Cholesterol and Cardiovascular Disease

• Cardiovascular diseases involve the deposition of "bad lipoproteins" like Chylomicron, VLDL, IDL, and LDL within the artery walls.
• This process forms plaque, which leads to atherosclerosis, also referred to as coronary artery disease (CHD) and cardiac diseases.
• Bad lipoproteins transfer lipids from the intestine and liver to tissues where they stick and accumulate.
• Good lipoproteins transfer lipids from tissues to the liver where they undergo metabolism and excretion.
• Drug therapy aims to lower high blood lipid levels, including cholesterol, triglycerides, and phospholipids
• Drug therapy goals involve decreasing LDL levels and increasing HDL levels.
• CHD stands for Congenital Heart Disease.
• CAD stands for Coronary Artery Disease.

Cholesterol Basics

• Cholesterol is a key component of cell membranes.
• It helps maintain cell membrane fluidity.
• Cholesterol acts as a precursor to multiple steroids.
• Normal cholesterol levels are below 170 mg/dL.
• High LDL and low HDL levels are risk factors for cardiovascular disease, increasing morbidity and mortality in CHD.

Bile Acid Sequestrants

• Bile Acid sequestrants (cholestyramine, colestipol, colesevelam) have been approved by the FDA .
• These are polymeric materials containing basic amines.
• They function by binding to bile acids like glycocholic and taurocholic acid.
• They prevent reabsorption in the GI tract and increase cholesterol conversion to bile acids.
• They are insoluble in water.
• They have a high molecular weight.
• The onset of action takes 24 - 48 hours.
• Peak effect takes 1 month.
• They have limited adverse events of constipation and possible fecal compaction
• In patients with pre-existing constipation caution is advised
• Oral medications should be taken 1 hour before or 4 hours after to prevent decreased oral absorption.
• They are not absorbed orally and are not metabolized in the GI tract.
• Instead, they are excreted in feces and complex with bile acids.

HMG-CoA Reductase

• A Key drug target in hypercholesterolemia therapy is the HMG-CoA reductase.
• It is the rate limiting step in cholesterol synthesis .
• The enzyme converts HMG-CoA to mevalonic acid.
• Mevastatin (Compactin) serves as the first HMG-CoA reductase inhibitor.
• It is a fungal metabolite identified in 1976.
• It binds with > 10,000 enzyme affinity vs HMG-CoA
• Mevastatin is Not commercialized.
• Lovastatin (Mevacor) was the first to market.
• It contains an extra methyl that doubles potency.
• Statins act as competitive inhibitors.
• They result in decreased cholesterol synthesis, increased LDL receptor expression and LDL uptake increases.
• Plasma LDL cholesterol decreases with statins.
• Lovastatin and simvastatin are pro dying.
• Caution is advised in taking with CYP3A4 Inhibitors.
• It must be monitored for liver function.
• Contraindicated in: Pregnancy, Nursing mothers.
• Should not be used in patients unable to produce LDL receptors.
• It is essential to consider risks and benefits, including development, liver function.

Specific Statins

• Atorvastatin (Lipitor/Pfizer): an upper portion “blue” Cyclic (Prodrug) or Open Ring (active drug) required for activity
• Simvastatin (Zocor) is structurally similar to Lovastatin
• It is minimal impact on properties
• Lovastatin (Mevacor/Merck) is a neutral Pro-drug
• It has low oral bioavailability of 5% (dose with food, and 33% drop if bioavailability fasting)
• it is moderate and metabolized by CYP3A4
• Pravastatin (Prevachol/BMS) It is no a pro-drug
• It can be used for patients taking CYP3A4 inhibitors
• Fluvastatin (Lescol) caution in CYP3A4 and CYP2C9 inhibitors