Lecture 20 - Hyperlipidemia-2

HYPERLIPIDEMIAS  Cholesterol is a necessary component of cell membranes and is a precursor of steroid hormones.  Cholesterol is derived from both exogenous (dietary) and endogenous (synthesized in the liver) sources.

 Excessively high plasma levels of cholesterol and related triglycerides constitute a major risk factor for the development of atherosclerosis and coronary artery disease.  Cholesterol and the triglycerides are transported in blood via large globular particles called lipoproteins.

CLASSIFICATION OF PLASMA LIPOPROTEINS

There are four types:

Chylomicrons:  Formed in the intestine from food.  They contain mainly triglycerides synthesized from fatty acids with more than 12 carbons and cholesterol.  Once absorbed into lymph and transported to plasma, chylomicrons are acted upon by lipoprotein lipase to release triglycerides which are subsequently stored as fat or converted to fatty acids.

VLDL  Formed in the liver from free fatty acids (FFA), cholesterol, and carbohydrate, VLDL are subsequently stripped of some of their triglycerides and converted to intermediate density lipoproteins (IDL) or remnants.

LDL  As IDL loses more triglycerides, it is converted into LDL. LDL contains mainly cholesterol.

HDL  Produced by the liver and converted to mature HDL in the circulation as a result of acquiring cholesterol esters and apoproteins from other lipoproteins.

HYPERLIPIDEMIAS  Hyperlipidemia is a condition in which the plasma concentration of cholesterol or triglyceride exceeds the normal limit.

Hyperlipidemias Could be 1. Primary – familial history –genetically determined 2. Secondary – due to diseases such as diabetes, liver diseases, alcoholism, nephrotic syndrome, hypothyroidism

Hyperlipidemias can be classified into 2. Hypercholesterolemia 3. Hypertriglyceridemia 4. Mixed (i.e. hypercholesterolemia and hypertriglyceridemia).

THERAPEUTIC STRATEGIES 2. Dietary control 3. Eliminate predisposing or aggravating factors – diabetes, alcoholism hypothyroidism, smoking hypertension 3. Drug treatment.

DRUG TREATMENT OF HYPERLIPIDEMIAS Administration of drugs that would lower plasma concentration of lipoproteins either by d. reducing the production of lipoproteins and/or e. enhancing the efficiency of their removal from the plasma.

Anti-lipidemic drugs HMG-CoA reductase inhibitors Fibric acid derivatives Bile acid sequestrants Nicotinic acid Probucol

Clofibrate  Lower VLDL, Intermediate density lipoproteins, and plasma triglyceride

Mechanism of Action:  Increases breakdown of VLDL and chylomicrons by increasing the activity of lipoprotein lipase.  interferes with hepatic synthesis and release of VLDL.  inhibits lipolysis in adipose tissues.  reduces hepatic synthesis of cholesterol probably as a result of altered VLDL metabolism.

Uses  Clofibrate is used to treat hyperlipidemias of various etiologies in which there is an increase in VLDL levels.  It has mild antidiuretic action in individuals with mild or moderate diabetes insipidus

Adverse effects  Clofibrate is generally well tolerated.  However, some side effects have been reported.  These include weight gain, alopecia, nausea, cholelithiasis and cholecystitis, leucopenia, rash and drowsiness.

Gemifibrozil  It is an analog of clofibrate.

Actions  Decreases VLDL and increases HDL and slightly reduces LDL

Mechanism of Action:  It decreases lipolysis in adipose tissues thus reducing the free fatty acid substrates for hepatic synthesis of triglycerides.  It also increases the clearance of VLDL from the circulation.

Uses  It is the drug of choice for patients with hypertryglyceridemia with or without hypercholesterolemia.

Adverse effects  Incidence of adverse effects is low nausea, vomiting, abdominal pain and epigastric pain

DRUGS AFFECTING PLASMA CHOLESTEROL Cholestyramine & Colestipol Mechanism of Action:  Cholestyramine and colestipol are non-absorbed resins that sequester bile acids in the intestine, preventing their absorption.  The decreased concentration of bile acids returning to the liver increases the conversion of cholesterol to bile acids, resulting in a decrease in hepatic cholesterol.

Mechanism of Action (Cont’d):  The liver responds to a lowering of its cholesterol content by forming more LDL receptors.  As a result of the greater of LDL receptors on hepatocyte plasma membranes, LDL catabolism is increased.

Actions  Reduce the concentration of cholesterol in the plasma by lowering the levels of LDL.  In most patients, the concentration of VLDL is slightly increased during therapy.  Treatment with these drugs is also associated with an increase in the number of LDL receptors.  Effectiveness of these compounds depends on the ability of hepatic cells to increase LDL receptors.  May also raise HDL levels slightly.

Uses  Treatment of hyperlipidemias.  Cholestyramine is the drug of choice for hypercholesterolemia.

Adverse effects  Abdominal pain, constipation, nausea.

Nicotinic Acid  It lowers plasma levels of both LDL-cholesterol and triglyceride.  It increases the concentration of HDL-cholesterol

 Decrease hepatic synthesis of VLDL. Since LDL is derived from VLDL, a reduction in the VLDL would also result in a decreased plasma LDL.  inhibits lipolysis  increases activity of lipoprotein lipase

Uses  Treatment of hyperlipoproteinemia

Adverse effects  Intense cutaneous flush, nausea, abdominal pain, hyperglycemia, jaundice and increase in plasma concentration of uric acid.

HMG-CoA Reductase Inhibitors Statins eg lovastatin, simvastatin, atorvastatin Dose-dependent decrease in LDL-cholesterol.  Increased HDL levels  Increase number of LDL-receptors

Mechanism of Action ♦ A potent inhibitor of HMG-COA reductase, the rate-limiting step in the synthesis of cholesterol. ♦ Increase the number of LDL receptor.

Statins ----They are effective orally even though Bioavailability could be affected by first pass metabolism in the liver. --- Lovastatin and Simvastatin are prodrugsThey are converted in the GIT into active compounds

Uses  First-line drug for patients at high risk of myocardial infarction due to hypercholesterolemia.  It is also effective in patients with hypercholesterolemia associated with diabetes mellitus or nephritic syndrome

Adverse effects  Long treatment may cause a rise in serum levels of the liver enzyme, transaminase.  Other adverse effects include myopathy and ocular damage (cataract).

Probucol  Lowers serum cholesterol and decreases LDL  Probucol treatment results in the production of structurally altered LDL, which is more rapidly removed from the circulation.  Probucol also has antioxidant properties.  This may reduce uptake of plasma lipids by microphages thus reducing their atherogenic nature.

Uses  Treatment of primary hypercholesterolemia associated with elevated LDL.  Usually reserved for patients resistant or hypersensitive to other cholesterol lowering drugs.

Adverse effects  Adverse effects are usually mild and of short duration.  They include nausea, diarrhea, flatulence, abdominal pain, Nausea, Vomiting.