Let's move to the HMG-CoA reductase. Now, HMG-CoA reductase
block a step in the conversion of HMG-CoA to cholesterol.
So competitive inhibition of the HMG-CoA reductase enzyme is
how we get the name statins, because it stops this enzyme.
Now most of the effects are due to LDL receptor expression.
What do I mean by that? Well, let's think of it this way.
Everytime you want to catch a LDL particle from the blood to
be used internally by the hepatocyte, you have to have a little
baseball glove on the surface of the cell. That baseball
glove catches the baseball which is the LDL particle.
Now the baseball glove which is the LDL receptor and the
baseball which is the LDL, get internalized into the cell
and get broken down in the cell. Normally the LDL receptor
is protected from being broken down and it goes back up
to the surface, but every now and then one of them are clipped
together with the baseball and they all get broken down.
So, that means that the cell has this intrinsic way of making
sure that the LDL receptors aren't too old. Now when you have
HMG-CoA reductase inhibitors, you're blocking intracellular
cholesterol production. So the cell, now has to rely on
external cholesterol in the LDL particles. So it starts making
more and more LDL receptors or more and more baseball gloves
to catch more and more baseballs because it's not making it's
own cholesterol. And that's how you get a reduction of LDL
cholesterol with an HMG-CoA reductase inhibitor. Now there is
a couple of secondary beneficial effects of the statins.
We call this pleotrophic effects. So, there is some wonderful things that happened because of the statins.
First of all, it actually may prevent bone loss suprisingly.
We know that it has some anti-inflammatory effects both systemically
and with respect to the generation of sclerotic lesions in
the vasculature. Now, this is above and beyond it's effect on
LDL. So we think there might be a direct anti-inflammatory
effect as well as the anti-cholesterol effect in terms of
atherosclerosis. We think that statins may even be protective
against contrast nephropathy, which is a bit of a suprise.
Now, the toxicity behind these agents include a mild elevation
of the CK values. You might get a mild transaminitis.
How mild is mild? Anything under 8 times the upper limit of
normal is acceptable. Anything above that is concerning.
Anything that shows more than 2 times the upper limmit of
normal is enough for me to be monitoring them at least once a
month. Now here is where we become a little bit concerned
and here's is where all the press around statins occur.
There is a potentially fatal reaction on patients who take
both statins and fibrates. Now this was first discovered
on a statin called cerivastatin also called Baycol. And
another fibrate called gemfibrozil. We noted that people were
getting very bad rhabdomyolysis and very bad tissue muscle
necrosis because of these combination drugs. Now, as time has
gone by, we've discovered that the newer generation of statins
are far less likely to cause this reaction and fenofibrate is
less likely to cause it than gemfibrozil. Right now if you are
taking a look at rosuvastatin and fenofibrate together, the risk
is in the 1 in 1000000 range. Now, you may also get some kind
of reactions like this with niacin as well. Remember that statins
are broken down by the 3A4 isoenzyme of cytochrome P450. So
that means that it's gonna have a lot of drug interactions
including grapefruit juice and bitter oranges on marmalade.
So going back to cerivastatin, it was withdrawn from the market
due to that rhabdomyolysis that I had been talking about. The
first generation of statins are lovastatin and simvastatin,
and these are introduced into the body in their drugs as
prodrugs and then they are metabolized into active agents.
There is an increased number of drug reactions with these
medications. You can see that those first agents have a
relatively poor reduction in LDL. In terms of fluvastatin
which is Lescol, atorvastatin which is known as Lipitor,
and rosuvastatin which is known as Crestor they are far more
effective in terms of cholesterol reduction and they have
fewer drug reactions. Now if you look at this graph carefully,
please note that the 60% reduction is at the bottom of the y-axis,
and the 0% reduction is at the top of the y-axis. So the lower
the graph line, the better the drug is. And you can see that
atorvastatin and rosuvastatin are probably the most potent
and most effective drugs on the market today. The important
points about statins. First of all, statin effects is mostly
due to increased LDL receptor expression. It is not because
of the reduction of internal cholesterol synthesis on it's
own, it's because of LDL receptor expression that we see
the changes. Normal LDL receptors are required for statins
to work. So if you have a theoretical disease where the LDL
receptor is defective, the statins not going to work. And
that's what happens with some types of homozygous familial
hypercholesterolemia because it is often a disease of
dysfunctional LDL receptors. And so we see that in this specific
disease, the statins don't work that well. So that's why it's
important to understand the mechanism of why it's working,
as opposed to just the mechanism itself. Let's move on to
ezetimibe. Ezetimibe is a prodrug and it undergoes glucuronidation
in the liver to become active. It inhibits cholesterol
transport or the cholesterol transporter. It prevents
absorption of dietary cholesterol into the hepatocyte. There
is a reactive increase in the LDL receptors which also helps
reduce the cholesterol. So on it's own ezetimibe isn't that
incredibly powerful. You're only gonna get about a 20% reduction
in cholesterol values but it is remarkably free of side effects.
It is very well tolerated. And it works beautifully in combination
with statins to give us a huge cholesterol reduction when we
use statin and ezetimibe together. In fact, there are some
products available in different countries that combine
ezetimibe and one of the statins in one pill.
In terms of the uses of ezetimibe, we use it to treat
hypercholesterolemia which makes sense.
As I've said before you're gonna get about a 20% reduction
using it on it's own, and a 25-30% additional LDL reduction,
when you add it on to a statin. Now listen, that sound like
very little but actually it's a lot. Consider this.
When you go from 5mg to 10mg of rosuvastatin, you
are only going to get a 6% additional reduction.
When you go from 10 to 20 of rosuvastatin, you get a 6%
additional reduction. And when you go from 20 to 40,
6% additional reduction. So getting a 25 to 30% add-on
reduction to a statin, that's huge. That's like quadrupling
or sometimes increasing the dose eight-fold to get the same
kind of reduction just from statin increases. That's why
using low dose statins or single dose ezetrol is actually more
effective than doubling or tripling the dose of statin.
We also can use ezetimibe in the treatment of phytosterolemia
which is an unusual disorder that you can look up on your own.
The toxicity is quite well tolerated. In fact it's better
tolerated than most medications. It may increase the
hepatotoxicity of most statins but that has been more of a
theoretical concern than a real concern. It is sold as
ezetrol in the United States and it is sold as a combination
with simvastatin as Vytorin in the United States.
I prefer using ezetrol in combination with rosuvastatin as
individual pills because rosuvastatin gives you so much more
reduction. Simvastatin is a drug that I no longer use when I
can avoid it because simvastatin has 80% of it's breakdown
going through cytochrome P450-3A4, whereas rosuvastatin does
not use 3A4 and so there is less concern about drug interaction.