Cholesterol Lowering DrugsStatinsThe statins are the most effective and best-tolerated agents for treating dyslipidemia. These drugs are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate-limiting step in cholesterol biosynthesis. Higher doses of the more potent statins (e.g., atorvastatin and simvastatin) also can reduce triglyceride levels caused by elevated VLDL levels. Some statins also are indicated for raising HDL-C levels, although the clinical significance of these effects on HDL-C remains to be proven.

MECHANISM OF ACTIONStatins exert their major effect—reduction of LDL levels—through a mevalonic acid–like moiety that competitively inhibits HMG-CoA reductase. By reducing the conversion of HMG-CoA to mevalonate, statins inhibit an early and rate-limiting step in cholesterol biosynthesis.

Statins are also known as HMG-CoA reductase inhibitors. They are the most effective drugs in lowering LDL cholesterol. They inhibit HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) an enzyme involved in the synthesis of cholesterol, especially in the liver. Decreased cholesterol production leads to an increase in the number of LDL membrane receptors, which increases clearance of LDL cholesterol from circulation.Generic Name : lovastatin, rosuvastatin, fluvastatin, atorvastatin, pravastatin, simvastatin.

Bile-Acid SequestrantsThe two established bile-acid sequestrants or resins (cholestyramine and colestipol) are among the oldest of the hypolipidemic drugs, and they are probably the safest, since they are not absorbed from the intestine. These resins are also recommended for patients 11 to 20 years of age. Because statins are so effective as monotherapy, the resins are most often used as second agents if statin therapy does not lower LDL-C levels sufficiently. When used with a statin, cholestyramine and colestipol usually are prescribed at submaximal doses. Maximal doses can reduce LDL-C by up to 25% but are associated with unacceptable gastrointestinal side effects (bloating and constipation) that limit compliance. Colesevelam is a newer bile-acid sequestrant that is prepared as an anhydrous gel and taken as a tablet. It lowers LDL-C by 18% at its maximum dose. The safety and efficacy of colesevelam have not been studied in pediatric patients or pregnant women.

MECHANISM OF ACTIONThe bile-acid sequestrants are highly positively charged and bind negatively charged bile acids. Because of their large size, the resins are not absorbed, and the bound bile acids are excreted in the stool. Since over 95% of bile acids are normally reabsorbed, interruption of this process depletes the pool of bile acids, and hepatic bile-acid synthesis increases. As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors, an effect similar to that of statins. The increase in hepatic LDL receptors increases LDL clearance and lowers LDL-C levels, but this effect is partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase. Inhibition of reductase activity by a statin substantially increases the effectiveness of the resins.

Bile acid sequestrants reduce serum cholesterol levels. They cause no change or sometimes even cause a slight increase in trigylceride concentrations and are therefore not suitable for patients with elevated triglyceride levels. After oral administration, they are not absorbed but bind to bile acids in the intestine and prevent their reabsorption. The bound complex is insoluble and is excreted in the faeces. Decrease in bile acid leads to an increase in hepatic synthesis of bile acids from cholesterol. Depletion of cholesterol from the liver increases LDL receptor activity, which removes LDL cholesterol from the blood.

Generic Name : Cholestipo, Cholestyramin, Colesevam

Niacin (Nicotinic Acid)Niacin, nicotinic acid (pyridine-3-carboxylic acid), one of the oldest drugs used to treat dyslipidemia, favorably affects virtually all lipid parameters.

Niacin is a water-soluble B-complex vitamin that functions as a vitamin only after its conversion to NAD or NADP, in which it occurs as an amide. Both niacin and its amide may be given orally as a source of niacin for its functions as a vitamin but only niacin affects lipid levels. The hypolipidemic effects of niacin require larger doses than are required for its vitamin effects.

Niacin is limited by its side effects especially vasodilatation. In doses of 1.5 to 3 g daily it lowers both cholesterol and triglyceride concentrations by inhibiting synthesis. It also increases HDL cholesterol.

MECHANISM OF ACTIONIn adipose tissue, niacin inhibits the lipolysis of triglycerides by hormone-sensitive lipase, which reduces transport of free fatty acids to the liver and decreases hepatic triglyceride synthesis. Niacin and related compounds (e.g., 5-methylpyrazine-2-carboxylic-4-oxide, acipimox) may exert their effects on lipolysis by inhibiting adipocyte adenylyl cyclase.

In the liver, niacin reduces triglyceride synthesis by inhibiting both the synthesis and esterification of fatty acids, effects that increase apoB degradation. Reduction of triglyceride synthesis reduces hepatic VLDL production, which accounts for the reduced LDL levels. Niacin also enhances LPL activity, which promotes the clearance of chylomicrons and VLDL triglycerides. Niacin raises HDL-C levels by decreasing the fractional clearance of apoA-I in HDL rather than by enhancing HDL synthesis.

DIVERSE EFFECTSTwo of niacin's side effects, flushing and dyspepsia, limit patient compliance. The cutaneous effects include flushing and pruritus of the face and upper trunk, skin rashes, and acanthosis nigricans. Flushing and associated pruritus are prostaglandin-mediated. Dry skin, a frequent complaint, can be dealt with by using skin moisturizers, and acanthosis nigricans can be dealt with by using lotions or creams containing salicylic acid . Dyspepsia and rarer episodes of nausea, vomiting, and diarrhea are less likely to occur if the drug is taken after a meal. Patients with any history of peptic ulcer disease should not take niacin because it can reactivate ulcer disease.

The most common, medically serious side effects are hepatotoxicity, manifested as elevated serum transaminases and hyperglycemia. Both regular (crystalline) niacin and sustained-release niacin, which was developed to reduce flushing and itching, have been reported to cause severe liver toxicity, and sustained-release niacin can cause fulminant hepatic failure .

Fibric Acid Derivatives: PPAR ActivatorsFibrates are regarded as broad-spectrum lipid lowering drugs. Their main action is to decrease triglyceride levels but they also tend to reduce LDL cholesterol and help to raise HDL cholesterol. Mechanism of action is not well established. Apparently it decreases plasma levels of triglycerides by decreasing their synthesis. Also reduces plasma levels of VLDL cholesterol by reducing its release into the circulation and increasing catabolism.

ADVERSE EFFECTS AND DRUG INTERACTIONSFibric acid compounds usually are well tolerated. Side effects may occur in 5% to 10% of patients but most often are not sufficient to cause discontinuation of the drug. Gastrointestinal side effects occur in up to 5% of patients. Other side effects are reported infrequently and include rash, urticaria, hair loss, myalgias, fatigue, headache, impotence, and anemia. Minor increases in liver transaminases and alkaline phosphatase have been reported. Clofibrate, bezafibrate, and fenofibrate have been reported to potentiate the action of oral anticoagulants, in part by displacing them from their binding sites on albumin. Careful monitoring of the prothrombin time and reduction in dosage of the anticoagulant may be appropriate when treatment with a fibrate is begun.Generic Name : fenofibrate, clofibrate, gemfibrozil.

Cholesterol Absorption InhibitorsThis is a new class of antihyperlipidemic drugs. It works by reducing the absorption of dietary cholesterol, through the intestines.Generic Name : Ezetimibe