Welcome to Pharmacology by Lecturio.
We're going to cover today a strange disease
called pulmonary hypertension.
It's not terribly common but I think it's
important that you know how the drugs that
treat it work.
Pulmonary hypertension just briefly is an
elevated blood pressure within the pulmonary
circulation, not the systemic circulation.
It is associated with shortness of breath,
It can be associated with peripheral edema
because you have an elevated right
ventricular and diastolic pressure, and it
can be associated with some
tachycardia. We have several methods of
We have the calcium channel blockers, we
have some vasoactive prostaglandins, we have
some vasoactive endothelin antagonists, we
type 5 inhibitors, and we have guanylate
activators. So, we have several different
types of treatment available
for this particular disease.
The first group that we'll talk about are
the calcium channel blockers.
Remember these are exactly the same drugs
that you see in hypertension so the
names are the same, the method of activity
is the same.
Unfortunately, we started to see an
increased mortality in our pulmonary
hypertension patients who were treated with
CCBs because we weren't choosing our
Only 5% of pulmonary hypertension patients
Half of them do not respond long term in
general to these
agents, with respect to pulmonary
hypertension, so, we have to be careful who
we give them to.
Now, there's no mortality studies per se to
support its use
so we have to be aware as well, that the
science doesn't support the use of
CCBs in pulmonary hypertension.
That's not to say that some of the pulmonary
hypertension specialist aren't using it, it's
just to say that the science isn't as
Now, we move onto the prostaglandins.
Essentially, we're talking about
prostacyclin or prostaglandin I2.
These are the different types of agents that
use prostaglandin I2
for the therapies.
They come under different types of
therapies, and they come under different
names, and they come under different
But bottom line, they're all prostacyclin.th
The solution is clear with a
pH of 10 which makes it kind of interesting
from a pharmacology point of view.
Remember that if you're administering this
agent and the solution is cloudy, you should
be suspect that there's something wrong with
the particular agent.
The effect is reversed after about 25
There is no evidence of platelet dysfunction
even though prostacyclin is associated with
platelet activity control.
And finally, the side effects associated
with this particular agent includes flushing;
sometimes, you can get a headache because of
vasodilation of cerebral arteries, and
low blood pressure or hypotension because of
Now, if you look back to our lecture on
inflammation, you saw me go
through this very complicated graphic which
has all this different
complex molecules associated with the
I just want to focus on one part of this and
we're going to simplify this graph just to
talk about prostaglandin I2.
So, let's take a look at the root product,
sorry, the root of the
production of prostaglandins.
We'll start out with the phospholipids.
Now, diacylglycerol or phospholipids are
converted into arachidonic acid,
either using phospholipase C or
The arachidonic acid is then converted into
H2. So, what enzyme converts arachidonic
Prostaglandin H2 synthase.
We also make prostaglandin D2.
And what enzyme makes prostaglandin D2?
Prostaglandin D Synthase.
We have prostaglandin E2.
What enzyme makes prostaglandin E2?
Similarly, we have prostaglandin F2, made
by, you guessed it, prostaglandin F
synthase. I'm not even gonna put it on the
chart here, but we also have
prostacyclin synthase that takes
prostaglandin H2 and makes
prostacyclin. Now prostacyclin and
prostaglandin I2 are named the same
thing, so to some people won't call it
prostaglandin synthase, they'll call it
PGI2 synthase, doesn't matter.
The point being is that you make
prostacyclin or PGI2 from
PGH2. Now, in the tissues, in the
convert the prostacyclin into PGF 1 alpha,
6-keto version of that.
So, this is the thing that's important for
our disease state.
This is the area we're going to focus on.
The other part of it is just to give you an
idea of where it fits into the
armamentarium of treatment.
The next category of drugs are the
endothelin receptor antagonists.
The first of these were called Bosentan that
were introduced early in the 2000s.
We have other agents that have come on to
the market since then.
These caused vasodilation directly at the
level of the endothelin.
But unfortunately, because they are
affecting the way the blood is flowing
through various organs including the
placenta, we don't like to give this to
pregnant women. They are competitive
antagonists of endothelin receptors,
ET-A and ET-B.
They are substrates of two major enzyme
First of all, the cytochrome system, types
3A4 and 2C9 so think
cyclosporine in this case.
You will have an interaction with a lot of
drugs because you are using the same
pathway of breakdown as probably 60% of the
drugs that are on the market.
So, be very aware of drug interactions when
you're using this product.
The other thing that is a concern when
you're using this medication is something
called OATP. This is a type of
that is in the liver that is used to get rid
of the drug from the body.
Remember that other drugs that go through
this same system can have
interactions with the endothelin receptor
There's not a lot of them out there but just
be aware that that can happen.
Another category of drugs used to treat
pulmonary hypertension are
phosphodiesterase type 5 inhibitors.
Now, you may be familiar with these drugs
already because they're used in erectile
dysfunction. The prototypical drug is
Sildafenil which is also sold
as Viagra for erectile dysfunction.
There are many other names that this is sold
under for erectile dysfunction but it's
also sold as a different name drug for
There are new analogs that have also come
onto the market as well.
This has a relatively long half-life and as
you are probably well-aware, it is an oral
medication, which makes it convenient.
Side effects including those side effects
that are associated with vasodilation
so headache; sometimes you can get nausea;
GI symptoms can occur as well like
diarrhea; you can get backpain from this
Other vasoactive type of side effects can
include flushing, and myalgias,
and you can also get a dyspepsia through an
How does this drug work?
The mechanism of action is actually quite
Remember that PDE5 is associated with cyclic
degradation. If you inhibit cyclic GMP
you have more cGMP available in the myocyte.
If you have more cGMP, you have vasodilation
of media within the blood vessel.
The next category of drugs used to treat
pulmonary hypertension are the
guanylate cyclase activators.
Now, the mechanism of action is kind of
You start off with a soluble GC.
It is the intracellular messenger for nitric
These drugs stimulate the soluble GC to do
You end up having an increased biosynthesis
of cyclic GMP, so you
have more cyclic GMP in the system.
This causes an altered intracellular calcium
flow into the
cell, so it changes the actin-myosin
contractility in the cell
and you end up with vasodilation.
So, increasing amounts of cyclic GMP caused
calcium; decreasing intracellular calcium
actin-myocin interaction and therefore, you
have more vasodilation.
We have two major drugs within this
One of them, Riociguat, acts independently
of nitric oxide and it
also increases the activity of the nitric
oxide guanylate cyclase
complex. So, to accentuate this Riociguat
can work in
concert with Nitric oxide to produce
antiproliferative effects, and the
Okay, so, let's go through how this works in
the real world.
You have two major enzyme systems.
The black part is the lumen of the blood
vessels so the inside of the blood vessel;
and surrounding the lumen is the endothelial
cells or the endothelium.
Inside the endothelium, you'll have the
nitric oxide system or synthase.
The smooth muscle cell is where the
guanylate cyclase is.
So here you have, NOS or nitric oxide
sometimes we call it eNOS because it's
endothelial or endothelium
nitric oxide synthase.
And here in the muscle you have the
guanylate cyclase which we were talking
about. Now, if you have a stimulus within
lumen, it can stimulate the nitric oxide
So, L-arginine which will be converted into
nitric oxide will
act on guanylate cyclase within the muscle
of the blood vessel to convert GTP into
GMP. Cyclic GMP causes that
system to relax, so that's how you end up
eNOS system to cause vasodilation.
So, when we look at the two drugs in this
category, I mentioned the first one, I
mentioned the second one first.
Now, let's talk about that first one.
Cinaciguat directly stimulates guanylate
cyclase without going through the eNOS
system. Riociguat has a dual mode of action.
It increases the activity of the nitric
oxide guanylate cyclase complex and that
increases cyclic GMP within the tunica media
or the muscle layer of the blood
vessel, and it also directly stimulates
guanylate cyclase independent of nitric