**1.10.2 Treatment of Hypercholesterolemia by available drug therapy**

Drug treatment to lower plasma lipoprotein /or cholesterol is primarily aimed at reducing the risk of athersclerosis and subsequent coronary artery disease that exists in patients with elevated circulating lipids. Drug therapy usually is considered as an option only if nonpharmacologic interventions (altered diet and exercise) have failed to lower plasma lipids.

#### **1.10.2.1 Members of statins family**

**These** are fungal HMG-CoA reductase (HMGR) inhibitors **from members of statins family. Atorvastin (Lipitor), simvastatin (Zocor) and lovastatin (Mevacor) belongs to this family, are widely used for lowering the plasma cholesterol. During the course of treatment, cellular uptake of LDL from plama is significantly increased**, since the intracellular synthesis of cholesterol is inhibited as cells are dependent on extracellular sources of cholesterol. Important isoprenoid compounds require mevalonate as the precursor as a result long term treatment carry some risk of toxicity. A component of the natural cholesterol lowering supplement, red yeast rice, is in fact a statin-like compound. Other beneficial effects of statins other than lowering blood cholesterol levels via their actions on HMGR are ability to reduce the prenylation of numerous pro-inflammatory modulators. Thus, inhibition of this post-translational modification by the statins interferes with the important functions of many signaling proteins which is manifest by inhibition of inflammatory responses.

#### **1.10.2.2 Fibrates compounds**

Second group drugs belongs to a series of compounds are derivatives of fibric acid and although known since 1930 but identified as cholesterol lowering drugs very recently. Fibrates are activators of the peroxisome proliferator activated receptor-α (PPARα) class of proteins and are classified as nuclear receptor co-activators. Fibrates result in activation of βoxidation and thereby decreasing the level of triacyl glycerol and cholesterol rich VLDL in liver as well as enhances the clearance of chylomicrons remnants, and increase in the level of HDLs. These drugs are also known to increase the lipase activity which in turn promotes rapid VLDL turnover. Gemifibrozil (Lopid) and Fenofibrate (Tricor) are two therapeutic drugs available in the market.

#### **1.10.2.3 Cholestyramine or colestipol**

**Cholestyramine or colestipol (resins)** compounds are nonabsorbable resins that bind bile acids which are then not reabsorbed by the liver but excreted. The drop in hepatic reabsorption of bile acids releases a feedback inhibitory mechanism that had been inhibiting bile acid synthesis. As a result, a greater amount of cholesterol is converted to bile acids to maintain a steady level in circulation. Additionally, the synthesis of LDL receptors increases to allow increased cholesterol uptake for bile acid synthesis, and the overall effect is a reduction in plasma cholesterol. This treatment is ineffective in homozygous FH patients since they are completely deficient in LDL receptors.

#### **1.10.2.4 Ezetimibe**

This drug is sold under the trade names Zetia® or Ezetrol® and is also combined with the statin drug simvastatin and sold as Vytorin® or Inegy®. Ezetimibe functions to reduce intestinal absorption of cholesterol, thus effecting a reduction in circulating cholesterol. The drug functions by inhibiting the intestinal brush border transporter involved in absorption of cholesterol. This transporter is known as Niemann-Pick type C1-like 1 (NPC1L1). NPC1L1 is also highly expressed in human liver. The hepatic function of NPC1L1 is presumed to limit excessive biliary cholesterol loss. NPC1L1-dependent sterol uptake is regulated by cellular cholesterol content. In addition to the cholesterol lowering effects that result from inhibition of NPC1L1, its' inhibition has been shown to have beneficial effects on components of the metabolic syndrome, such as obesity, insulin resistance, and fatty liver, in addition to atherosclerosis. Ezetimibe is usually prescribed for patients who cannot tolerate a statin drug or a high dose statin regimen. There is some controversy as to the efficacy of ezetimibe at lowering serum cholesterol and reducing the production of fatty plaques on arterial walls. The combination drug of ezetimibe and simvastatin has shown efficacy equal to or slightly greater than atorvastatin (Lipitor®) alone at reducing circulating cholesterol levels.

#### **1.10.2.5 New approaches for the treatment of hypercholesterolemia**

In the last decade, a number of epidemiological and clinical studies have demonstrated a direct correlation between the circulating levels of HDL cholesterol and a reduction in the potential for atherosclerosis and coronary heart disease (CHD). Individuals with low levels of HDL (below 40mg/dL) are at higher risk of coronary heart disease CHD) then individual with level above 50mg/dL. Clinical studies have demonstrated that infusion of HDL component, apolipoprotein A-1 (apoA-1) in patients, significantly increases the level of HDL. The newest strategies are targeted to up regulate the level of HDL cholesterol instead of decreasing the level of total cholesterol. Cholesterol ester transfer protein (CETP) is secreted primarily from the liver and plays a critical role in HDL metabolism by facilitating the exchange of cholesteryl esters (CE) from HDL for triglycerides (TG) in apoB containing lipoproteins, such as LDL and VLDL. The activity of CETP directly lowers the cholesterol levels of HDLs and enhances HDL catabolism by providing HDLs with the TG substrate of hepatic lipase. Thus, CETP plays a critical role in the regulation of circulating levels of HDL, LDL, and apoA-I. It has also been shown that in mice naturally lacking CETP most of their cholesterol is found in HDL and these mice are relatively resistant to atherosclerosis. CETP inhibitors have failed in the clinical trials as their use has increased negative cardiovascular events and death rates in test subjects.
