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STATINS

STATINS. BY Dr M KUGATHASAN MD ( St.Petersburg ). OBJECTIVES. CHOLESTEROL STATINS SIMVASTATIN CURREENT ISSUES ON STATINS QUESTIONS REFERENCES. Statins : Powerful Inhibitors of Cholesterol Biosynthesis. H. O.

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STATINS

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  1. STATINS BY DrM KUGATHASAN MD (St.Petersburg)

  2. OBJECTIVES • CHOLESTEROL • STATINS • SIMVASTATIN • CURREENT ISSUES ON STATINS • QUESTIONS • REFERENCES

  3. Statins: Powerful Inhibitors of Cholesterol Biosynthesis

  4. H O CholesterCHOLESTEROLol: What is itCccccCholesterolhhhhxcc?1 • Cholesterol is a fatty steroid made primarily in the liver of most animals and humans. • It is an integral component in the synthesis of hormones, can also be found in cell walls of animals and humans. • Isolated cholesterol is a white, flaky solid that is insoluble in aqueous environments. Cholesterol

  5. Lipoprotein Classes Chylomicrons,VLDL, and their catabolic remnants LDL HDL > 30 nm 20–22 nm 9–15 nm Potentially pro-inflammatory Potentially anti-inflammatory

  6. Two types of transportation for cholesterol • In order to transport the steroid through blood, cholesterol is attached to a set of proteins called lipoproteins. There are two types of lipoproteins: high density and low density lipoproteins. • High-density lipoproteins –collectcholesterol particles as they travel through blood vessels and deposits them in the liver where they are transferred to bile acids and disposed off. • Low-density lipoproteins –deposits on the walls of blood vessels, and over time, builds up into cholesterol plaque and blocks blood vessels, especially arteries that feed blood to the heart. • The liver manufactures, secretes and removes LDL cholesterol from the body. To remove LDL cholesterol from the blood, there are special LDL receptors on the surface of liver cells. • LDL receptors remove LDL cholesterol particles from the blood and transport them inside the liver. A high number of active LDL receptors on the liver surfaces is necessary for the rapid removal of LDL cholesterol from the blood and low blood LDL cholesterol levels. • A deficiency of LDL receptors is associated with high LDL cholesterol blood levels. • Diets that are high in cholesterol diminish the activity of LDL receptors!!!!

  7. (-) The Role of Lipoproteins in Atherogenesis Endothelialinjury High plasmaLDL HDL Adherenceof platelets LDL+VLDL LDL infiltrationinto intima LCATAPO-A1 Releaseof PDGF Oxidativemodificationof LDL Liver Othergrowthfactors +Macrophages Foam cells Fatty streak Cholesterolexcreted Advancedfibrocalcificlesion

  8. Biological Role:1 • Why we need Cholesterol • It is an important component of cell linings • It helps in the digestion of lipids • It is a key component in the building of hormones • High blood cholesterol • Usually a result of high LDL/low HDL cholesterol levels • Leads to • narrowing of artery walls (atherosclerosis) • decreased blood and oxygen supply to heart • heart attack • death • Coronary heart disease1: Leading cause of death in western countries.

  9. Initial treatment of hypercholesteraemia was directed toward limiting LDL-cholesterol levels through: Low-cholesterol diet and regular exercise. Exercise burns fat so it is not coverted to cholesterol which the Body will have to dispose off. • This approach was not very successful because high blood • cholesterol is also hereditary (Familial Hypercholestraemia (FH))1 and a chronic condition. People with FH have defective or nonexistent LDL receptors and need rigorous, long-term treatment. • Scientific Approach: • Know and understand how the body makes cholesterol • Find a way to effectively control cholesterol levels with • minimum adverse effects

  10. Goals Recommendations Cholesterol Management Guidelines As set forth by the NCEP • Obtain a fasting lipid profile in all patients. For those with an MI, a fasting lipid profile should be obtained within 24 hours of admission. • Start therapeutic lifestyle changes in all patients, including: • Reduced intake of saturated fat (<7% of total calories) and cholesterol (<200 mg/day) • Addition of plant stanols/sterols (2 g/day) and viscous fiber (10-25 g/day) to enhance LDL-C lowering • Weight reduction • Increased physical activity

  11. Goals Recommendations Cholesterol Management Guidelines (Continued) As set forth by the NCEP HMG-CoA reductase inhibitors (statins) are used first-line to achieve the LDL-C goal If the LDL-C level is above goal, statin therapy should be intensified + the addition of a second LDL-C lowering agent If the TG level is >150 mg/dl or the HDL-C level is <40 mg/dl, weight loss, physical activity, and smoking cessation should be emphasized If the TG level is 200-499 mg/dl after initiation of LDL-C lowering therapy, nicotinic acid or a fibrate should be considered If the TG level is >500 mg/dl, nicotinic acid or a fibrate should be considered before starting LDL-C lowering therapy

  12. Therapies to Lower LDL Class Drug(s) 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors [Statins] Atorvastatin (Lipitor) Fluvastatin (Lescol XL) Lovastatin (generic and Mevacor) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) Bile acid sequestrants Cholestyramine (generic and Questran) Colesevelam (Welchol) Colestipol (Colestid) Cholesterol absorption inhibitor Ezetimibe (Zetia) Nicotinic acid Niacin Dietary Adjuncts Soluble fiber Soy protein Stanol esters

  13. VLDLR LDL Mechanism of Action VLDL Cholesterol synthesis Apo B LDL receptor (B–E receptor) synthesis LDL-R–mediated hepatic uptake of LDL and VLDL remnants Apo E Serum LDL-C Intracellular Cholesterol Apo B Serum VLDL remnants Serum IDL Hepatocyte Systemic Circulation The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and increases uptake of non-HDL particles from the systemic circulation

  14. ER = extended release; IR = immediate release; LA=long acting; TG=triglycerides; FCT=film coated tablet; SR=sustained release

  15. Gall Bladder Liver Bile Acid Sequestrant: Mechanism of Action  Cholesterol 7- hydroxylase • Conversion of cholesterol to BA • BA Secretion Bile Acid Enterohepatic Circulation Terminal Ileum • LDL Receptors • VLDL and LDL removal Reabsorption of bile acids • BA Excretion  LDL-C BA=Bile acid, LDL-C=Low density lipoprotein cholesterol, VLDL=Very low density lipoprotein cholesterol

  16. Ezetimibe: Mechanism of Action Production in liver Absorption from intestine Bloodstream Dietary cholesterol LDL-C VLDL Biliary cholesterol Cholesterolsynthesis Chylomicrons Fecal sterols and neutral sterols

  17. LDL Nicotinic Acid: Mechanism of Action Mobilization of FFA Apo B Serum VLDL results in reduced lipolysis to LDL VLDL VLDL TG synthesis VLDL secretion Serum LDL HDL Liver Circulation Hepatocyte Systemic Circulation Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in reduced LDL-C levels and increased HDL-C levels

  18. Fibrate: Mechanism of Action Fibrate + TG LPL + VLDL Intestine IDL LDL-R CE FC FC CE Liver Nascent HDL Macrophage Mature HDL

  19. Therapy TC LDL-C HDL-C TG Patient tolerability Statins* ¯ 19-37% ¯ 25-50% ­ 4-12% ¯ 14-29% Good Ezetimibe ¯ 13% ¯ 18% ­ 1% ¯ 9% Good Bile acid sequestrants ¯ 7-10% ¯ 10-18% ­ 3% Neutral or ­ Poor Nicotinic acid ¯ 10-20% ¯ 10-20% ­ 14-35% ¯ 30-70% Reasonable to Poor Fibrates ¯ 19% ¯ 4-21% ­ 11-13% ¯ 30% Good Cholesterol Management Pharmacotherapy

  20. Who should receive statin therapy?

  21. In 1Hh9Histor76…….. • ML-236A, ML-236B, ML-236C: metabolites isolated from a fungus (Penicilliumcitrinum) were found to reduce serum cholesterol levels in rats. • This work was done by Akira Endo, Masao Kuroda and Yoshio Tsujita at the Fermentation Research Laboratories, Tokyo, Japan.3 Preliminary experiments showed that these fungal metabolites had no effect on mevanolate or other steps in the biosynthetic pathway. This led to the speculation that their action was somewhere between the mevanolate and the HMG-CoA β

  22. Target: HMG-CoA Reductase (HMGR) • The enzyme that catalyzes the conversion of HMG-CoA to mevanolate. • This reaction is the rate-determining step in the synthetic pathway. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)

  23. Who Should Receive Statins? • ≥40 yrs old or • Macrovascular disease or • Microvascular disease or • DM >15 yrs duration and age >30 years or • Warrants therapy based on the 2012 Canadian Cardiovascular Society lipid guidelines Among women with childbearing potential,statins should only be used in the presence of proper preconception counseling & reliable contraception. Stop statins prior to conception.

  24. Statin Options

  25. Statin Therapy Beneficial Among Patients SIMVASTATIN PLACEBO Rate ratio & 95% CI (10269) (10267) STATIN better PLACEBO better Previous MI 999 (23.5%) 1250 (29.4%) Other CHD (not MI) 460 (18.9%) 591 (24.2%) No prior CHD CVD 172 (18.7%) 212 (23.6%) PVD 327 (24.7%) 420 (30.5%) Diabetes 276 (13.8%) 367 (18.6%) ALL PATIENTS 2033 (19.8%) 2585 (25.2%) 24% reduction (P<0.00001) HPS = Heart Protection Study 0.4 0.6 0.8 1.0 1.2 1.4

  26. Statin Therapy Should be Concomitant with Lifestyle Therapy • Smoking cessation • Energy-restricted diet (see CPG Chapter 11) • Low cholesterol • Low saturated and trans fatty acids • Low refined carbohydrates • Include viscous fibres, plant sterols, nuts, soy proteins • Alcohol in moderation • Physical activity (see CPG Chapter 10)

  27. Simvastatin • IS IT SUITABLE FOR EVERYONE? • DRUG DRUG INTERACTIONS • SIDE EFFECTS

  28. CURRENT ISSUES ON STATINS • BMJ • SAGA • DAILY EXPRESS

  29. Take home messagesssonclutttsions • Coronary heart disease, a condition caused by hypercholestraemia is a major leading cause of death in most western countries. • The discovery of natural statins (lovastatin and compactin) lead to innovative approaches to treatment of high cholesterol. • These natural statins have also served as templates for making synthetic statins, most of which are on the market today. • With understanding of the SAR of statins and their interactions with HMGR (bonding nature, etc), we can improve the effectiveness of these drugs and limit side-effects.

  30. Questions?

  31. efeRRRRRRrences REFERENCES • Lee, D. Cholesterol and the heart. http://www.medicinenet.com/cholesterol/ (Sept 2004). • Diwan, J. J. Cholesterol Synthesis. http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm (Sept 2004). • KUMAR AND CLARKE 8TH Edition. • BMJ – 349:1.44 No 7968,7970. • BRITISH HEART FOUNDATION – STATINS. • NHS CHOICES SIMVASTATIN. • SAGA – Dr MALCOM KENDRICK.

  32. “If you are going through hell, keep going” By: Sir Winston Leonard Spencer Churchill THANK YOU

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