Okay. Let's move on to RAAS agents,
the renin angiotensin aldosterone pathway.
So, let's take a look at how the pathway works.
We start off with the prohormone
In the kidney, renin converts
angiotensinogen into angiotensin I.
And it is then converted by the angiotensin
converting enzyme into angiotensin II.
Now, ACE inhibitors will
block this particular enzyme.
And when that happens, you
will have less angiotensin II.
Now, the other thing that happens
with this agent is that when you block
the conversion of angiotensin
I into angiotensin II,
you're also similarly blocking
the breakdown of bradykinins.
Now, bradykinins are things that you don't
really want in the body because they can
cause cough and these other
symptoms that I've got listed here.
So, ACE inhibitors cause cough because
they also inhibit the breakdown of bradykinin.
Let's get back to angiotensin II.
You notice on the end of our slide
there, on the far end of our slide,
we also have non-ACE pathways.
So there is still some conversion
of angiotensin I into angiotensin II
even if you blocked the ACE
enzyme with an ACE inhibitor.
This brings us down to the angiotensin receptor.
So, we have angiotensin receptor blockers.
And what we want to do is we want
to block the production of aldosterone.
Now remember that aldosterone
has lots of effects on the body.
It decreases water and sodium excretion,
and it will actually cause a higher blood pressure.
So, by giving a drug that blocks the conversion of
angiotensin II into
into the various aldosterone
molecules, it's going to be very important
so that's why we block it with the ARB.
Now remember, I already mentioned that
spironolactone is an aldosterone blocker,
it blocks it right at the receptor site
so it's a very effective agent as well.
But the downside is, is that for
using an ACE inhibitor or an ARB,
we're not going to be using
spironolactone for the specific reason
that we don't want the potassium to go too high.
The new direct renin inhibitors.
There's only one drug in
this drug class called aliskiren,
acts directly at the level of renin to
prevent this whole cascade from occuring.
Now, let's go over the different
groups of drugs in this class.
So, the ACE inhibitors are listed here.
This is actually, believe
it or not, only a partial list,
but these are the most commonly used drugs.
The prototypical drug is captopril, the
one I also want you to remember is enalapril.
And quite frankly, in clinical
practice I use neither now,
but for the purposes of exams, those
are the ones that you want to remember.
ACE inhibitors, if you
noticed, end in P-R-I-L, -pril.
So, anything that's a -pril,
is generally an ACE inhibitor.
The angiotensin receptor blockers end in -sartan.
So, there's candesartan, eprosartan, irbesartan.
The prototypical drug is actually losartan,
but if you remember any of them, you'll be fine.
The direct renin inhibitors
or renin inhibitors is aliskiren.
It's sold as Rasilez in well pretty
much everywhere in the world.
It's a sole drug, it is going to be
important to know for your exam
and we'll talk about its clinical use in a minute.
And then finally, the aldosterone
antagonists like spironolactone,
they fall into two categories.
I mentioned them already in
the diuretic section of our lecture,
but I also mention it here because
it is technically a RAAS drug as well.
Let's compare the two major groups
of renin angiotensin aldosterone drugs.
Let's compare ACE inhibitors
head to head to the ARBs.
First of all, let's just say that both classes of
drugs are really fantastic antihypertensive agents.
And in my books, I think they are the first
class of drugs that you would want to choose.
In guidelines, whether they are the
British guidelines, the Canadian guidelines
or the American guidelines, we talk about
having several classes as first line agents.
But in practicality, most people
go to one of these two agents first.
In many many studies, they have been shown
to be beneficial, both in morbidity and mortality.
That includes heart failure, microvascular
disease which includes retinopathy and nephropathy,
as well as left ventricular hypertrophy
reduction, and even stroke reduction
through it's blood pressure actions.
So, let's talk about the side
effects from these medications.
Hyperkalemia is a common side effect with ACE
inhibitors, about 1 in 100 patients will develop it.
It's slightly less with the angiotensin
receptor blockers at 0.3 %.
A cough is quite common in ACE inhibitor patients.
The studies will tell you it's
anywhere between 2 and 20%.
I personally believe that that's
underestimating the numbers.
The ARBs will tell you that the
cough rates are around 0.001 %.
I personally have never seen a credible
case of cough brought about by ARBs.
So the ARBs are clearly superior in
terms of cough, and in many cases
when a patient comes in complaining of
cough on an ACE, we put him on an ARB.
Pancreatitis, depending on
what region of the world you're in,
the rates are about 1 in 5,000, so
guaranteed you will see one in your practice.
The pancreatitis rates with
ARBs is about 1 in 15,000.
Now, if you have a patient who's on an
ACE inhibitor, and they develop pancreatitis,
should you put them on an ARB?
The answer is no, because now, that ARB patient
has a 1 in 10 risk of developing pancreatitis.
And that's just simply too high.
At that point, I would use a
different type of blood pressure drug.
Angioedema is another potential
risk factor with both drugs.
Angioedema's risk factor are around
1 in 2,000 with the ACE inhibitors,
depending on what study you're looking at.
And with the ARBs, we get numbers
roughly around 10 times less or 1 in 20,000.
Once again, if you develop
angioedema on an ACE inhibitor,
I generally don't recommend that you use
an ARB, try using a different class of drug.
Going on to the aldosterone
antagonists and the direct renin inhibitors,
the aldosterone antagonists
are poor antihypertensive agents,
but we still use it quite a bit as a fourth line
The direct renin inhibitors are
actually very good antihypertensives,
and in particular, they are good
in a special kind of hypertension
called hyperreninemic hypertension.
In large scale studies, we've actually shown
mortality reduction and morbidity reduction,
especially in heart failure.
The direct renin inhibitors have
small scale studies and pilot studies
showing improvement in heart failure
or projected improvements in heart failure.
In terms of side effects, hyperkalemia is rare.
Side effects of diarrhea are often
seen with the direct renin inhibitors.
Remember that you do get feminizing characteristics
because it has an antiandrogen activity.
This is actually used as an advantage
in many women who have hirsutism,
and one of the side effects with the
direct renin inhibitors is potential headache,
although that potential risk is kind of small.
Let's move on to principles
of therapy using RAAS drugs.
We do not combine ACE inhibitors and ARBs.
ACEis and ARBs are often combined with a diuretic.
And we prefer hydrochlorothiazide
as our agent of choice
because hydrochlorothiazide causes a low
potassium and ACEis and ARBs causes high potassium
and they seem to balance out.
ACEi's and ARBs are often combined
with a calcium channel blocker as well.
They are particularly potent in this
combination and in fact, in the United States,
and in other regions of the world,
you can purchase pills that have
an ACE inhibitor and a calcium channel blocker,
or an ARB and a calcium
channel blocker, all in one tablet.
ARBs are much better tolerated
in most patient populations.
And quite frankly, they're more likely
to be taken long term by your patients.
A major study done in Canada showed that
ARB compliance at two years was about 80%,
whereas ACE inhibitor compliance was about
40% in the same patient population at the same time.
So, ARBs tend to be taken by the patients,
on a more regular basis, for a longer time.