Lipid lowering agents

A t h e r o g e n e s i s

involves several stages:

endothelial dysfunction with altered PGI2 and NO synthesis

monocyte attachment

endothelial cells bind LDL

oxidatively modified LDL is taken up by macrophages

having taken up oxidised LDL, these macrophages (now foam cells) migrate subendothelially

atheromatous plaque formation

rupture of the plaque

LIPIDS, including CHOLESTEROL and TRIGLYCERIDES (TG), are transported in the plasma as lipoproteins, of which there are four classes:

- chylomicrons transport TG and CHO from the GIT to the tissues, where
they are split by lipase, releasing free fatty acids. They are taken up in muscle and adipose tissue. Chylomicron remnants are taken up in the liver
- very low density lipoproteins (VLDL), which transport CHO and newly synthesized TG to the tissues, where TGs are removed as before, leaving:
- low density lipoproteins (LDL) with a large component of CHO, some of which is taken up by the tissues and some by the liver, by endocytosis via specific
LDL receptors
- high density lipoproteins (HDL).which absorb CHO derived from cell breakdown in tissues and transfer it to VLDL and LDL

Normal Lipoprotein Metabolism

Structure

Lipoproteins have hydrophobic core regions containing cholesteryl esters and triglycerides surrounded by unesterified cholesterol, phospholipids, and apoproteins.

Certain lipoproteins contain very high-molecular-weight B proteins that exist in two forms:

B-48, formed in the intestine and found in chylomicrons and their remnants;

B-100, synthesized in liver and found in VLDL, VLDL remnants (IDL), LDL (formed from VLDL), and Lp(a).

Synthesis & Catabolism

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.

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 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 subsides.

Increased levels of LDL can also result from increased secretion of VLDL and from decreased LDL catabolism.

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.

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.

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.

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.

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.

LDL

Adhesion of macrophages and foam cell to the endothelium

HDL Prevent Foam Cell Formation

treatment

Lipid lowering agent
HMG-COA REDUCTASE INHIBITOR
RESINS
EZETIMIBE
NIACIN
FIBRATES

STATINS

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors. The reductase catalyses the conversion of HMG-CoA to mevalonic acid; blocks the synthesis of CHO in the liver:

Simvastatin + pravastatin + atorvastatin

decrease hepatic CHO synthesis: lowers total and LDL

increase in synthesis of CHO receptors

+ increased clearance of LDL

Stimulates the expression of more enzyme  restores CHO synthesis to normal.

C l i n i c a l u s e

Secondary prevention

of myocardial infarction and stroke in patients who have symptomatic atherosclerotic disease (angina, transient ischemic attacks) following acute myocardial infarction or stroke

Primary prevention

of arterial disease in patients who are at high risk because of elevated serum CHO concentration, especially if there are other risk factors for atherosclerosis

Atorvastatin

lowers serum CHO in patients with homozygous familiar hypercholesterolemia

FIBRATES

Bezafibrate Ciprofibrate Clofibrate Gemfibrozil Fenofibrate

Mechanism Of Action

fibrates activatePPAR (peroxisome proliferator-activated receptors), especially PPARα. The PPARs are a class of intracellularreceptors that modulate carbohydrate and fat metabolismand adipose tissue differentiation.

Activating PPARs induces the transcription of a number of genes that facilitate lipid metabolism.

EFFECTS

Fibrates are agonists of the PPAR-α receptor in muscle, liver, and other tissues. Activation of PPAR-α signaling results in:

Increased β-oxidation in the liver

Decreased hepatic triglyceride secretion

Increased lipoprotein lipase activity, and thus increased VLDL clearance

Increased HDL

SIDE EFFECTS:

rhabdomyolysis,

Idiosyncratic destruction of muscle tissue

myopathy

Drugs that hinder absorption

2-EZITIMIBE

Inhibit cholestrol transport in jejunum enterocyte NPC1L1(Niemann pickC1-LIKE1 protein)

Dec. cholesterol absorption

Dec. cholesterol incorporation into chylomicron

Dec. Of cholesterol chylomicron remanents inc. expression of hepatic gene

STIMULATE LDL Receptor expression

Cholestrol biosynthesis

p.kinetics

Absorption intestine as glucronide conjugate

Excretion FECES 70%

Urine 10% glucronide conjugate

Side effect

Diarrhea

Headache

Abdominal pain

INTERACTION:

With bile acid binding resin

Bile acid binding resin

MOA

Resin +ve charge bind to –ve chaerge bile acid

Large size excreted in feces

Bile acid level

Compensation cholesterol converted into bile acid

Cholesterol level

As a result LDL receptor level

LDL Clearance circulation

Compensatory increase HMG -COA

forms

Clostipol tablet

Clostipol/colestyramine powder

Mix with water to form slurry

Side effects

Given as Cl salt hyperchlorimic acidosis

Dyspepsia

Bloating

Flatulance

Nicotinic acid derivatives

Niacin

Forms

Acid NICOTINIC ACID

AMIDE NICOTINAMIDE

MOA

It stimulate G-protein coupled oraphan receptor called HM74b

Gi –protein coupled receptor

Dec. cAMP production

Dec. hormone sensitive Lipase activity

Dec .TG lipolysis

Dec. FFA

P. KINETICS

HALF LIFE 60MIN

METABOLISM LIVER

EXCRETION URINE( as nicotinuric acid)

High dose major portion is excreted unchanged

Side effects

Dyspepsia

Flushing

Hepatotoxicity

Clinical uses

Hypertriglyceridemia

Inc LDL-C LEVEL

OMEGA -3 FATTY ACID

PUFA( poly unsaturated fatty acid)

Eicosopentanoic acid

Docosahexanoic acid