Professor Mark Saltzman: Not very much,
you don't think about it when you go buy a couple of tablets
of aspirin, you go buy a bottle of aspirin
or Ibuprofen because it costs something but it doesn't cost so
much. So, if you had to pay two times
as much because you lost half of it, because it was degraded
before it got absorbed, that might be okay.
You're more likely to use it because it's a pill and not an
injection and you're willing to pay more for that convenience.
Often, drugs that are orally administered,
they're not 100% bioavailable, only a fraction of it gets into
your blood, but they're molecules that can
be produced cheaply enough that you can still take a dose that's
larger than what you would need, knowing that half of it is not
going to enter your body. Does that make sense?
The other thing about aspirin is that it's not--I'll
use aspirin as an example, realizing that nobody uses
aspirin for headaches anymore, but it's a good example because
it's a molecule that's very safe.
A safe drug is one in which the concentration at which it causes
toxic effects is much higher than the concentration at which
it causes good effects, or the effect that you want.
We know in aspirin that if you get your concentration up to a
certain level your headache will go away.
You'd have to get a much higher level in your blood before you
began to see side effects or unwanted effects.
In aspirin those side effects are that your ears start to ring
because it starts to effect the--your mechanisms of hearing,
the cells within your cochlear start to be affected by
concentrations of the drug at a certain level.
You have to take a lot in order to get up there.
This difference between an effective dose and a toxic dose
is very important for drugs. Drugs that have a big
difference between the safe dose and the effective dose are ones
that you can give to patients and trust them to take safely.
You could imagine if the toxic dose was very close to the
effective dose that might not be a drug that you would want to
have patients administering themselves because what if they
accidentally take one too many pills,
or they take them too close together, they could produce
toxic side effects. Aspirin is an example where you
have a big window between effective and toxic.
Chemotherapy drugs are drugs where there's a very narrow
window between effective and toxic and so those are usually
given with the help and guidance of a physician.
There's a similar mode of administration called sublingual
or buckle. Here, the drug is not
swallowed, it's taken in the mouth but it's--but you hold the
pill or the capsule underneath your tongue and you allow it to
dissolve there. So, the drug enters your body
because it's absorbed through the membranes in your mouth,
particularly the membranes under your tongue.
This is a common mode of administration for
nitroglycerin. If you have grandparents or
friends who are older that have certain kind of heart disease
where they get chest pain, they might carry with them
tablets of nitroglycerin. If they begin to experience
pain they'll put one of these tablets underneath their tongue
and they'll let it dissolve. There's a number of reasons
for doing this. The most important one is that
when you're taking a drug orally, you're taking advantage
of the mechanisms that your body has for getting food and
nutrients, and you're using those
mechanisms to get a drug. When molecules are absorbed
through your intestine, they go through the intestinal
wall, they enter the bloodstream that surrounds the intestine.
Then, the way that your anatomy is set up all of the blood flow
from your intestine goes directly to your liver and from
your liver it goes back into the vena cava and then to the heart.
Now, why would you design a system like that,
where all the blood from your intestine goes right to your
liver first? Justin?Student:
[inaudible]Professor Mark Saltzman: Purifying and
processing of the stuff that comes from the intestine,
stuff like food, nutrients that are extracted
from food, sugars, fats, proteins that are
extracted from food that go to your liver.
Why do they go to your liver? Because your liver is a very
important metabolic organ and it is important for processing
proteins and fats, and sugars.
So, by sending all those molecules that are absorbed from
the intestine to the liver first,
you get a jump start on processing of these molecules
into the substrates that you need for life.
That's a really good set up for nutrition, but I also mentioned,
remember that biotransformation or breakdown of drugs often
occurs in the liver. So, if drugs are absorbed the
same way that food is they go right to the liver,
and--I'm pointing here because that's where my liver is,
they go right to the liver and your liver starts to break it
down right away before it even gets to your bloodstream really,
before it circulates to the rest of your body.
I lose a fraction of drug because it's degraded within the
gut, I lose a fraction because it can't absorb very rapidly,
and I lose another fraction because the liver breaks it down
before it ever gets back to my heart and then your heart can
circulate it. Well, it turns out that the
blood supply to the membranes in your mouth don't go to the
liver, it's unusual. They go directly into the
superior vena cava and into your heart.
So, drug molecules that are absorbed in your mouth bypass
the liver and they go directly to your--the rest of your body
first. Then of course they're going to
end up in the liver as things get circulated around.
They avoid going to the liver the first time and that's
called, here on this graph, avoiding first-pass metabolism
in the liver. This metabolism that occurs on
the first shot right from the intestine is called first-pass
metabolism. Nitroglycerin would be very
readily broken down in the liver.
So this way it goes directly to the heart without ever having to
pass through the liver and it can quickly treat heart disease.
Now, why don't you do that with all sorts of things?
Well, it only works for certain kinds of compounds,
compounds that can be absorbed through those membranes in your
mouth so they have to very lipid soluble.
They also have to be very potent because one difference
between your mouth and the intestine is that the surface
area in your mouth is fairly small.
Only a limited number of drugs can absorb through,
whereas--why is your intestine so long?
You know that your intestinal--you took it out and
stretched it out it would be a tube, a continuous tube,
that's about 30 feet long. Why is your intestine that
long, packed into this small space?
So that it can have a big surface area to absorb lots of
stuff; big surface area--lots of
absorption, small surface area--little absorption.
It has to be a very potent drug in order to be absorbed at a
sufficient concentration through this limited space.
I think those are the main concepts that I wanted to
introduce by thinking about these different methods of
administration. There's more of them listed
here, some of them have to do with what Caitlin mentioned.
If you want a drug that works in the eye, for example,
a drug to treat glaucoma, why take a drug orally and
expose your whole body to the drug when you could just put
drops in your eye directly? And that's how many glaucoma
drugs are delivered? You might have eye drops that
you just put into the space underneath your eye,
for example, and that's a more targeted
delivery. Targeted because you are
putting the drug at the site where it's needed.
I'm sure you have examples of that;
topical ointments like antibacterial cream you might
put on something if you have a cut and you want to keep it from
being infected. You don't take antibiotics by
mouth and have them all over your body, you put a little
topical treatment on the site because you're targeting the
drug to the site that you need.
On the next slide there's some other more uncommon modes
of administration, ***, transdermal,
vaginal. We won't talk very much about
those, and next week we'll talk about special kinds of drug
delivery systems that are useful for certain kinds of
administration like what are called controlled release
implants, we'll talk about next time.
I want--I've given you a lot of words and I've tried to
introduce a lot of concepts by thinking about things that you
know about. I want to try to put this in
some framework that allows you to think about quantitatively
what it means--what these factors mean.
We're going to introduce drugs into a patient and what we would
like to know is how rapidly do those drugs become available,
what fraction of the drugs become available,
and how long does the one dose we give last?
As I mentioned, that's complicated,
complicated because our anatomy is complicated,
and complicated because we're all different individuals and
our anatomy and physiology differs.
So, it's a hard thing to, do to describe how even one
particular kind of drug acts in a population of people is
difficult. We have to start somewhere
so we're going to start with a simplification.
That simplification is that these complex
things--people--can be represented by very simple
constructs. The simple construct that I
show here is that instead of a person we're going to consider
the person to be a well stirred vat of liquid,
water for example. Now, how can you get away with
that? Well, one to say you can get
away with it is that we are mostly water,
our bodies are 90% water and so if you wanted to describe us
sort of in the simplest possible way we're water,
that's largely what we are. We're structured water with a
particular kind of shape and form, but we're largely water.
We could describe where drugs go in the body by just
thinking about how they dissolve in water.
All you'd need to know is, 'What's the volume of the
water?' So, if I give a dose what
concentration do you get, I give ten milligrams.
If your volume is five liters, what's the concentration you
achieve inside? What did I say?
Ten milligrams? I forgot what number I said
now, ten milligrams divided by five liters, two milligrams per
liter. That's the concentration and
that's the simplest way to define it.
Now, how can I get away with saying that we're well-stirred?
I indicate that in this simple drawing by having a--this is a
propeller that's stirring the vat of liquid,
how can I get away with saying we're well-stirred?
Well, in some senses we are, that's what our circulatory
system does, and I'm going to talk about that in the weeks to
come, but our heart is a very
effective--our heart and our blood vessels are a very
effective system for distributing molecules very
rapidly throughout a large volume and so we are stirred--we
are well-stirred in certain senses.
Now, you could object to this simple model for lots of
different reasons but we're going to start with it because
it's a very simple place to start.
We're going to say then when we administer a drug we're
introducing a drug into this well stirred vat of water that
has a particular volume. We're going to administer some
dose and we're going to produce some concentration.
Now, what happens afterwards? Does that concentration stay
the same forever? No, it doesn't because we--our
body has mechanisms for getting rid of drugs.
We're going to describe that in our simple model by having an
arrow pointing out that tells you how--that tells you that
drugs are eliminated when they're within your body.
We're going to make this a very simple process also and say
that drugs are eliminated in proportion to their
concentration.
The more drug you have the faster it gets eliminated,
and as you have less and less drug it gets eliminated more
slowly. Now, this--the simplest way to
describe this is to say that the rate of disappearance of a drug
is equal to some constant times the concentration.
The rate of disappearance of a drug is equal to some constant
times the concentration. This constant is called a rate
constant and this is the concentration that would be
within the body. This is a first-order equation.
Means that the rate at which the drug is eliminated is
proportional to concentration to the first-power or linear with
concentration. As drug concentration goes
down, since k is a constant for any particular
drug. It's one number,
as the concentration drops from two milligrams per liter to one
milligram per liter, the rate that your body
eliminates it goes down by half as well.
I like to think about this as you could think about
concentration as money in your wallet,
and the rate at which I spend money anyway is proportional to
the amount that I have in my wallet;
when I have more I spend more, when I have less I spend less,
and the last dollar goes really slowly.
The same thing here, when you have a lot of
concentration your body gets rid of it fast, but the last
molecules go out very slowly. If we take this simple model
and then apply it, and we introduce a dose
directly into the body, now this well-stirred vat,
and we say that it has some volume and we say that drug is
eliminated with some rate constant k,
we could derive a simple equation.
This is derived in the book, in the box at the back of the
chapter, that would tell us how concentration varies with time
and that equation is shown here. The concentration is equal to
the dose that I introduced which is M_0 divided
by the volume of the body, times e^(-kt),
where k is this rate constant for disappearance of
the drug; C = (M_0/V)*
e^(-kt). Now, if you don't
understand when you look at the book where this equation comes
from, that's not important.
Some of you will and some of you won't, but you could trust
me that this is the equation that results from those simple
assumptions that I talked about. C is the concentration
that's available in your bloodstream or in this vat of
fluid, that's available for action.
M_0 is the amount that's introduced,
and remember I introduced it in a special way,
I injected it right into the body.
I injected it all into the body, the whole dose at time
t equals 0. I introduced it all into the
body at once so it was all available to circulate.
That assumes the bioavailability is 100% and that
I've introduced it all at one particular time.
What is this really a representation of?
It's a representation of intravenous injection where I
have syringe and I inject all of the drug at once.
In that case, what this equation tells you is
that the concentration immediately after you inject the
drug is the highest, and after that it continually
goes down. It goes down in an exponential
fashion with a time course that depends on this constant
k. Does that make sense?
If I have intravenous administration of a drug that's
eliminated by a first-order process, as soon as I administer
it, the concentration is a peak. After that it goes down and the
rate at which it goes down depends on this rate constant
k. What I also show you here is
that if I plugged into this equation I asked the question,
'When does the concentration go down by a factor of two,
when does it go down by 50%?' I would look on this graph here
and say 50% of the drug is gone by this time.
I could calculate that time at which the drug concentration
goes down by half and that's equal to the ln(2/k),
this rate constant here, so when this number is smaller
the half life is longer. Molecules with a high
k are eliminated rapidly; molecules with a low k
are eliminated slowly. That half-life is a good
measure of how long the drug activity lasts in your body;
it's a good way of thinking about how long I'd have to wait
before I needed another dose, for example.
What this graph shows you here is just plotted on a semi-log
plot. The difference between these
curbs, if I had drugs with different half-life,
a drug with a half-life of 600 minutes last a long time;
concentration doesn't drop until a long time,
it has many, many hours.
If it has a half-life of 60 minutes, concentration drops to
10% of its initial level after a few hours.
If I have a drug with the half-life of six minutes
concentration drops to 10% of its initial level after only a
few minutes. So, we're going to take this
model and extend it next time and talk about more complicated
modes of administration and talk about sort of new forms of drug
delivery, forms that you can expect to
see in the next few years.