Hypolipidemia, HYPOLIPIDEMIC DRUGS - Vijay.pptx

Definition of hypolipidemia, classification of hypolipidemic drugs , management of hypolipidemia

1. Hypolipidemic Drugs -By Dr. Vijay R Junior Resident King George’s Medical University, Lucknow

2. Content Introduction Metabolism Hypolipidemic drugs Pharmacotherapy of hyperlipidaemia

3. Introduction Dyslipidaemia Abnormal amount of lipids in blood Disorder of lipoprotein metabolism Lipoprotein overproduction and deficiency Lipids typically include cholesterol levels, lipoproteins, chylomicrons, VLDL, LDL, apolipoproteins, and HD L

4. Dyslipidemia is a major cause of Atherosclerotic cardiovascular disease (ASCVD), Ischemic cerebrovascular disease Peripheral vascular disease Cardiovascular disease is the number one cause of death globally (WHO) Common causes of dyslipidaemias Genetic disorders, Lifestyle factors and Metabolic diseases such as diabetes mellitus.

5. Hyperlipoproteinemia Primary : due to A single gene defect: is familial and called ‘monogenic’ or genetic Multiple genetic, dietary and physical activity related causes : polygenic or multifactorial Secondary : Associated with diabetes, myxoedema, nephrotic syndrome, chronic alcoholism, drugs (corticosteroids, oral contraceptives, beta blockers)

6. Lipid metabolism

7. LIPOPROTEIN Macromolecule = Lipid + protein (apoproteins) Lipid – free and esterified cholesterol, TGs, and phospholipids Divided into 6 classes on the basis of their particle size and density

8. HDL pathways and reverse cholesterol transport

9. Pharmacotherapy of hyperlipidaemia

10. HMG-COA Reductase Inhibit ors Most efficacious, most commonly used and best tolerated All statins produce peak LDL-CH lowering after 1-2 weeks therapy Different statins differ in their potency and maximal efficacy in reducing LDL-CH HMG-COA reductase activity maximum at midnight

11. MECHANISM OF ACTION Inhibit HMG- Co A reductase competitively (HMG-Co A to Mevalonic acid) Inhibit biosynthesis of cholesterol Depletion of cholesterol in hepatocytes Increase LDL receptors expression on hepatocytes Increased hepatic uptake of LDL , IDL & decreased plasma LDL

12. LOVASTATIN First clinically used statin Oral administration -Absorption incomplete & extensive 1st pass metabolism, T-half – 2-4 hrs. Dose- 10-40 mg /day , maximum- 80 mg. SIMVASTATIN Twice as potent & efficacious than lovastatin Greater rise in HDL-CH , T-half – 2-4 hrs Dose – 10-40 mg/day, maximum- 80 mg.

13. PRAVASATIN Efficacy nearly similar to lovastatin Additional decreases plasma fibrinogen level, T-half- 1-3 hrs Dose – 10-40 mg/day ATORVASTATIN Most commonly used due to high efficacy LDL-CH lowering is 55-60 % at 80 mg /day ceiling dose Anti-oxidant property, Longer plasma T-half – 14-18 hrs Dose – 10-40 mg/day , maximum -80 mg

14. ROSUVASTATIN Highly potent & efficacious ( 10 mg rosuvastatin= 20 mg atorvastatin) Greater LDL-CH reduction in severe hypercholesterolemia Rises Plasma HDL by 10-15 %, T-half – 18 -24 hrs . Dose – 5-20 mg once daily , maximum 40 mg /day PITAVASTATIN Latest most potent statin LDL-CH lowering is 40 % at 4 mg/ day ceiling dose Use in combination with gemfibrozil is avoided Dose – 1-4 mg/day , maximum 4 mg/day

15. Adverse effects Myopathy It is the only serious reaction Rare < 1 in 1000 Rhabdomyolysis Myopathy & liver injury are common when given with nicotinic acid/ gemfibrozil or CYP3A4 inhibitors GI complaints Headache & sleep disturbance Rashes

16. HMG-COA Reductase Inhibitors USES Primary hyperlipidaemia (1 st choice of drugs) Secondary hypercholesterolemia All types of atherosclerotic cardiovascular disease -new onset angina - MI - Acute coronary syndrome - Thrombotic stroke - Peripheral arterial disease

17. Pleiotropic Effects of Statins Anti- Inflammatory (↓CRP) Anti- Thrombotic Anti- Platelets ↑NO levels Anticoagulants (↓plasma fibrinogen) ↓ Uric acid

18. LIPOPROTEIN LIPASE ACTIVATOR ( FIBRATES ) Activators of PPAR α - gene transcription regulator ( Expressed mainly in liver & brown adipose tissue) 1 st generation – Gemfibrozil 2 nd generation - Bezafibrate Fenofibrate

19. LIPOPROTEIN LIPASE ACTIVATOR ( FIBRATES ) MECHANISM OF ACTION Increases lipoprotein lipase synthesis – ↑ clearance of triglyceride rich lipoprotein ↑ clearance of VLDL ↑ fatty acid oxidation – Lowers triglycerides ↑ HDL-Cholesterol by activation of apoA-I & apoA-II activation

20. GEMFIBROZIL ↓ plasma TG level by ↑ breakdown and ↓ hepatic synthesis of TG Completely absorbed orally Metabolised by enterohepatic circulation, Excreted in urine. T-half is 1 – 2 hours, Dose 300-600 mg per day. USES Hypertriglyceridaemia Acute pancreatitis ( for prevention) Familial hyperlipemia & Endogenous hypertriglyceridemia.

21. LIPOPROTEIN LIPASE ACTIVATOR ( FIBRATES )……… SIDE EFFECT Epigastric distress Loose motions Skin rash Blurred vision and headache CONTRAINDIACTION Children Pregnant women Renal failure

22. LIPOPROTEIN LIPASE ACTIVATOR ( FIBRATES )……… BEZAFIBRATE Greater LDL-CH lowering property than gemfibrozil. Circulating fibrinogen and glucose level decrease Absorbed orally Metabolised by enterohepatic circulation Dose 200 mg BD or TDS with meal

23. LIPOPROTEIN LIPASE ACTIVATOR ( FIBRATES )……… Side effects of Bezafibrate GI upset Myalgia Rashes Contraindications of Bezafibrate Renal failure Pregnant female Children

24. LIPOPROTEIN LIPASE ACTIVATOR ( FIBRATES )……… FENOFIBRATE Greater LDL CH lowering action than others fibrates Most suitable fibrate for combining with statins T-half 20 hours Dose -200 mg per day with milk

25. LIPOPROTEIN LIPASE ACTIVATOR ( FIBRATES )……… SIDE EFFECT OF FENOFIBRATE Myalgia Hepatitis Cholelithiasis Rhabdomyolysis & Rashes. CONTRAINDICATION OF FENOFIBRATE Chronic kidney disease Diabetes Fibrate therapy should be discontinued after 2 months If an adequate lowering of TGs level not obtained

26. LIPOLYSIS AND TRIGLYCERIDE SYNTHESIS INHIBITORS NICOTINIC ACID (Niacin) : ↑ HDL-CH up to 25-30%, ↓ TGs and LDL cholesterol. ↓ lipoprotein levels MECHANISM OF ACTION ↓ intracellular lipolysis by lipase Direct inhibition of TGs synthesis in liver ↓Apo A1 degradation(HDL)

27. LIPOLYSIS AND TRIGLYCERIDE SYNTHESIS INHIBITORS………. USES Hypertriglyceridaemia Familial hypertriglyceridemia Mixed hypertriglyceridaemia Heterozygous hypercholesteremia

28. LIPOLYSIS AND TRIGLYCERIDE SYNTHESIS INHIBITORS………. SIDE EFFECT Flushing (MC) Contraindication : Pruritis and rashes Diabetes (cutaneous vasodilation) Pregnancy Dyspepsia Childrens Skin dryness Hyperuricemia Other long term effects are : liver dysfunction and Jaundice

29. LIPOLYSIS AND TRIGLYCERIDE SYNTHESIS INHIBITORS………. Dose : Start with 100 mg TDS gradually increase 2-4 gm daily divided dose Aspirin taken before niacin substantially attenuate flushing by inhibition of PG synthesis Laropiprant combining with it to reduce flushing Use of sustained release (ER/SR) tablet to subdue flushing

30. STEROL ABSORPTION INHIBITOR EZETIMIBE MECHANISM OF ACTION Inhibition of cholesterol absorption by intestinal mucosa (NPC1L1 transport protein) Niemann Pick C1 – like 1 protein Compensatory hepatic CH production ↑ LDL – CH lower by 15 – 20%

31. EZETIMIBE……. Enhance cholesterol synthesis block by combining with statins t1/2 = 22 hrs Low dose statins + ezetimibe effective as high dose of statin alone 60% decrease LDL –CH No specific adverse effect Dose – 10 mg OD

32. BILE ACID SEQUESTERANT (RESINS) MECHANISM OF ACTION Highly positively charged molecules that bind negatively charged bile acids. Safest as not absorbed from intestine. Due to large size, resins are not absorbed and bound bile acids are excreted in stool Pool of bile acids depleted

33. BILE ACID SEQUESTERANT……… Not popular clinically because they SIDE EFFCTS: Unpalatable Heart burn Inconvenient Flatulence Have to be taken in larger dose Dyspepsia Interfere with absorption of many drugs Malabsorption of Vit K Poor patient acceptability and folic acid All the hypolipidemic drugs are absolutely C/I in pregnancy except Resins - DOC in pregnancy.

34. PCSK 9 inhibitors ( Proprotein convertase subtilisin/ kexin type 9) A lirocumab E volocumab I nclisiran (mRNA) 1 st two are monoclonal antibodies Injectable and expensive

35. PCSK9, a product of hepatocytes S ecreted into the plasma W here it binds to the LDL receptors facilitating lysosomal degradation of LDL receptors ↓ the expression of LDL receptors on the cell membrane ↓ the clearance of LDL cholesterol.

36. USES Adults R educe the risk of MI , stroke, and unstable angina P rimary hyperlipidemia, H eterozygous familial hypercholesterolemia H omozygous familial hypercholesterolemia

37. Newer Drugs Saroglitazar - PPAR α and PPAR γ agonist Icosapent ethyl - Omega -3 Fatty Acid Ethyl Esters Lomitapide - Inhibitor of Microsomal Triglyceride Transfer Bempedoic Acid - ATP-Citrate Lyase Inhibitor Evinacumab - dgnb - Inhibitor of Angiopoietin- Like Protein 3 Torcetrapib, Anacetrapib - CETP inhibitor. Anacetrapib banned → ↑↑ MI/Stroke, ↑ HDL. Avasimibe - ACAT 1 inhibitor. Under Clinical trails

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