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- D/D interactions
Lovastatin, simvastatin, and atorvastatin are primarily metabolized by CYP3A4 system of intestines and liver to more water-soluble metabolites that are excreted in both the bile and urine
CYP3A4 enzyme inhibitors (e.g. macrolide antibiotics, cyclosporine, HIVprotease inhibitors, tacrolimus, nefazodone, & fibrates) increase plasma statin levels and thus increase the risk of toxicity
CYP3A4 enzyme inducers (e.g. phenytoin, griseofulvin, barbiturates, rifampin, and thiazolidinediones) increase expression of CYP3A4 and can reduce the plasma concentrations of the statins

26. Statins- D/D interactions
The metabolism of fluvastatin and rosuvastatin is mediated by CYP2C9
Therefore, inhibitors of CYP2C9 such as metronidazole, sulfinpyrazone, amiodarone, and cimetidine may increase plasma levels of fluvastatin and rosuvastatin
Pravastatin is catabolized through other pathways, including sulfation. Pravastatin and rosuvastatin appear to be the statins of choice for use with verapamil, the ketoconazole group of antifungal agents, macrolides, and cyclosporine
Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily

27. 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

28. Niacin (Nicotinc acid)
Niacin, nicotinic acid (pyridine-3-carboxylic acid), one of the oldest drugs used to treat dyslipidemia
It favorably affects virtually all lipid parameters; it decreases VLDL and LDL levels, and Lp(a), & increases HDL levels significantly
Niacin is the most effective agent for increasing HDL
Niacin

29. Niacin (Nicotinc acid)-MOA
Inhibition of VLDL secretion:
Niacin stimulates the HM74A (HM74b)-Gi-adenylyl cyclase pathway in adipocytes, inhibiting cAMP production and decreasing hormone-sensitive lipase activity and release of free fatty acids—the primary producer of circulating free fatty acids
The liver normally utilizes these circulating fatty acids as a major precursor for triacylglycerol synthesis. Thus, niacin causes a decrease in liver triacylglycerol synthesis, which is required for VLDL production

30. Niacin (Nicotinc acid)-MOA
Inhibition of VLDL secretion:
LDL is derived from VLDL in the plasma. Therefore, a reduction in the VLDL concentration also results in a decreased plasma LDL concentration. Thus, both plasma triacylglycerol (in VLDL) and cholesterol (in VLDL and LDL) are lowered

31. Niacin (Nicotinc acid)-MOA
Niacin raises HDL-C levels by decreasing the fractional clearance of apoA-I in HDL rather than by enhancing HDL synthesis, thereby increasing the apoA-I content of plasma and augmenting reverse cholesterol transport
By boosting secretion of tissue plasminogen activator and lowering the level of plasma fibrinogen, niacin can reverse some of the endothelial cell dysfunction contributing to thrombosis associated with hypercholesterolemia and atherosclerosis

32. Model of niacin's mechanism of action
HDL=high-density lipoprotein; FA=fatty acid; TG=triglycerides; apo=apolipoprotein; VLDL=very low-density lipoprotein; LDL=low-density lipoprotein. Adapted with permission from Curr Atheroscler Rep. 2000;2:36-46

33. Niacin (Nicotinc acid)-Clinical uses
HDL deficiency: niacin is the most potent antihyperlipidemic agent for raising plasma HDL levels, which is the most common indication for its clinical use
Heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia: in combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with

34. Niacin (Nicotinc acid)-ADEs
Intense cutaneous flush (accompanied by an uncomfortable feeling of warmth) The most common side effects of niacin therapy are an after each dose when niacin is started or the dose increased. Administration of aspirin prior to taking niacin decreases the flush, which is prostaglandin mediated
Pruritus, rashes, dry skin or mucous membranes, and acanthosis nigricans, which contraindicates use of niacin because of its association with insulin resistance
Some patients also experience nausea and abdominal pain
Niacin inhibits tubular secretion of uric acid and, thus, predisposes to hyperuricemia and gout. Allopurinol can be given with niacin if needed

35. Acanthosis nigricans: is a cutaneous skin disorder typically characterized by hyperpigmented, velvety, hypertrophic plaques

36. Niacin (Nicotinc acid)-ADEs
Reversible elevations in aminotransferases up to twice normal may occur, usually not associated with liver toxicity. However, liver function should be monitored at baseline and at appropriate intervals
Impaired glucose/carbohydrate tolerance (niacin-induced insulin resistance), which is usually reversible except in some patients with diabetes
Rarely, niacin is associated with arrhythmias, mostly atrial, and a reversible toxic amblyopia
Niacin may potentiate the action of antihypertensive agents, requiring adjustment of their dosages
Birth defects have been reported in animals given very high dosages

37. Fibric Acid Derivatives (Fibrates)
Agents: gemfibrozil & fenofibrate
All of the fibrate drugs are absorbed rapidly and efficiently (>90%)
More than 95% of these drugs in plasma are bound to protein, nearly exclusively to albumin
The half-lives of fibrates differ significantly, ranging from 1.5 hours (gemfibrozil) to 20 hours (fenofibrate) The drugs are widely distributed throughout the body, and concentrations in liver, kidney, and intestine exceed the plasma level
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

38. Fibric Acid Derivatives (Fibrates)- MOA
Fibrates are ligands/agonists for the nuclear transcription receptor, PPAR-α, which is expressed primarily in the liver and brown adipose tissue and to a lesser extent in kidney, heart, and skeletal muscle
Fibrate-mediated gene expression ultimately leads to:
Increase in oxidation of fatty acids in liver and striated muscle
Decrease triacylglycerol concentrations by increasing the expression of lipoprotein lipase and decreasing apo CII concentration (an inhibitor of lipolysis)
Increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII

40. Hepatic and peripheral effects of fibrates
Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-α , which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins

41. Fibric Acid Derivatives (Fibrates)- Clinical uses
Hypertriglyceridemias in which VLDL predominate and in dysbetalipoproteinemia (type III hyperlipidemia), in which intermediate-density (IDL) lipoprotein particles accumulate
Hypertriglyceridemia that results from treatment with viral protease inhibitors

42. Fibric Acid Derivatives (Fibrates)- ADEs
Gastrointestinal effects: mild GIT disturbances, which occur in up to 5% of patients
Lithiasis: Because these drugs increase biliary cholesterol excretion, there is a predisposition to the formation of gallstones. Therefore, fibrates should be used with caution in patients with biliary tract disease or in those at high risk such as women, obese patients, and Native Americans
Muscle: Myositis (inflammation of a voluntary muscle) can occur with gemfibrozil & fenofibrate; thus, muscle weakness or tenderness should be evaluated. Patients with renal insufficiency may be at risk , because of reduced protein binding and impaired drug elimination. Risk of myopathy increases when fibrates are given with reductase inhibitors

43. Fibric Acid Derivatives (Fibrates)- ADEs
Drug interactions: Both fibrates compete with the coumarin anticoagulants for binding sites on plasma proteins, thus transiently potentiating anticoagulant activity. INR times should therefore be monitored when a patient is taking both drugs. Similarly, these drugs may transiently elevate the levels of sulfonylureas.
Contraindications: The safety of these agents in pregnant or lactating women has not been established. They should not be used in patients with severe hepatic and renal dysfunction or in patients with preexisting gallbladder disease

44. Bile Acid–Binding Resins
Agents: Colestipol, cholestyramine, & colesevelam
They have significant LDL cholesterol–lowering effects, although the benefits are less than those observed with statins
They are large polymeric cationic exchange resins that are insoluble in water that bind negatively charged bile acids and bile salts in the small intestine. The resin/bile acid complex is excreted in the feces, thus preventing the bile acids from returning to the liver by the enterohepatic circulation

45. Bile Acid–Binding Resins
The interruption of the reabsorption process depletes the pool of bile acids, and hepatic bile-acid synthesis increases. As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors. The increase in hepatic LDL receptors increases LDL clearance and lowers LDL-C levels, but this effect is partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase

46. Bile Acid–Binding Resins- Clinical uses
The bile acid–binding resins are the drugs of choice (often in combination with diet or niacin) in treating Type IIa and Type IIb hyperlipidemias
Cholestyramine may be helpful in relieving pruritus caused by accumulation of bile acids in patients with biliary obstruction
Digitalis toxicity because the resins bind digitalis glycosides
VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin, requiring the addition of a second agent such as niacin

47. Bile Acid–Binding Resins (ADEs)
Gastrointestinal effects: The most common side effects are gastrointestinal disturbances, such as constipation, bloating, diarrhea, & heartburn
Impaired absorptions: malabsorption of vitamin K leading to hypoprothrombinemia
Drug interactions: intestinal absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, and ascorbic acid

48. Inhibitors of Intestinal Sterol Absorption
Ezetimibe selectively inhibits intestinal absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood
It acts by blocking a transporter protein ,NPC1L1, in the brush border of enterocytes

49. Ezetimibe binds to the NPC1L1 protein on epithelial cells, blocking the absorption of cholesterol

50. Ezetimibe- Clinical uses
Primary hypercholesterolemia: Ezetimibe lowers LDL cholesterol by 17 percent and triacylglycerols by 6 percent, and it increases HDL cholesterol by 1.3 percent
Phytosterolemia

51. Ezetimibe- ADE
Ezetimibe is generally well tolerated but can cause diarrhoea, abdominal pain or headache; rash and angio-oedema have been reported
Low incidence of reversible impaired hepatic function with a small increase in incidence when given with a HMG-CoA reductase inhibitor
Myositis has been reported rarely
Bile acid sequestrants inhibit absorption of ezetimibe, and the two agents should not be administered together