Welcome to pharmacology by Lecturio. Todays lecture is going
to focus on the control of cholesterol and other lipids.
I'm Dr. Pravin Shukle. Let's start our lecture by taking a
look at how we control lipid in humans. We have several classes
of drugs. The first and oldest class of drugs are the bile
acid sequestrants. These are sometimes called resins by
the pharmacists. Another class of drugs include niacin and
the fibrates. The third class of drugs includes the
HMG-CoA reductase inhibitors, commonly called statins. The
fourth class of drug is ezetimibe, a single drug in that class.
The fat absorption inhibitors. And finally the PCSK9 inhibitors,
a new kind of treatment using immune modulation to control cholesterol.
We also have another class of drugs called the MTP inhibitors
that are not yet available for use but will be by the time
that you listen to this lecture. Have a look at all of the
drug classes. Let's start off with the bile acid sequestrants.
Now the bile acid sequestrants depend on the circulation of
cholesterol in and out of the cell. There are several key
components that we want to learn about. There are the HMG-CoA
reductase inhibitors that are working inside the cell.
The resins are working outside the cell or outside the
hepatocyte. The gut is portrayed at the top of the screen
and the blood is portrayed at the bottom of the screen. Let's
talk about the resins. The resins are going to block uptake
of cholesterol from the gut. Remember that 92% of bile acids
are reabsorbed normally. If you lose bile acids,
bile acids being made from cholesterol, you are going to
have lower levels of cholesterol that are reabsorbed.
Resins prevent the reabsorption of bile acids. Now the liver
is forced to make more bile acids to account for the lost.
So the liver uses intracellular cholesterol to make up for
that. Now what ends up happening is it sucks up more
of the LDL from the blood to use as fuel. This is how LDL
levels drop when we use resins. There is a mild reduction
in LDL levels when you are using a resin. You may also increase
your triglyceride and very low density lipoproteins in familial
hypertriglyceridemia and familial hypercholesterolemia. Let's
take a look at how niacin works now. Now take a look down
at the bottom of the cell you can see niacin in green. Niacin
is going to reduce VLDL synthesis. It also has a secondary
reduction in LDL, and it also reduces the breakdown or
catabolism of HDL. In the capillary endothelium, you have
increased VLDL clearance. This reduces your plasma
triglycerides. In adipose tissue, niacin will reduce
lipase activity. This reduces plasma free fatty acids and
triglycerides. And in terms of a secondary effect in the
hemostatic system, niacin or Niaspan will reduce fibrinogen
and TPA. This is a side effect known from Niaspan and I
encourage you to take a look at the hematological pharmacology
lectures to get a good idea of what is happening there.
Let's talk about fibrates. Fibrates are commonly gemfibrozil
and fenofibrate. These are the two most common.
There are some other that are out on the market but you
should know these two. Now there is a molecule called
PPAR-alpha. Peroxisome-activated receptor, the alpha type.
Now, PPAR-alpha has a couple of jobs. It increases gene
expression of ApoA-I,-II and ApoC-III. And these molecules,
these apoproteins are responsible for increasing HDL
levels in the blood. It also increases gene expression for
lipoprotein lipase. Now lipoprotein lipase clears triglycerides
at the endothelium. And it will also increase the oxidation
of free fatty acids within the hepatocyte. So, the fibrates
are a lot more complicated than most people think. We
generally say that it binds cholesterol. That's not actually
true. There is a real metabolic change that's occuring in the
cell because of these agents. In terms of the uses of fibrates
they are used to treat hypertriglyceridemia. There is a
tremendous worry about toxicity with these medications
especially when we use them in combination with statins, and
i'll explain that in a minute. One of the downsides of these
fibrates is that they may actually increase LDL and i'll
explain that too. A common side effect systemically is rash.
You can also have an increased white blood cell count and you
can potentiate anticoagulants. So this is the hemostatic issue
that I was talking about. In terms of increase in white blood
cells, almost all patients seem to experience some rise
in their white counts when they take a fibrate. And this is not
a reason to stop the drug, it's just a reason to keep an eye on it.
I receive several consults a month asking me why the white
counts are so high when patients are on fibrates.
And I just tell them you know what, I tell the referring
doctor don't worry about it, just keep an eye on it,
make sure it doesn't get out of hand.
The risk of myopathy is discussed later.