Statins and its pleiotropic effects 2

STATINS

1. STATINS AND ITS PLEIOTROPIC EFFECTS PRESENTED BY- DR.AAKANKSHA PRIYA PGY 1 AIIMS PATNA MODULATOR – DR.P.P GUPTA PROFESSOR AND HEAD OF DEPARTMENT DEPT.OF PHARMACOLOGY AIIMS PATNA

2. OVERVIEW Introduction Cholesterol and its synthesis Statins and its mechanism of action Pleiotropic effects of statins Research article on statin safety and vitamin D. Bibliography

3. INTRODUCTION Cardiovascular diseases (coronary heart disease) principal cause of morbidity and mortality in developing as well as developed countries. Atherosclerosis is the main underlying cause of disorders in CVDs. An association has been established between Elevated levels of plasma Cholesterol and increased atherosclerotic diseases. Several landmark clinical trials Eg : Scandinavian simvastatin survival study, cholesterol and Recurrent Events, Heart Protection study etc have demonstrated the benefit of lipid lowering with 3-hydroxy-3-methylglutaryl coenzyme A[HMG CoA] reductase enzyme inhibitors /statins for primary and secondary of CHDs. Statins also exerts many pleiotropic effects too.

4. CHOLESTEROL Cholesterol and its derivatives are important components of cell membrane, immediate precursors of steroid hormones, bile acids and Vitamin D synthesis.

5. CONT… Cholesterol in excessive amounts, becomes an important risk factors for CVDs. Demonstrated in clinical trials from “FRAMINGHAM HEART SOCIETY” and “MULTIPLE RISK FACTOR INTERVENTION TRIAL.” >2/3 body cholesterol is synthesized in Liver. Therefore, inhibition of hepatic biosynthesis is target of choice for reducing Serum cholesterol.

6. CHOLESTEROL SYNTHESIS PATHWAY

7. DISCOVERY OF STATINS Statins(similar to HMG CoA Reductase) were first isolated from a mold , Penicillium citrinum in 1976 by Endo et al. First statin was studied in Rats is Compactin ,( Mevastatins ) but was withdrawn due to its hepatocellular toxicity. Lovastatin become the first statin approved to be used in humans was isolated from aspergillus terreus by Hoffman et al. in 1979.

8. MECHANISM OF ACTION OF STATINS Competitive inhibitors of HMG CoA Reductase Statins occupies a portion of binding site of HMG CoA Reductase, thus blocking access of substrate to the active site on the enzyme There by reducing the conversion of HMG CoA to Mevalonate(Rate – Limiting step)

9. CONT…

10. TYPES OF STATINS.. Lovastatin Simvastatin Atorvastatin Rosuvastatin Pravastatin Pitavastatin

11. UNDERSTANDING OF PLEIOTROPIC EFFECTS Pleiotropic effects are those effects which are independent of direct reduction in Low density lipoproteins cholesterol(LDL-C). Plays an important role in reducing cardiovascular morbidity and mortality.

12. TYPES PLEIOTROPIC EFFECTS OF STATINS Improves Endothelial Function. Provides stability to the Plaques. Acts as an Anti Inflammatory agents. Provides Oxidative modification of LDL Acts as an Anti-Coagulant.

13. CNS – in case of Ischemic stroke and Dementia HEART – on Myocardium. LUNGS – copd . OTHER ORGAN PROTECTIVE EFFECTS OF STATINS

14. STATINS AND ENDOTHELIAL FUNCTIONS Main role of Vascular Endothelium – vasoconstriction /relaxation. Hypercholesterolemia adversely affects the processes by which the endothelium modulates arterial tone. Statins therapy enhances endothelial production of Vasodilator NITRIC OXIDE thus leading to improve endothelial functions. This mechanism is Independent of change of Plasma Cholesterol levels.

15. OTHER FAVOURABLE EFFECTS ON ENDOTHELIUM Restores endothelial NOS activity even in presence of HYPOXIA and OXIDIZED LDL-C. Increases the expression of Tissue – type Plasminogen activator(t-PA). Inhibits expression of endothelin-1(potent vasoconstrictor). Upregulation of Endothelial progenitor cells. Increases half life of mRNA.

16. STATINS AND PLAQUE STABILITY Plaque rupture is a major cause of Acute Coronary syndrome. Statins reduces macrophage Cholesterol accumulation. And also Reduces secretion of Metalloproteinase(a proteolytic enzyme)

17. Cholesterol-independent effects of atorvastatin prevent cardiovascular morbidity and mortality in a mouse model of atherosclerotic plaque rupture Roth, Lynn, Vascular Pharmacology, Volume 80, 50-58 Copyright © 2016 Elsevier Inc.

18. AS AN ANTI INFLAMMATORY AGENTS Atherosclerosis is a complex inflammatory process characterised by presence of monocytes /macrophages and T lymphocytes in the atheroma. Inflammatory cytokines secreted by these macrophages and T lymphocytes can modify Endothelial functions, SMC proliferation, collagen degradation, and Thrombosis.

19. Role of statins are- Decreases T- cell recruitment and activation. Reduction in expression of inflammatory cytokines and chemokines. Attenuation of expression of CD40(TNF family) in T-cells. Inhibition of SMC proliferation.

20. CLINICAL EVIDENCE OF INFLAMMATION High-sensitive C-reactive proteins( hs -CRP) is an acute phase reactant that is produced in the liver in response to proinflammatory cytokines. Elevated levels of hs -CRP indicate the risk for coronary artery disease, coronary ischemia and myocardial infarction.

21. RESEARCH ARTICLE ON hs -CRP TOPIC- Effect of Atorvastatin on hs -CRP in Acute Coronary Syndrome(ACS) PUBLISHED IN- British journal of pharmacology RESEARCH DONE AT- CMC Hospital Ludhiana AUTHOR – Gupta et al. AIM – to evaluate the effect of lower dose(20mg) Atorvastatin in patients with ACS.

22. METHOD USED.. It was prospective, open study conducted on patients enrolled for over 15months. Patients diagnosed with ACS as per criteria were included. Group A(n=50) received atorvastatin 20mg/day for 4 weeks along with std anti anginal treatment. Group B(n=50) received std anti anginal treatment without atorvastatin.

23. RESULT Data was analyzed using student t test, ANOVA and chi square test. GROUPS Hs-CRP at the begin Hs-CRP at the end % change Group A 2.32 0.57 82 Group B 1.91 1.04 54

24. CONCLUSION hs – CRP decreased in both but decrease in group A (p<0.001) was significant. The use of lower dose(20mg) of atorvastatin can offer an attractive approach for early treatment of ACS patients.

25. PROVIDES OXIDATIVE MODIFICATION OF LDL Key role in mediating the uptake of Lipoprotein cholesterol by macrophages and in other process, including cytotoxicity within lesions. Statins reduces susceptibility of lipoproteins to oxidation of both in vivo and ex vivo by neutralising reactive oxygen species and NADPH oxidase activity.

26. EFFECTS OF STATINS ON MYOCARDIUM

27. Cont …. In human studies it has been proved that statins could inhibit cardiac hypertrophy through antioxidation mechanism involving of Rac 1and NADPH oxidase.

28. Pleiotropic effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in pulmonary diseases: A comprehensive review Krishna, Rama K., Pulmonary Pharmacology & Therapeutics, Volume 30, 134-140 Copyright © 2014

29. STATINS AS ANTI COAGULANT According to JUPITER trial done by (Glynn et al 2009) concluded that there were 43% reduction in venous thromboembolic events in patients treated with Rosuvastatin, 20mg. Role of statin— Inhibition of platelets adhesion/aggregation. Reduces fibrinogen concentration. Reduces blood viscosity.

30. STATINS AND ITS EFFECT ON ISCHEMIC STROKE Heart Protection Study(HPS) conducted study in those aged over 70yrs and those presented with different levels of B.P/Lipids, even when pretreatment LDL-C was below 116mg/dl were prescribed statins. As a result there was 28% reduction in ischemic stroke in over 20,000 people with cerebrovascular diseases. Role of statin (seen in animal studies) is by upregulating of eNOS in prevention of ischemic stroke.

31. STATINS AND DEMENTIA Dementia is syndrome of chronic /progressive nature with multiple disturbances of higher cortical functions. For Eg : Alzheimer disease. In a nested case control study, based on the UK-based General Practice Research Database showed that among people of aged over 50yrs with statin therapy, risk for developing dementia was significantly reduced, independent of their lipid status.

32. STATINS IN PULMONARY DISEASE COPD- statins have Immunomodulatory effects including – Reducing Neutrophil migration Cytokine production Adverse matrix remodelling Reducing small airway inflammation.

33. ASTHMA – In laboratory animals , statins have shown immunomodulatory role in allergic lung inflammation. In human trials statins have shown negative , or perhaps only modest benefit.

34. ORIGINAL RESEARCH ARTICLE TOPIC – Statin therapy and Vitamin D RESEARCH DONE AT- Chettinad Hospital and Research Institute Chennai TN. PUBLISHED IN – International Journal of Basic and Clinical Pharmacology.

35. AIM AND METHOD USED.. AIM- To Evaluate association between statins and vitamin D. METHOD- the study was a prospective cross-sectional study. 125 participants who fulfilled the selection criteria were enrolled in the study. 65 subjects belonged to control group and 60, statin group. The blood sample were collected for vitamin D estimation. The result were correlated with demographic profile, nature of statin and muscular side effects and compared with control group.

36. SELECTION CRITERIA- Statin group- all subjects who were on any one of statins for more than 1 year. Control group- apparently healthy individuals. Subjects who were on vitamin D supplementation were excluded from both groups.

37. METHOD CONT…. From the eligible subjects, 5ml of blood was collected by direct venous puncture Vitamin D(total) was estimated with High sensitivity chemiluminescence immunoassay method. Vitamin D level in blood was classified as – Sufficient – 30-100ng/ml Insufficient – 20-29ng/ml Deficient - <20ng/ml.

38. RESULT Statistical comparison was made for vitamin D level using Independent samples t- test as well as vitamin D status using chi square test. The mean vitamin D level in statin group was 15.82ng/ml and 20.57ng in control group. This difference was found to be statistically significant(p=0.006 and 0.033) Myalgia was reported by 30 among 60 subjects(50%) in statin group and 5 among 65 subjects (7.69%) in control group.

39. CONT …. 13.85% in control group and 10% in statin group had sufficient vitamin D level. 18.33% in control group and 36.92% in statin group insufficient vitamin D level. 49.23% in control group and 71.67% in statin group had deficiency of vitamin D level.

40. DATA OF VITAMIN D LEVEL IN STATIN GROUP. Age(years) N Mean vitamin D(ng/ml) SD <40 40-60 14 15.03 12.22 >60 46 15.26 12.35 Gender Male 28 16.65 10.02 Female 32 13.94 13.90

41. DATA OF VITAMIN D LEVEL IN CONTROL GROUP. Age(years) N Mean Vitamin D(ng/ml) SD <40 12 15.13 6.46 40-60 29 20.64 7.11 >60 24 23.04 6.53 Gender Male 35 22.48 6.68 Female 30 18.20 7.29

42. VITAMIN D LEVEL IN STATIN AND CONTROL GROUP(ng/ml)

43. VITAMIN D STATUS Vitamin D status Statin group(%) Control group(%) Sufficient 6(10.00) 9(13.85) Insufficient 11(18.33) 24(36.92) Deficiency 43(71.67) 32(49.23)

44. GRAPHICAL REPRESENTATION OF VITAMIN D STATUS

45. SUMMARY.. STATIN PLEIOTROPY BENEFITS Increased synthesis of Nitric oxide Improved endothelial dysfunction Inhibition of free radical release Decreased synthesis of endothelin-1 Inhibition of LDL-C oxidation Upregulation of endothelial progenitor cell Reduced number and activities of inflammatory cells Reduced inflammatory response Reduced levels of c-reactive proteins Reduced macrophages cholesterol accumulation Stabilization of atherosclerotic plaques Inhibition of platelets aggregation Reduced thrombogenic response Reduced fibrinogen concentration Reduced blood viscosity

46. BIBLIOGRAPHY Goodman and Gilman. The Pharmacological basis of therapeutics.12 th ed.china.McGraw-Hill,2011. Bertram G. Katzung . Basic & clinical Pharmacology. 14 th ed. Chennai. McGraw-Hill, 2018. Liao JK, Laufs U. Pleiotropic effect of statins. Annu Rev Pharmacol Toxicol , 2005; 45: 89-118. Roth L et al. cholesterol- independent effects of Atorvastatin. Vascular Pharmacology, 2016; 80:50-58.

47. CONT… 5.Krishna RK et al. Pleiotropic effects of the HMG CoA inhibitors in pulmonary diseases. Pul pharma & therapeutics., 2015 ;30: 134-140. 6.Davignon J. Pleiotropic effects of pitavastatins . Br J Clin Pharmacol , 2011; 73:4, 518-535. 7.Gupta et al. Effect of Atorvastatin on hs -CRP in ACS. Br J clin Pharmacol , 2008 ; 66:3, 411-413. 8.Radhakrishanan A et al. statin therapy and vitamin D. IJBCP, 2005; 4:6 1113-1117.