December 8, 2022

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Hello my name is lindsay clemons and we’re going to be talking today about a tourist statin or lipitor the brand name so why do we have a need for a tourist statin so a tourist statin is a drug that lowers blood cholesterol and so around 95 million us adults aged 28 years old and older have total cholesterol levels higher than 200 milligrams per deck later now

The average total cholesterol level that you want to have to be healthy is 130 milligrams and so 200 is about twice as much and so that is quite a few people i have twice as much cholesterol as they need so levels of high ldl cholesterol in particular is linked to increase cardiovascular disease risk which is the leading cause of death in the u.s. now what is ldl

Cholesterol so ldl stands for low density lipoprotein and this is just a type of lipoprotein that we have in our body we have five different kinds but the two that you are most familiar with would be ldl which we associate with bad cholesterol and then hdl which we associate with good cholesterol and hdl stands for high density lipoproteins but in fact high-density

Lipoproteins are linked to a decrease in atherosclerosis and what asked atherosclerosis is is a buildup of plaque in the arteries and this also contributes to stroke as well as cardiovascular disease and stroke is the fifth leading cause of death in the u.s. so we want basically low levels of ldl and higher levels of hdl if we can get them there so taurus patent

What it does is it lowers the levels of ldl cholesterol and triglycerides in the blood and triglycerides also contribute to a thickening of arterial walls which can also lead to atherosclerosis as well so what is the cause of cardiovascular disease when it’s cholesterol based so in the beginning we have our endothelial cells in the arterial wall and these have been

Stressed mostly they’re going to be in the curves of the arteries because those are where you get the most stress mechanical stress and so then when it’s stressed like that ldl is recruited and is put underneath its sub endo dermal in the cells and then what happens after that these lipoproteins have been retained here what happens is that the library proteins are

Modified by oxidation vacation or enzymatically and then this activates the endothelial cells so after that you have increased expression of the monocytes here and so then this leads to the attachment transmigration of the monocytes monocytes then become macrophages they differentiate into macrophages the macrophages then uptake the lipids that have been aggregated

In here and then from there they become foam cells and so these foam cells are basically what the plaque is for atherosclerosis and so this is the initiation of forming that plaque and actually once you have these foam cells the inflammatory signaling pathway is activated and this leads to more cell recruitment and ldl modification and so it’s kind of a positive

Feedback loop in that way so how does atorvastatin help exactly so what a tourist statin is is a competitive inhibitor of the hmg co-reductase so what does that mean so when you have the cholesterol pathway you’re going from acetyl co a here and then you’re going all the way to cholesterol and that’s more than 20 different individual steps so what a tourist aten

Does is it inhibits this step right here it inhibits the reductase and so this is actually the rate limiting step in this pathway and you can either call it thee in the validate pathway or you could say it’s the cholesterol pathway so this pathway synthesizes more than just cholesterol so it’s good that it’s not a complete inhibitor but what atorvastatin also

Does is even though you would think it’s inhibiting the cholesterol at the end it’s doing that but actually more importantly it’s increasing the number of ldl receptors in hepatocyte in the liver and what those do are they just uptake the ldl from your blood and so that also decreases the amount of cholesterol in your blood because you’re not producing as much

Cholesterol and you’re taking away cholesterol and what a taurus tonton also does is it slightly decreases the triglycerides which as we said before contribute to atherosclerosis as well and it include it increases the hdl levels which also helps to decrease atherosclerosis so what exactly is important in this molecule so we have right here the h mg co 8 which

Our drug is trying to act like to get into the enzyme and so this part right here has h mg like moiety and this is what you need this is what all statins have and so this is a very important part of the molecule so here is another part of the molecule it’s this is a nice an isopropyl group which has hydrophobic binding and then we have our central ring which is a

Pearl in this instance for this stem it doesn’t really have any binding importance it’s just important to keep everything at the distance that you need it and then over here we have our floral phenyl group and the floral phenyl group interacts with the arginine 590 residue in the binding site and so for differences between other statins and this stuntin we have an

Extra hydrogen bonding site right over here with our serine 565 residue and so if we can look over here here is a model of what the binding site looks like in the reductase and so here we have our floral phenyl group binding to an hour arginine we have our my group here by you are staring our isopropyl hydrogen bonding our and hydrophobic interactions over here

And then we have our h mg like moiety right over here you

Transcribed from video
Atorvastatin 1 By Lindsey Clemens