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 called angiotensinogen.
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 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 -pril.
So, anything that's a -pril, is generally an ACE inhibitor.
The angiotensin receptor blockers end in -sartan.
So, there's candesartan, eprosartan.
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 sold 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 4th line drug.
The direct renin inhibitors are actually very good
antihypertensives, and in particular,
they are good in a special kind of hypertension called
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 improvement 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.
In some cases, we think that perhaps in severe heart failure
or nephrotic proteinuria, we may want to combine it,
but major studies have shown that people
generally don't do well combining these medications.
I would recommend, in clinical practice,
if you're going to be combining these drugs,
that you enlist the help of a nephrologist
before you do that.
ACEi's and ARBs are often combined with a diuretic. And we
prefer hydrochlorothiazide as our agent of choice because
hydrochlorothiazide causes a low potassium and ACEi's and
ARBs cause a 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.
In terms of using the direct renin inhibitors in combination,
the initial thought was was that we would always be using
aliskiren in combination with an ACE. This probably
won't be happening that much in the future because
we started to see problems in some of the studies
when we use combination therapy.
So, this idea has really fallen out of favour,
perhaps in the last six or seven months.
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 inhibitors 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.