HYPERLIPIDEMIA • Plasma lipids are transported in complexes called lipoproteins. • Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. • Hyperlipemia: indicatesincreased levels of triglycerides.
HYPERLIPIDEMIA • The two major clinical sequelae of hyperlipidemias • Atherosclerosis: Atherosclerosis is the leading cause of death for both genders in the USA and other Western countries. • Acute pancreatitis: Occurs in patients with marked hyperlipemia. Control of triglycerides can prevent recurrent attacks of this life-threatening disease.
Atherosclerosis • Lipoproteins that contain apolipoprotein (apo) B-100 carry lipids into the artery wall. These are • low-density lipoproteins (LDL), • intermediate-density lipoproteins (IDL), • very-low-density lipoproteins (VLDL), and • lipoprotein(a) (Lp[a]). • Cellular components in atherosclerotic plaques include foam cells, which are transformed macrophages and smooth muscle cells filled with cholesteryl esters. • These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. • Chemical modification of lipoproteins by free radicals creates ligands for these receptors. • The atheroma growth: • the accumulation of foam cells, collagen, fibrin, and frequently calcium. • slowly occlude coronary vessels, • rupture of unstable atheromatous plaques, • activation of platelets and formation of occlusive thrombi. • The leading cause of death.!!
Atherosclerosis • High-density lipoproteins (HDL) exert several anti atherogenic effects. • They participate in removing of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. • Low levels of HDL (hypoalphalipoproteinemia) are an independent risk factor for atherosclerotic disease. • Cigarette smoking is a major risk factor for coronary disease. It is associated with; • reduced levels of HDL, • inhibiting of cholesterol removal from the artery wall, • cytotoxic effects on the endothelium, • increased oxidation of lipoproteins, and • stimulation of thrombogenesis. • Diabetes, also a major risk factor, is another source of oxidative stress.
Atherosclerosis • Normal coronary arteries can dilate in response to ischemia, increasing delivery of oxygen to the myocardium. • This process is mediated by nitric oxide, acting upon smooth muscle cells of the arterial media. • This function is impaired by atherogenic lipoproteins, thus aggravating ischemia. • Reducing levels of atherogenic lipoproteins and inhibiting their oxidation restores endothelial function. • Because atherogenesis is multifactorial, therapy should be directed toward all modifiable risk factors. • Atherogenesis is a dynamic process. • Quantitative angiographic trials have demonstrated net regression of plaques during aggressive lipid-lowering therapy. • Clinical trials have shown significant reduction in mortality from new coronary events and in all-cause mortality.
Schematic Illustration of a Lipoprotein Particle Lipoproteins have hydrophobic core regions containing cholesteryl esters and triglycerides surrounded by unesterified cholesterol, phospholipids, and apoproteins. Certain lipoproteins contain very high-molecular-weight apoproteins (B type) that exist in two forms: B-48, formed in the intestine and found in chylomicrons and their remnants; and B-100, synthesized in liver and found in VLDL, VLDL remnants (IDL), LDL (formed from VLDL), and Lp(a) lipoproteins. TG: Trigiglycerides CE: Cholesteryl esthers
THE PRIMARY HYPERTRIGLYCERIDEMIASHypertriglyceridemia is associated with increased risk of coronary disease. • VLDL and IDL have been found in atherosclerotic plaques. • These patients tend to have cholesterol-rich VLDL of small particle diameter. • Hypertriglyceridemic patients with coronary disease or risk equivalents should be treated aggressively. • Patients with triglycerides above 700 mg/dL should be treated to prevent acute pancreatitis because the LPL clearance mechanism is saturated at about this level.
Primary Chylomicronemia • Chylomicrons are not present in the serum of normal individuals who have fasted 10 hours. • The recessive traits of deficiency of lipoprotein lipase or its cofactor are usually associated with severe lipemia (2000-2500 mg/dL of triglycerides when the patient is consuming a typical American diet). • These disorders might not be diagnosed until an attack of acute pancreatitis occurs. • Patients may have eruptive xanthomas, hepatosplenomegaly, hypersplenism, and lipid-laden foam cells in bone marrow, liver, and spleen. • Marked restriction of total dietary fat is the basis of effective long-term treatment. • Niacin or a fibrate may be of some benefit if VLDL levels are increased.
DRUGS USED IN HYPERLIPIDEMIA • HMG-CoA reductase inhibitors • Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin • Niacin • Fibric Acid Derivatives • Gemfibrozil,fenofibrate, clofibrate • Bile acid-binding Resins • Colestipol, cholestyramine,colesevelam • Inhibitors of Intestinal sterol absorption • Ezetimibe
HMG-CoA reductase inhibitors(3-Hydroxy-3-methylglutaryl-coenzyme A ) • These compounds are structural analogs of HMG-CoA. • They are most effective in reducing LDL. • Other effects include decreased oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions. • It has become standard practice to initiate reductase inhibitor therapy immediately after acute coronary syndromes, irrespective of lipid levels.
HMG-CoA reductase inhibitors(3-Hydroxy-3-methylglutaryl-coenzyme A ) • Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL. • Women who are pregnant, lactating, or likely to become pregnant should not be given these agents. • Use in children is restricted to those with special indications (homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia). • Elevations of serum aminotransferase activity (up to three times normal) occur in some patients. Sign of hepatotoxicity.
Inhibitors of Intestinal sterol absorption • Ezetimibe is the first member of a group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. • Its primary clinical effect is reduction of LDL levels. • Ezetimibe is a selective inhibitor of intestinal absorption of cholesterol and phytosterols. • A transport protein, NPC1L1, appears to be the target of the drug. • It is effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile. • Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol. • Ezetimibe is synergistic with reductase inhibitors, producing decreases as great as 25% in LDL cholesterol.
Acronyms • Apo Apolipoprotein • CETP Cholesteryl ester transfer protein • CK Creatine kinase • HDL High-density lipoproteins • HMG-CoA 3-Hydroxy-3-methylglutaryl-coenzyme A • IDL Intermediate-density lipoproteins • LCAT Lecithin:cholesterol acyltransferase • LDL Low-density lipoproteins • Lp(a) Lipoprotein(a) • LPL Lipoprotein lipase • PPAR-a Peroxisome proliferator-activated receptor-alpha • VLDL Very-low-density lipoproteins