Hyperlipidemias

Introduction Hyperlipidemia is a major cause of atherosclerosis and atherosclerosis-associated conditions, such as coronary heart disease (CHD), ischemic cerebrovascular disease, and peripheral vascular disease Markedly lowering blood cholesterol can halt and even reverse to some extent the progression of atherosclerosis

Introduction Triglycerides (TG) and cholesterol are essential constituents of the organism TG represents a form of energy store Cholesterol is a basic building block of biological membranes Both lipids are water insoluble and require appropriate “packaging” for transport in the aqueous media of lymph and blood Plasma lipids are transported in complexes called lipoproteins

Plasma lipoprotein metabolism Lipoproteins are macromolecular assemblies that contain lipids and proteins Lipoproteins consist of a central core of hydrophobic lipid (including triglycerides and cholesteryl esters) encased in a hydrophilic coat of polar phospholipid, free cholesterol and apolipoprotein Apolipoproteins or apoproteins, provide structural stability to the lipoproteins, and also may function as ligands in lipoprotein-receptor interactions or as cofactors in enzymatic processes that regulate lipoprotein metabolism

Plasma lipoprotein metabolism According to the amount and the composition of stored lipids, as well as the type of apolipoprotein, one distinguishes four transport forms: Low-density lipoprotein LDL-C particles Very low-density lipoprotein (VLDL) particles High density lipoprotein (HDL) particles Chylomicrons

Plasma lipoprotein metabolism There are different pathways for exogenous and for endogenous lipids In the exogenous pathway, cholesterol and TG absorbed from the ileum are transported as chylomicrons, in lymph and then blood, to capillaries in muscle and adipose tissue TG are hydrolysed by lipoprotein lipase (LPL), and the tissues take up the resulting free fatty acids (FFA) and glycerol Chylomicron remnants are rapidly cleared from the plasma by the liver

Plasma lipoprotein metabolism In the endogenous pathway, cholesterol and newly synthesised TG are transported from the liver as VLDL to muscle and adipose tissue, where TG is hydrolysed to FA and glycerol Depletion of triglycerides produces remnants (IDL), some of which undergo endocytosis directly by liver (40% to 60%) The remainder of IDL is converted to LDL by further removal of triglycerides mediated by hepatic lipase (HL)

Plasma lipoprotein metabolism About 70% of LDL is removed from plasma by hepatocytes Cells take up LDL-C by endocytosis via LDL receptors that recognise LDL apolipoproteins LDL-C provides the source of cholesterol for incorporation into cell membranes and for synthesis of steroids Cholesterol can return to plasma from the tissues in HDL particles

Plasma lipoprotein metabolism Cholesterol is esterified with long-chain fatty acids in HDL particles, and the resulting cholesteryl esters are transferred to VLDL or LDL particles by a transfer protein present in the plasma and known as cholesteryl ester transfer protein (CETP) Cholesterol liberated in hepatocytes is stored, oxidised to bile acids, secreted unaltered in bile. The bile acids, metabolites of cholesterol, are normally efficiently reabsorbed in the jejunum and ileum

Lipoprotein Disorders Dyslipidemias, including hyperlipidemia (hypercholesterolemia) and low levels of high-density-lipoprotein cholesterol (HDL-C), are major causes of increased atherogenic risk Risk of heart disease increases with concs of the atherogenic lipoproteins (LDL, VLDL, & chylomycrone), is inversely related to levels of HDL, and is modified by risk factors

The Primary Hyperlipoproteinemias Disorder  Manifestations  Primary chylomicronemia (familial lipoprotein lipase or cofactor deficiency) Chylomicrons, VLDL increased Familial hypertriglyceridemia-Severe VLDL, chylomicrons increased   Moderate VLDL increased; chylomicrons may be increased Familial combined hyperlipoproteinemia VLDL predominantly increased   LDL predominantly increased VLDL, LDL increased Familial dysbetalipoproteinemia VLDL remnants, chylomicron remnants increased Familial hypercholesterolemia     Heterozygous LDL increased   Homozygous Familial ligand-defective apo B Lp(a) hyperlipoproteinemia Lp(a) increased

Drugs Used in Hyperlipidemia Antihyperlipidemic drugs target the problem of elevated serum lipids with complementary strategies The main agents used clinically are: Statins: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors Fibrates Inhibitors of cholesterol absorption Nicotinic acid or its derivatives

HMG-CoA Reductase inhibitors Agents: Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin The statins are the most effective and best-tolerated agents for treating dyslipidemia These drugs are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate-limiting step in cholesterol biosynthesis

Statins- Mechanism of action Inhibition of HMG CoA reductase: Statins competitively inhibit HMG-CoA reductase (the rate-limiting enzyme in cholesterol synthesis) By reducing the conversion of HMG-CoA to mevalonate, statins inhibit an early and rate-limiting step in cholesterol biosynthesis Because cholesterol synthesis occurs predominantly at night, reductase inhibitors—except atorvastatin and rosuvastatin—should be given in the evening if a single daily dose is used

Statins- Mechanism of action Increase in LDL receptors: Depletion of intracellular cholesterol causes the cell to increase the number of specific cell-surface LDL receptors that can bind and internalize circulating LDLs

Statins- Clinical uses These drugs are effective in lowering plasma cholesterol levels in all types of hyperlipidemias alone or with resins, niacin, or ezetimibe Patients who are homozygous for familial hypercholesterolemia lack LDL receptors and, therefore, benefit much less from treatment with these drugs

Statins- ADEs Liver: Elevations of serum aminotransferase activity (up to three times normal) occur in some patients This is often intermittent and usually not associated with other evidence of hepatic toxicity Therefore, it is prudent to evaluate liver function and measure serum transaminase levels periodically (every 3 months)

Statins- ADEs Muscle: The major adverse effect of clinical significance associated with statin use is myopathy Myopathy and rhabdomyolysis (disintegration or dissolution of muscle) have been reported only rarely. Between 1987 and 2001, the FDA recorded 42 deaths from rhabdomyolysis induced by statins Patients usually suffered from renal insufficiency or were taking drugs such as cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin Plasma creatine kinase (CK) levels should be determined regularly

Statins- Contraindications Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant Children or teenagers. However, there use is restricted to selected patients with familial hypercholesterolemia or familial combined hyperlipidemia