1. Hypolipidemic Drugs

2. HYPERLIPIDEMIA
Plasma lipids are transported in complexes called lipoproteins.
Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias.
Hyperlipemia: indicates increased levels of triglycerides.

3. 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.

4. 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.!!

5. 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.

6. 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.

7. 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

10. apo C

11. NORMAL LIPOPROTEIN METABOLISM
CHYLOMICRONS
Chylomicrons are formed in the intestine and carry triglycerides of dietary origin, unesterified cholesterol, and cholesteryl esters.
They transit the thoracic duct to the bloodstream.
Triglycerides are removed in extrahepatic tissues through a pathway shared with VLDL that involves hydrolysis by the lipoprotein lipase (LPL) system.
Decrease in particle diameter occurs as triglycerides are depleted.
Surface lipids and small apoproteins are transferred to HDL.
The resultant chylomicron remnants are taken up by receptor-mediated endocytosis into hepatocytes.

12. NORMAL LIPOPROTEIN METABOLISM
VERY-LOW-DENSITY LIPOPROTEINS
VLDL are secreted by liver and export triglycerides to peripheral tissues.
VLDL triglycerides are hydrolyzed by LPL, yielding free fatty acids for storage in adipose tissue and for oxidation in tissues such as cardiac and skeletal muscle.
Depletion of triglycerides produces VLDL remnants (IDL), some of which undergo endocytosis directly by liver.
The remainder is converted to LDL by further removal of triglycerides mediated by hepatic lipase.
This process explains the "beta shift" phenomenon, the increase of LDL (beta-lipoprotein) in serum as hypertriglyceridemia decreases.
Increased secretion of VLDL and decreased LDL catabolism Increase the levels of LDL.

13. NORMAL LIPOPROTEIN METABOLISM
LOW-DENSITY LIPOPROTEINS
LDL is catabolized chiefly in hepatocytes and other cells by receptor-mediated endocytosis.
Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes.
Cells also obtain cholesterol by synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase.
Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell.
Normally, about 70% of LDL is removed from plasma by hepatocytes.
Even more cholesterol is delivered to the liver via IDL and chylomicrons.
Unlike other cells, hepatocytes can eliminate cholesterol by secretion in bile and by conversion to bile acids.

14. NORMAL LIPOPROTEIN METABOLISM
LP(A) LIPOPROTEIN
Lp(a) lipoprotein is formed from LDL and the (a) protein, linked by a disulfide bridge.
The (a) protein is highly homologous with plasminogen but is not activated by tissue plasminogen activator.
It occurs in a number of isoforms of different molecular weights. Levels of Lp(a) vary from nil to over 500 mg/dL and are determined chiefly by genetic factors.
Lp(a) can be found in atherosclerotic plaques and may also contribute to coronary disease by inhibiting thrombolysis.
Levels are elevated in nephrosis.

15. NORMAL LIPOPROTEIN METABOLISM
HIGH-DENSITY LIPOPROTEINS
The apoproteins of HDL are secreted by the liver and intestine.
Much of the lipid comes from the surface monolayers of chylomicrons and VLDL during lipolysis.
HDL also acquires cholesterol from peripheral tissues, protecting the cholesterol homeostasis of cells.
Free cholesterol is transported from the cell membrane by a transporter, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin: cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species.
Cholesterol is also exported from macrophages by the ABCG1 transporter to large HDL particles.
The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP).
Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins.
HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not cause endocytosis of the lipoproteins.

16. THE PRIMARY HYPERTRIGLYCERIDEMIAS Hypertriglyceridemia 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.

17. 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 ( 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.

21. 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

22. 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.

23. 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.

24. 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.

25. 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