Understand the antihyperlipidemic agents once and all! In this quick board review lecture I’m gonna cover the anti-hyperlipidemic agents and that includes the following groups. The HMG-CoA reductase inhibitors, the fibrates, niacin, bile acid sequestrants and cholesterol absorption inhibitors. Let’s get started. The HMG-CoA reductase inhibitors are a very important group of drugs. Five out of five you’ve got to know these drugs for your exams. The more common name for these drugs is the statins. However, the mechanism of action is actually found in the first name. They are reversible and competitive inhibitors of HMG-CoA reductase. That is a very important rate-limiting enzyme in the pathway that produces cholesterol in our liver de novo. On the right I have a picture to explain this but I’m gonna break it down and walk through the steps. Starting with acetyl-CoA. Acetyl-CoA is an important molecule in biologic reactions and it plays an important part in the synthesis of cholesterol. Acetyl-CoA is basically an acetyl group that is linked to coenzyme A. Let me just shorten coenzyme A to just CoA. In that first step on our list below you can see that if we combined two acetyl-CoAs together through the enzyme thiolase we get a molecule called acetoacetyl-CoA. If we then take that molecule and add another acetyl-CoA through the enzyme HMG-CoA synthase we have HMG-CoA, and this is where the statins work. The statins block the next step. What’s supposed to happen is that this HMG-CoA is supposed to be reduced to mevalonic acid. Again, the statins block this from happening and therefore ultimately inhibit or decrease the production of cholesterol de novo in the liver. Major side effects for the statins include hepatic toxicity, however, while this can be severe, only about one to two people per 10,000 patient years have this problem. What’s more common by far is myositis or myalgias. It is very common that your patients could complain of muscle aches while on this medication. And in severe cases, they could have Rhabdomyolysis from it. As for examples for the statins, we have these four here. Rosuvastatin, atorvastatin, simvastatin and lovastatin and I organized this list in this way on purpose. On the right side of this little list are the equivalencies. Rosuvastatin is the strongest of these four statins with an equivalency of 1.0. Lovastatin is the weakest of these statins with an equivalency of eight. In other words you would need theoretically and it doesn’t work out exactly but you would need about eight milligrams of lovastatin to equal the effect that you get with one milligram of rosuvastatin. And finally if you really want to impress your preceptors look up the ASTEROID Trial which was done in 2006. It showed that patients who are treated with 40 milligrams of rosuvastatin actually had a regression of their atherosclerotic plaques at a two-year follow-up. Moving on, now the fibrates. These drugs are pretty easy to pick out in a group because they end in -fibrate or -fibrozil. These drugs are often given in combination with the statins because there’s not a lot of good evidence to support using them alone. As for their mechanism of action, they act by stimulating or activating the peroxisome proliferator-activated receptor subtype alpha, or abbreviated PPAR alpha. Don’t confuse this with PPAR gamma. The PPAR gamma is stimulated by the related class of drugs, the thiazolidinediones which are used for diabetes. Naturally in the body, these PPAR alpha receptors are found on the cell nucleus. They are used in the regulation of carbohydrates and fatty acids. When we stimulate these receptors with the fibrates we change that metabolism and this works by having the drug bind the receptor which makes the receptors move into the nucleus. Once in the nucleus, the PPAR alpha binds another receptor called the retinoid X receptor and that complex binds DNA on sequences that are called peroxisome proliferator hormone response elements. These response elements are responsible for the expression of proteins that are involved in the metabolism of fatty acids and triacylglycerides. For example, you would see an increase in the expression of lipoprotein lipase. This would increase the metabolism of triacylglycerides. Also it would increase the expression of apolipoprotein A1 and apolipoprotein A2. Those are lipoproteins that are important in the structure of an HDL particle. The side effects for the fibrates include GI upset, this is really common. You very well could see your patient complain of a stomach ache on the fibrates.