HYPOLIPIDEMICS

Plasma Lipids cholesterol and triglycerides

Essential fatty acid linoleic acid and linolenic acid

Poly-unsaturated Fatty Acid

Lipids with special functions

1.Phospholipids-next largest lipid component of the body after triglycerides

lecithin, cephalins and glycolipids

2.Lipoproteinstrigycerides+phospholipids+cholesterol with apoproteins

Triglyceride(mostly) +phospholipids +protein

Apoproteins-B-48, C, E, A-I, A-II

B. VLDL-principal carrier of triglycerides Catabolism of VLDL results in the formation of LDL. (Beta-shift)

Apoproteins-C species, B-100, E

A. Chylomicrons

D. LDL-cholesteryl esters (mostly) Apoproteins-B-100

E. HDL Apoprotein +phospholipids + cholesterol Apoproteins-A-I, A-II, C, E

C. IDL- triglycerides + cholesteryl esters Apoproteins-B-100, E, C

HDL formed during the catabolism of chylomicrons. HDL2 is the major reason for the inverse correlation

between HDL level and coronary risk. Low HDL---independent risk factor for coronary disease. Cigarette smoking

is a major risk factor for coronary disease because it is associated

with low level of HDL.

APOLIPOPROTEINS

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

Apo B-100 synthesized in the liver, found in VLDL,VLDL remnants (IDL), LDL and Lp(a) lipoproteins

Apo A-I cofactor for lecithinApo C-II required cofactor for

lipoprotein lipaseApo E required for uptake of

lipoprotein remnants by the liver

Cholesterol

Member of the large group of compound called STEROLS.

Exogenous (present in food intake)Endogenous (synthesized in the cell) BILE ACIDS (80%)-breakdown products. Main site of metabolism- LIVER and then intestines

Characteristic cellular components in atherosclerotic plaques. They are transformed

macrophages and smooth muscle cells that are filled with CHOLESTERYL ESTERS. They are the result of endocytosis of chemically

modified lipoproteins via as many as 4 molecular species of scavenger receptors

(inability of these receptors to be down regulated by high intracellular levels of

cholesterol).

Foam Cells

Predisposing Factors in developing CADAge: Male > 45 years of age

Female > 55 years of age

NOTE: Premature CAD 1* male below 55 female below 65 Cigarette smoking Hypertension ≥140/90 Low HDL <40 mg Obesity body mass index (BMI) >25 kg/m2 waist circumference male above 40 inches female above 35 inches

Total Cholesterol< 200 mg/dl DESIRABLE

200-239 mg/dl BORDERLINE to HIGH≥240 mg/dl VERY HIGH

HDL <40 mg/dl LOW

NOTE: <50 mg/dl as low for female>60 mg/dl HIGH

Normal Values

LDL<100 mg/dl OPTIMAL

100-129 mg/dl NEAR OPTIMAL130-159 mg/dl BORDERLINE HIGH

160-189 mg/dl HIGH>190 mg/dl VERY HIGH

TRIGLYCERIDES<150 mg/dl NORMAL

150-199 mg/dl BORDERLINE HIGH200-499 mg/dl HIGH

>500 mg/dl VERY HIGH

No CHD and 0-1 risk factor LDL >160

No CHD +2 risk factors LDL>130

With CHD or CHD equiv LDL>100

Lifestyle MODIFICATION

Primary Hyperlipoproteinemi

as

A. Primary chylomicronemia Familial lipoprotein lipase or cofactor deficiency

Increased VLDL and chylomicrons

B. Familial hyperglyceridemiaSevere--↑ VLDL, chylomicronsModerate- ↑ VLDL, may ↑chylomicrons

C. Familial combined hyperlipoproteinemia

↑VLDL, ↑LDL, ↑VLDL and LDL

D. Familial dysbetalipoproteinemia ↑ VLDL and chylomicron remnants

E. Familial hypercholesterolemia Heterozygous or homozygous ↑LDL

F. Lp(a) hyperlipoproteinemia ↑ Lp(a)

SECONDARY CAUSES OF HYPERLIPOPROTEINEMIA

A. HypertriglyceridemiaDM, alcohol ingestion,

severe nephrosis, estrogens, uremia, corticosteroid excess, hypothyrodism,

glycogen storage disease, hypopituitarism, acromegaly,

Immunoglobulin-lipoprotein complex disease, lipodystrophy, isotretinoin

B. Hypercholesterolemia Hypothyrodism

Early nephrosis, resolving lipemia Immunoglobulin-lipoprotein complex disorder, anorexia nervosa, cholestasis, hypopituitarism, corticosteroid excess

LIPID ALTERING DRUGS

A. VLDL SECRETION INHIBITORS Niacin (Nicotinic Acid)

B. FIBRIC ACID DERIVATIVES Clofibrate, Fenofibrate, Bezafibrate, Gemfibrozil

C. BILE ACID BINDING RESINS Cholestyramine, Colestipol

D. HMG ( 3 hydroxy-3 methyl glutaryl )-CoA REDUCTASE INHIBITORS Simvastatin, Lovastatin,

Pravastatin, Fluvastatin

Rosuvastatin, Atorvastatin

E. PROBUCOL

F. INHIBITORS OF INTESTINAL STEROL ABSORPTION

Ezetimibe

NICOTINIC ACID

Water soluble B-complex vitaminHypolipidemic properties of nicotonic acid are unrelated to its role as vitamin. Nicotinamide does not have hypolipidemic properties.Nicotinic acid is used most frequently in an attempt to raise low HDL levels and to lower VLDL and LDL levels. When tolerated, it is effective as either primary therapy or, commonly, as adjunctive therapy.

Mechanism of Action decreased production of VLDL, which may be due, at least in part, to a transient inhibitory effect of nicotinic acid on lipolysis, a decreased delivery of free fatty acids to the liver, and a decrease in triglycerides synthesis and VLDL-triglyceride transport. Enhanced clearance of VLDL also may occur, possibly owing to enhanced activity of lipoprotein lipase.

The decrease in LDL levels could be due to

decreased VLDL production and enhanced

hepatic clearance of LDL precursor.

Nicotinic acid also raises HDL cholesterol

levels via mechanism not yet understood,

but a decrease in the clearance rate of

apo A-I.

Nicotinic acid does not alter the rates of

cholesterol synthesis or bile acid excretion.

Absorption,Fate and Excretion

Nicotinic acid is absorbed readilyHalf-life is short.The short half-life necessitates frequent dosing. High doses of nicotinic acid are eliminated primarily by renal clearance of uncharged drug. At lower doses, the major excretion products are metabolites, principally products of catabolism of the pyridine dinucleotides.

Adverse Effects Intense flushing and associated pruritus (cutaneous vasodilatation) and warm sensation(prostaglandin mediated) that usually involves the face and upper part of the body. Flushing may be more tolerable if a patient begins with low dose and gradually increase the dose over a period of weeks. May be avoided by taking aspirin before NIACIN is given.

Dry skin is another common side effect of

prolonged nicotinic treatment. Others include

rashes, acanthosis nigricans, nausea and

abdominal discomfort.

↑transaminases and alkaline phosphatase but not

associated with serious liver toxicity.

Rarely, severe acute hepatic necrosis may occur

↑in blood sugar; may aggravate diabetes

↑ uric acid; may aggravate gout

Arrhythmia and toxic amblyopia

Therapeutic Uses The usual therapeutic dose is 2 to 6 g/day divided into 3 doses taken with meals. Because of its many side effects, nicotinic acid is most frequently used as adjunctive therapy to lower LDL levels in patients with familial hypercholesterolemia already on bile acid sequestrant and/or a statin.

Second major use is in patients with low HDL levels and elevated triglyceride levels, such as those with familial combined hyperlipoproteinemia. Mixed hyperlipidemia, cholesterol and triglyceride levels, is another clinical indication for treatment with nicotinic acid.

Fibric Acid Derivatives Clofibrate was the most widely prescribed hypolipidemic drug a number of years. Its usage declined dramatically, however, following results, the obvious potential of this drug to increase gallstone formation and its relative inefficiency in reducing LDL levels has led to its virtual abandonment.

Mechanism of Action ↓VLDL, modestly raise HDL levels and have variables effects on LDL levels. The effects on VLDL levels probably result primarily from an increase in lipoprotein lipase activity, especially in muscle. This would lead to enhanced hydrolysis of VLDL triglyceride content and an enhance VLDL catabolism.

Effects on Lipoprotein Levels

The effects of the fibric acid agents on lipoprotein levels differ widely depending on the starting lipoprotein profile, the presence or absence of a genetic hyperlipoprotein-emia, the associated environmental influences, and the drug used.Elevated triglyceride and cholesterol levels may be dramatically lowered, and tuboeruptive and palmar xanthomas may regress completely.

Gemfibrozil treatment of patients with mild hypertriglyceridemia (e.g. triglycerides < 400 mg/dl) usually produces a decrease in triglyceride levels of 50% or more, an increase in HDL cholesterol concentrations of 15% to 25% and either no change or an increase in LDL cholesterol levels, particularly in subjects with familial combined hyperlipidemia. The second generation agents, such as fenofibrate,bezafibrate, and ciprofibrate, lower VLDL levels to a degree similar to that produced by gemfibrozil, but they also decrease LDL levels by 15 % to 20%.

In patients with more marked hypertriglyceridemia, (triglyceride levels of 400 to 1000 mg/dl), a similar fall in triglycerides occurs, but increases in LDL of 10% to 30% frequently are seen. In contrast, treatment of patients with heterozygous familial hypercholesterolemia usually produces a decrease in LDL levels of 10% with gemfibrozil, and of 20% to 30% with other agents.

Absorption, Fate and Excretion

All of the fibrate drugs are absorbed rapidly and efficiently (>90%) when given with a meal but less efficiently when taken on an empty stomach. More than 95% of these drugs in plasma are protein-bound, nearly exclusively to albumin. Half-lives differ significantly within this group. Gemfibrozil has a half-life of 1.1 hours; fenofibrate has a half life of 20 hours. The drugs are widely distributed and concentrations in liver, kidney and intestine exceed the plasma level.

Gemfibrozil is transferred across the placenta. The fibrate drugs are excreted predominantly as glucuronide conjugates; 60% to 90% of an oral dose is excreted in the urine, with smaller amounts appearing in the feces. Excretion of these drugs is impaired in renal failure, though excretion of gemfibrozil was reported to be less severely compromised in renal insufficiency than excretion of other fibrates.

Adverse Effects and Drug Interactions

Gastrointestinal side effects like nausea and abdominal discomfort are most common Other side effects are reported infrequently and include rash, urticaria, hair loss, myalgias, fatigue, headache, impotence, breast tenderness in men, anemia and renal dysfunction. Minor increases in liver transaminases and decreases in alkaline phosphatase have been reported.

Reported cases also like GIT and hepatobiliary CA. Enhances hypoglycemic effect of sulfonylureas. Potentiates anti-coagulant effect on coumarin by decreasing platelet activity.A myositis-flulike syndrome occasionally occurs in subjects on gemifibrozil and may occur in up to 5% of patients treated with a combination of an HMG CoA reductase inhibitor and gemfibrozil, particularly when higher doses of the reductase inhibitors are used. Clofibrate, and indeed all the fibrates, increase the lithogenicity of the bile.

BILE ACID-BINDING RESINS

Lower LDL cholesterol in hypercholesterolemic subjects. Because they are non-systemic agent, they are in principle the safest agents available. They may be particularly appropriate for use in young patients, such as young adults with familial hypercholesterolemia.

They also are frequently used as adjunctive therapy with other agents, such as statins or nicotinic acid. While safety and absence of serious side effects in their major attraction, annoying gastrointestinal side effects limit

their widespread use.

Mechanism of Action

Normally, up to 97% of bile acids are reabsorbed into the entero-hepatic

circulation via the jejunum, and only a few % are excreted in the feces. The anion

exchange resins are not absorbed, the net effect is to promote bile acid excretion.

Inhibition of the return of bile acids to the liver results in an increase in conversion of cholesterol

to bile acids. The loss of bile acids, as well as neutral steroids, leads to a compensatory

increase in the number of hepatic LDL receptors and to induction of HMG CoA reductase activity. Thus, hepatocyte cholesterol content is restored

both by enhanced uptake of plasma LDL-mediated by increased LDL receptor expression

and by enhanced endogenous cholesterol biosynthesis.

These results both in decreased plasma LDL levels and in restoration of bile acid production.

Adverse Effects The side effects that limit their usage most often

are the associated bloating, abdominal discomfort, constipation, heartburn, steatorrhea

and malabsorption of Vit. K and folic acid. Usually the first two symptoms gradually disappear with

continued use, but for some subjects the constipation persists. Fecal impaction has been

reported. May even increase VLDL and triglycerides. May even impaired absorption of some drugs like digitalis, vancomycin, thiazide,

warfarin, iron, tetracycline, folic acid, phenylbutazone and aspirin

HMG CoA REDUCTASE INHIBITORSMechanism of Action

Inhibitors of HMG CoA reductase block synthesis of cholesterol in the liver by

competitively inhibiting HMG CoA reductase activity thus ↓LDL and TAG and ↑ HDL

cholesterol.

Therapeutic Uses

The initial choice of which statin to use depends on the degree of cholesterol lowering desired.Useful alone or in combination with bile acid binding resins or niacin.

For greater lowering of LDL, particularly in subjects with familial hypercholesterolemia, higher doses of lovastatin or simvastatin usually are required.A baseline determination of CPK activity and a panel of liver function tests should be obtained before beginning therapy, and analysis of liver transaminases should be repeated at 2 to 3 month intervals after that.

Adverse Effects The most important adverse effects are increases in hepatic transaminases in serum and myopathy. Increase creatinine kinase activity. Myopathy may be worsen if used with clofibrate, niacin, cyclosporine and erythromycin. May also cause lens opacity, lupus-like hypersensitivity and rhabdomyolysis

These compounds may cause fetal harm if given to pregnant women. They should be given to women childbearing potential only if they are unlikely to become pregnant and only in situations of extreme hypercholesterolemia not responsive to other agents. Contraindication also in lactating women and children.

ProbucolMarketed for several years for its hypolipidemic properties, but because of its erratic ability to lower LDL levels and its potent and persistent ability to lower HDL cholesterol levels, it is now considered a second or third line therapeutic agent. However, probucol is the only hypolipidemic drug that lowers cholesterol and causes regression of xanthomas in patients with homozygous familial hypercholesterolemia by reducing atherogenesis due to inhibition of foam cell formation.

The ability of probucol to inhibit atherosclerosis has been attributed to its antioxidant properties. Mechanism of action is unclear. Inhibits sterol biosynthesis. Improves transport of cholesterol from periphery to the liver. May even ↓ HDL substantially and ↓ LDL only marginally.

Adverse Effects

Gastrointestinal symptoms (diarrhea, flatulence, nausea), headache and dizziness may occur in up 10% of patients. Toxicity may include arrythmias.

Therapeutic Uses

Probucol is used primarily in subjects with homozygous familial hypercholesterolemia in whom it reduces tendon and planar xanthomas.

Inhibitors of Intestinal Sterol

Absorption

EZETIMIBE First memberInhibits phytosterol and cholesterol intestinal absorption. Readily absorbed and conjugated in the intestine through entero-hepatic circulation. Half life is 22 hours. Excreted in the feces by 50%.Undergoes glucorunidation in the intestine and the absorbed glucuronide is excreted into the bile by the liver.Used in primary hypercholesterolemia. Liver function test is requested initially and at 2-4 months.