1. Hyperlipidemias

2. 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

3. 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

4. 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

6. 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

8. 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

9. 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)

10. 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

11. 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

13. 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

14. 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

15. 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

17. 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

18. 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

20. 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

22. 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

23. 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)

24. 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

25. 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