Anti-Hyperlipidemic Drugs: Statins

In the liver, dietary intake is absorbed into the gut. Some of the cholesterol is re-absorbed through the bile, which is why we use bile acid sequesterance, by taking that out we can reduce the amount that gets into the circulation-- it’s a good strategy, but poor compliance. Clearly 70-80% of cholesterol is synthesized in the liver. So the liver is a target of the statins, which inhibit the liver synthesis of cholesterol. This is the reason that the statins are the number one prescribed lipid lowering drug, because they are potent and inhibit the liver.

Within the Krebs Cycle, the rate limiting step involves HMG CoA. HMG CoA reductase is essential for the conversion of the intermediates all the way down to the synthesis of cholesterol—this is the rate limiting step. A fungal extract is capable of inhibiting HMG CoA reductase, so was called a HMG CoA reductase inhibitor—now we simply call them the statin drugs. The agents do vary in their potency, among the statins.

The prototype statin is lovastatin (Mevicor), which is now available also as a generic drug. Lovastatin is a prodrug, and is converted to an active metabolite once it has been ingested (this sometimes appears on tests!!!). Atorvastatin (Lipitor) is the number one prescribed agent for lipid lowering drugs, it is a $3 billion/ year product!

The doses of all the drugs are pretty similar except for Cerivastatin (Baycol), which has been removed from the market. It was withdrawn due to safety issues, but other statins are NOT dangerous… the class as a whole is safe, there are differences in metabolism and in terms of risk for a condition known as rhabdomyalysis (which affects skeletal muscle). Atorvastatin is the most widely used, as you can see it has a 39-50% reduction in LDL concentration.

Lovastatin is a prodrug, highly bound to plasma proteins and is rapidly extracted by the liver (first-pass extraction). Administration with food enhances the bioavailability. This is an important notation because pt’s like to know whether or not to take the med with food. However, with pravostatin, bioavailability is reduced if taken with food—so this differs between different drugs of the same class. All of these drugs are really once a day agents. Most cholesterol is synthesized according the circadian rhythms—peak synthesis occurs at night. So physicians will tell their pt to take the drugs before bed to maximize their effects.

Category: Pharmacology Notes