HYPERLIPIDEMIA

The high risks of lipids and its relevance towards the development of different cardiovascular diseases has been known to all where this present slide focuses on that only along with the different treatment procedures,.

1. HYPERLIPIDEMIA PRESENTED BY : ANAND SAGAR TIWARI M.PHARM ( FIRST SEMESTER) DEPARTMENT OF PHARMACOLOGY GUIDED BY : Mr. ASHOK KUMAR DASTAPUR

2. OVERVIEW Basic concepts Hyperlipidemia Effect on heart Anti- hyperlipidemics

3. INTRODUCTION Hyperlipidemia is defined as abnormally raised/elevated levels of any or all lipids in the blood. It results from abnormalities in lipid metabolism or plasma lipid transporters or a disorder in the synthesis and degradation of plasma lipoproteins . Hyperlipidemia is a broad term also called hyperlipoproteinemia is a common disorder in developed countries. It is the most common form of dyslipidemia. Lipoproteins are transported in a protein capsule where the size of the capsule or lipoprotein determines its density. Lipoproteins of low density are the main cause for hyperlipidemia.

4. CLASSIFICATION Hyperlipidemia may be basically classified as: Familial (Primary hyperlipidemia): Caused by specific genetic abnormalities Secondary hyperlipidemia : Results from another underlying disorder that leads to alterations in the plasma lipid and protein metabolism. Idiopathic hyperlipidemia : Cause is unknown.

5. FAMILIAL HYPERLIPIDEMIA Familial hyperlipidemia are classified according to the Fredrickson classification , which is based on the pattern of lipoproteins on electrophoresis or ultracentrifugation . It does not account for HDL directly and it does not distinguish among the different genes that may be partially responsible for some of these conditions. It can be classified as: Hyperlipoproteinemia type 1(Familial lipoprotein lipase deficiency) Hyperlipoproteinemia type 2 (FH & PH) Hyperlipoproteinemia type 3 (Familial dysbetalipoproteinemia) Hyperlipoproteinemia type 4 (Hypertriglyceridemia) Hyperlipoproteinemia type 5(Familial combined hyperlipidemia)

6. Hyperlipidemias are also classified as in which type of lipids are elevated: HYPERCHOLESTEROLEMIA HYPERTRIGLYCERIDEMIA or BOTH IN CASE OF COMBINED HYPERLIPIDEMIA

7. Lipids are carried in plasma in lipoproteins after getting associated with several apoproteins. Plasma lipid concentrations are dependent on the concentration of lipoproteins . The core of lipid consists of triglycerides(TGs) or cholesteryl esters(CHEs). The outer polar layer consists of and apoproteins phospholipids, free cholesterol(CH). Based on the particle size and density lipoproteins are classified into 6 types .

8. Classification of lipoproteins Lipoproteins can be classified into 6 types based on their particle size and density. Also they all have some role to play . These can be described as follows along with their sources: Chylomicrons : Role in dietary TG transport obtained from diet Chylomicrons remnants : Role in dietary CH transport obtained from diet and Chy . VLDL : Role in endogenous TG transport synthesized in liver. IDL : Role in transporting CH & TG to liver and source of LDL obtained from VLDL. LDL : Role in transport of CH to tissues and liver and obtained from IDL. HDL : Role in the removal of CH from tissues and it is present in tissue cell membrane

9. Chylomicrons Greek chylos meaning juice (of plants and animals) and micron meaning (small particle) are lipoprotein molecules that consist of triglycerides(85-92%), phospholipids(6-12%) , cholesterol(1-3%) , and proteins(1-2%). Due to their density relative to lipoproteins, they are also commonly known as Ultra Low Density Lipoproteins(ULDL) in modern usage. These transport lipids absorbed from the intestine to adipose, cardiac and skeletal muscle tissue where their triglyceride components are hydrolyzed by the activity of lipoprotein lipase , allowing the free fatty acid to be absorbed by the tissues.

10. ORIGIN Chylomicrons are formed in the ER in the absorptive cells (enterocytes) of the small intestine. In the villi microvilli a lot of surface area for absorption. Newly formed chylomicrons are secreted through the basolateral membrane into the lacteals joining to lymph to form chyle. Lymphatic vessels carry the chyle to the venous return of the systemic circulation. From there the chylomicrons supply the tissue with fat absorbed from the diet.

11. Chylomicrons remnants Once triglyceride stores are distributed, the chylomicron returns APOC2 to the HDL(but keeps APOE), and , thus, becomes a chylomicron remnant, now only 30-50 nm . APOB48 and APOE are important to identify the chylomicron remnant in the liver for endocytosis and breakdown .

12. Intermediate density lipoproteins Intermediate density lipoproteins (IDLs) belong to the lipoprotein particle family and formed from the degradation of VLDL as well as HDL . Each native IDL particle consists of proteins that encircles various lipids , enabling ,as a water soluble particle, these lipids to travel in the aqueous blood environment as part of the fat transport systems within the body. Size is in the range of 25-35 nm . IDL transport a variety of triglyceride fats and cholesterol and ,like LDL, can also promote the growth of Atheroma .

13. VLDL , a large triglyceride-rich lipoprotein secreted by the liver transports triglyceride to adipose tissues and muscle . The VLDL are removed in the capillaries by the enzyme lipoprotein lipase and the VLDL returns to the systemic circulation as IDL. The IDL particles have lost most of their triglyceride but they retain cholesteryl esters . Some of the IDL remain in the circulation where they are converted into LDL . IDL contain multiple copies of the receptor ligand ApoE in addition to a single copy of ApoB-100 .

14. Very Low Density Lipoprotein(VLDL) VLDL with density relative to extracellular water is a type of lipoprotein made by the liver from triglycerides , cholesterol and apolipoproteins . These have a diameter of 30-80 nm . It functions as a the body’s internal transport mechanism for lipids and transports endogenous triglycerides, phospholipids, cholesterol and cholesteryl esters . It serves for long range transport of hydrophobic intracellular messengers like the morphogen Indian Hedgehog (protein).

15. Low Density Lipoprotein (LDL) LDL is one of the five major groups of lipoprotein which transport all fat molecules around the body in the extracellular water. However LDL can contribute to atherosclerosis if it is oxidized within the walls of the arteries. Though regarded as bad lipids they are not exactly bad and conduct nutrients to vessels that large LDL cannot reach. A single LDL particle is about 220-275angstroms in diameter, typically transporting 3000-6000 fat molecules/particle . LDL particles are thought to evade the endothelium and become oxidized since the oxidized forms may be easily retained by the proteoglycans .

16. High Density Lipoprotein (HDL) High density lipoproteins are of the five major groups of lipoproteins. They are typically composed of 80-100 proteins per particle (organized by one, two or three ApoA ; more as the particles enlarge picking up and carrying more fat molecules) and transporting up to hundreds of fat molecules per particle. It is the smallest of lipoproteins and contains the highest proportion of proteins to lipids . Mainly transports cholesterol to liver or steroidogenic organs as adrenals, ovary and testes and finally removed by HDL receptors such as s cavenger receptor BI(SR-BI).

17. TREATMENTS

18. Statins(HMG-CoA reductase inhibitors) These are a class of lipid lowering agents that reduce mortality and illness in those who are at a higher risk of cardiovascular disease. They inhibit the enzyme HMG-CoA reductase which plays a central role in the production of cholesterol and high cholesterol levels are associated with CVD . These are effective in lowering LDL cholesterol and are widely used for primary prevention in people at high risk of heart related diseases. e .x . Atorvastatin, Lovastatin, Simvastatin etc.

19. Mechanism of action ( MoA ) 70-75% of plasma LDL is removed by hepatocytes by receptor mediated endocytosis and cholesterol esters from LDL molecules are hydrolyzed in the liver to free cholesterol . d e novo synthesis of cholesterol takes place in liver by a pathway involving formation of mevalonic acid by the enzyme HMG-CoA reductase . Statins inhibit this rate limiting step. Thus decreasing hepatic cholesterol synthesis and increasing synthesis of high affinity LDL receptors . Increased clearance of cholesterol-rich plasma LDL with subsequent reduction in plasma LDL cholesterol where the effect is dose dependent with full effect seen in 6 weeks .

20. PHARMACOKINETICS Orally administered and absorption of statins varies between 40-90%. Fluvastatin is absorbed almost completely. Lovastatin and simvastatin are prodrugs and hydrolyzed in the GI tract to the active metabolites. Atorvastatin , rosuvastatin are fluorinated compounds that are active as such . All undergo first-pass metabolism and most of the dose is excreted in the bile; only about 5-20 % is excreted in the urine.

21. SIDE EFFECTS Muscle pain Increased risk of Diabetes Mellitus. Abnormal blood levels of liver enzymes. Severe side effect includes Muscle damage

22. Adverse drug reaction Mostly mild and dose dependent they may cause reversible rise in the hepatic aminotransferase level . Rarely it may be marked and accompanied by muscular pain (myositis) and even myopathy. Rhabdomyolysis is rare. Rarely statins may cause impotence, gynecomastia, memory loss, insomnia, mood changes and depression . Also they are contraindicated in pregnancy and in woman planning to be pregnant, during breast-feeding, in children and in patients with severe liver disease.

23. Drug interactions Combination of a statin with a fibric acid derivative and nicotinic acid potentiates the rise in plasma CPK level . Lovastatin , simvastatin undergo metabolism by CYP3A4 and their toxicity can be increased by the concurrent use of hepatic microsomal enzyme inhibitor such as ketoconazole, isoniazid, erythromycin etc. Fluvastatin and rosuvastatin are metabolized by hepatic CYP2C9 . Inhibitors of this enzyme like ketoconazole and cimetidine can increase the plasma levels of these statins. Max. dose is 10 mg in patients taking Amiodarone , dilitiazem and 20 mg in people with amlodipine and ranolazine .

24. Therapeutic uses Statins are useful in both primary and secondary prophylaxis of hypercholesterolemia . Indicated during MI or any cardiovascular event Patient less than 70 years old with known IHD. Diabetes mellitus. Subjects with strong family history of premature cardiovascular disease. Individuals with clinical evidence of ASCVD . Subjects with primary elevation of LDL> 190mg%

25. DRUG STARTING/MAX DOSE Lovastatin 10/80 Pravastatin 10/20 Simvastatin 5/20 Fluvastatin 20/60 Atorvastatin 10/40 Rosuvastatin 2.5/20

26. Cholesterol Absorption inhibitors EZETIMIBE : Mechanism of action This prodrug , 2-azetidinone is converted in intestine to an active metabolite ezetimibe glucournide (t1/2-22 hr.). It binds to intestinal mucosal transporter NPC1L1 protein and decreases delivery of dietary and biliary cholesterol to the liver. Thus inhibiting absorption of cholesterol by the small intestine. Reduction of hepatic cholesterols stores causes increase in LDL receptors on the hepatocytes and an increased LDL cholesterol decreases with minimal increase in HDL-C . It also interrupts the entero - hepatic cycling of cholesterol.

27. Adverse Reactions Fatigue Dizziness Abdominal discomfort Diarrhoea Arthralgia Hypersensitivity reactions

28. Therapeutic uses It can be used as monotherapy in the dose of 5-10 mg/day . It acts synergistically when combined with statins and particularly useful in patients who don’t tolerate large doses of statins.

29. Nicotinic Acid Niacin also known as nicotinic acid is an organic compound and a form of vitamin B3 . This vitamin in large doses effectively and rapidly reduce plasma TG by lowering VLDL levels . LDL levels diminish more slowly and HDL levels rise during therapy.

30. Mechanism of action In the adipose tissue, nicotinic acid inhibits adenylyl cyclase , and prevents lipolysis by hormone sensitive lipase. This reduces the transport of fatty acids to the liver. In the liver it reduces both synthesis and esterification of fatty acids. The end result is reduction in the hepatic production of VLDL and in plasma TG , VLDL cholesterol and LDL cholesterol .

31. Adverse Reactions Intense cutaneous flushing Pruritus by increasing the local prostaglandin levels. Nausea Diarrhoea, Vomiting Clinical jaundice Hyperglycemia Hyperuricemia Abnormalities of liver function

32. Therapeutic uses Nicotinic acid is useful in all forms of hyperlipoproteinemia except type 1 and is a drug of choice in type 5 hyperlipoproteinemia . Usual dose is 2-8 g/day .

33. Fibrates The fibrates are a class of amphipathic carboxylic acids . They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents. These are the derivatives of fibric (isobutyric acid) and include gemfibrozil , benzafibrate and fenofibrate .

34. Mechanism of action These drugs stimulate the nuclear transcription receptor, Peroxisome Proliferator Activated Receptor-alpha that controls the expression of gene, which mediate TG metabolism . They increase lipoprotein lipase activity ( lpL ) and the hydrolysis of TG and promote HDL production. They reduce the incorporation of fatty acids into VLDL in the liver, thus inhibiting its synthesis and secretion. The plasma TG declines by 50% and cholesterol by 10-15%.

35. Pharmacokinetics Almost completely absorbed from the gut, are highly protein bound (more than 90%). L argely excreted unchanged in the urine .

36. Adverse reactions Allergic reactions Nausea and Diarrhoea. Serious effect on skeletal(myositis) and cardiac muscles reported. Long therapy causes gallstone formation Therapeutic uses : These drugs are effective in reducing mainly plasma TG. Fenofibrate is preferred to gemfibrozil.

37. Bile Acid Sequesterants

38. Mechanism of action Basic ion exchange resins supplied in the chloride form. Bind bile acids in the intestine interrupting their enterohepatic circulation. Fecal excretion of bile salts and CH is increased. This indirectly leads to enhanced hepatic metabolism of CH to bile acids . More LDL receptors are expressed on liver cells clearance of plasma IDL , LDL and indirectly that of VLDL is increased .

39. Adverse reactions Nausea and vomiting Heartburn and constipation Interferes with fat absorption and fat soluble vitamins. Also interferes with the absorption of thyroid hormones, tetracyclines , warfarin and phenobarbitone.

40. Combination therapy Several drug combinations are available for the treatment of combined hyperlipidemia (elevated LDL-C and elevated triglycerides, generally with concurrent low HDL-C). Statins plus niacin have been successfully used in this setting. Statin plus fibrate and stain plus fish oil combinations also is helpful. The potential benefits of combination therapy must be weighed against the potential disadvantages, including complexity of the medication regimen, higher cost, problems with adherence and increased incidence of adverse effects.

41. LATEST TRENDS in HYPERLIPIDEMIA THERAPY

42. Reference Essentials of medical pharmacology : KD Tripathi Pharmacology and Pharmacotherapeutics : Rege , Satoshkar, Bhandarkar Internet