Welcome to pharmacology by Lecturio.
Today, we’re gonna talk about the control of cholesterol using our pharmacological agents.
When we take a look at the different types of agents that we use in lipid control there are several groups.
First of all, we have the bile acid sequestrants, these are also known as resins.
We have a drug called niacin which works in a slightly different way.
We have fibrates, we have HMG-CoA reductase inhibitors.
We have a drug called ezetimibe, which is a drug alone in its class.
We have some fat absorption inhibitors.
We have the newer PCSK9 inhibitors which are generally monoclonal antibody therapies
and we have the very, very new MTP inhibitors.
I have not mentioned the CETP inhibitors
because they haven’t been particularly useful in real world practice so I’m going to skip them.
There you have it. These are the effective medications in lipid control.
Now when we take a look at a human cell,
we can see that there’s several points of activity to try and reduce cholesterol biosynthesis.
We have, at the top of this image, the gut.
Then we have the luminal membrane of the cells and below we have blood.
Now, let’s start off with the resins, the first category.
These include drugs like cholestyramine and colestipol.
Ninety two percent of bile acids are reabsorbed from the gut in over the course of the normal day.
Resins prevent that reabsorption.
The liver needs to make more bile acids to make up for the lack of bile acids that the cell is resorbing
and it needs to use up cholesterol to do so as a fuel and as a substrate.
So what ends up happening is that the cell recept, the cell expresses more LDL receptors
and it sucks up LDL receptors out of the blood into the cell
and uses it as fuel to make more bile acids.
The net effect of using these resins is a mild LDL reduction.
You may however increase triglyceride and VLDL levels in certain diseases states
like familial hypercholesterolemia and familial hypertriglyceridemia.
Another agent is niacin which works within the cell to reduce VLDL synthesis
or very low-density lipoproteins.
There is a secondary reduction when you do this and that reduces the LDL levels.
This also reduces the catabolism or breakdown of HDL so theoretically,
this should be a really good drug theoretically
because not only is it reducing the atherogenic particles VLDL and LDL,
but it is improving or increasing the antiatherogenic particle HDL.
Unfortunately, it hasn’t really born out in real world practice.
Now in terms of the capillary, endothelium and its effect,
we have increased VLDL clearance as well and we have reduced plasma triglycerides.
In terms of its effect on adipose tissue, it reduces lipase activity at the adipose tissue
and it reduces plasma free fatty acids and triglyceride levels.
In terms of Niaspan’s effect on the hemostatic system, it reduces fibrinogen
and it also reduces TPA.
Other fibrates include gemfibrozil and fenofibrate.
These are agents that are working through special molecule
called PPAR alpha allows for increased gene expression of two molecules ApoA-I, ApoA-II
and may also increase gene expression of ApoC-III - these all increase HDL levels.
When you have increased gene expression for lipoprotein lipase
to help clear triglyceride at the level of the endothelium
and you increase free fatty oxidation in the liver
you end up having improved overall profiles of the different lipids.
In terms of its uses we use it to treat hypertriglyceridemia. In terms of its toxicity,
unfortunately, you may see an increase in LDL; you may see rashes -
so patients will complain of a rash after taking it.
You may see a slight elevation in your white blood cell count
and there is a concern about potentiating some of the anticoagulants through an unknown mechanism.
We may also see an increase risk of myopathy.
Now in terms of the medications both niacin and the fibrates,
we’ve been honestly a little bit disappointed in their real-world significance.
Niacins trials have really failed for the most part so its use has really fallen off.
That isn’t to say that it’s a useless drug - I’m not suggesting that at all.
I’m just saying that we haven’t been as impressed by the results in clinical trials as we would like.
Fibrates haven’t really had great mortality data, so where do fibrates fall in the treatment spectrum?
Well, certainly we still use fibrates for the treatment of hyper triglyceridemia
and it’s going to be an important tool in our tool box.
Remember that prolonged hypertriglyceridemia,
particularly when its severe can increase the risk of pancreatitis over and above your risk
for cardiovascular disease - so it is an important treatment for preventing pancreatitis.
Okay, that’s the brief overview on lipid pharmacology.
I hope that you found this useful.
Go out, write your exam, show them what you know.